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Tocilizumab - Roche

Drug Profile

Tocilizumab - Roche

Alternative Names: Actemra; ACTPen; Anti-IL-6 receptor antibody - Chugai; Anti-interleukin-6 receptor antibody - Chugai; Atlizumab; HPM-1; MRA; MRA - Chugai; MRA-SC; R-1569; RG-1569; rhPM-1; RO4877533; RoActemra

Latest Information Update: 03 Jun 2020

At a glance

  • Originator Chugai Pharmaceutical; Osaka University
  • Developer Assistance Publique Hopitaux de Paris; Biomedical Advanced Research and Development Authority; Charite - Universitatsmedizin Berlin; Chugai Pharmaceutical; Hospital for Special Surgery; JW Pharmaceutical; Roche; University Hospital Inselspital; University Hospital Tubingen; University of Bern; University of Pittsburgh
  • Class Anti-inflammatories; Antineoplastics; Antirheumatics; Antivirals; Immunotherapies; Monoclonal antibodies; Skin disorder therapies
  • Mechanism of Action Immunosuppressants; Interleukin 6 receptor antagonists
  • Orphan Drug Status

    Orphan designation is assigned by a regulatory body to encourage companies to develop drugs for rare diseases.

    Yes - Drug hypersensitivity; Giant lymph node hyperplasia; Vasculitis; Systemic scleroderma
  • New Molecular Entity Yes

Highest Development Phases

  • Marketed Drug hypersensitivity; Giant cell arteritis; Giant lymph node hyperplasia; Juvenile rheumatoid arthritis; Rheumatoid arthritis
  • Registered Adult-onset Still's disease; Vasculitis
  • Phase III COVID 2019 infections; Osteoarthritis
  • Phase II Amyotrophic lateral sclerosis; Dermatomyositis; Familial Mediterranean fever; Polymyalgia rheumatica; Polymyositis; Pulmonary arterial hypertension; Schnitzler syndrome
  • Phase I/II Urogenital cancer
  • No development reported Chronic lymphocytic leukaemia
  • Discontinued Ankylosing spondylitis; Crohn's disease; Multiple myeloma; Pancreatic cancer; Systemic lupus erythematosus; Systemic scleroderma

Most Recent Events

  • 28 May 2020 Phase-III clinical trials in COVID-2019 infections (Combination therapy) in Europe, Canada, USA (IV)
  • 14 May 2020 Genentech initiates enrolment in the phase III EMPACTA trial for COVID-2019 infections (IV) in USA (NCT04372186)
  • 01 May 2020 Genentech plans a phase III trial for Pneumonia (in patients with COVID-19) in May 2020 (IV) (NCT04372186)

Development Overview

Introduction

Tocilizumab is a humanised anti-interleukin-6 (IL-6) receptor monoclonal antibody, being developed by Roche, for the treatment of rheumatoid arthritis, juvenile rheumatoid arthritis, giant lymph node hyperplasia, giant cell arteritis, Takayasu arteritis, cytokine release syndrome, adult onset Still's disease, amyotrophic lateral sclerosis, osteoarthritis, familial mediterranean fever, dermatomyositis, polymyalgia rheumatica, polymyositis, Schnitzler syndrome, pulmonary arterial hypertension and chronic lymphocytic leukaemia. The drug was originally developed by Chugai Pharmaceutical, in collaboration with Osaka University, and has been co-developed with Roche. Tocilizumab is directed against the interleukin-6 receptor (IL-6R), with immunosuppressant activity. The targets and binds to both the soluble form and the membrane-bound form of IL-6R, thereby blocks the binding of IL-6 to its receptor, and prevents IL-6-mediated signaling. Intravenous tocilizumab has been launched in the EU, the US, and 90 other countries including Switzerland, Japan, India, and Canada, for the treatment of patients with mid- to late-stage rheumatoid arthritis, juvenile rheumatoid arthritis and giant lymph node hyperplasia (Castleman's disease). Subcutaneous tocilizumab is available in the UK, for giant cell arteritis and in Ireland, Switzerland, the US, Japan and the UK for rheumatoid arthritis. The drug is also approved for giant cell arteritis in multiple countries including the US, New Zealand, Canada, Japan and EU. The drug has been approved for the treatment of CART cell-induced cytokine release syndrome in the US and for Vasculitis in Japan. It is also approved for the treatment of Takayasu arteritis in Japan. The drug is approved for the treatment of adult onset Still's disease in Japan and is under regulatory review for the treatment of cytokine release syndrome in European Union. Clinical development for amyotrophic lateral sclerosis, COVID 2019 infections, takayasu arteritis, osteoarthritis, familial mediterranean fever, dermatomyositis, polymyalgia rheumatica, polymyositis, Schnitzler syndrome, pulmonary arterial hypertension, urogenital cancer and chronic lymphocytic leukaemia is ongoing worldwide.

Genentech also plans to develop tocilizumab for the treatment of COVID-19 Pneumonia (COVID-19 Infections) [1] .

A single-dose prefilled autoinjector of tocilizumab 162 mg/0.9 ml (ACTPen™) is approved in the US as an additional formulation for the treatment of adult patients with moderate to severe active rheumatoid arthritis, adult patients with giant cell arteritis. ACTPen is approved in the US for the treatment of active polyarticular or active systemic juvenile idiopathic arthritis in patients, aged two years and older. ACTPen is approved in the EU for the treatment of rheumatoid arthritis and giant cell arteritis.

Clinical development was discontinued for the treatment of ankylosing spondylitis, Crohn's disease, multiple myeloma, pancreatic cancer, systemic scleroderma and systemic lupus erythematosus in several countries. Phase III development for rheumatoid arthritis was being conducted in Egypt, Morocco and Saudi Arabia, however, no recent development has been reported. Phase I development of subcutaneous formulation was underway for juvenile rheumatoid arthritis in Europe and the US, however, no recent development has been reported. Phase I development as a combination therapy was ongoing for rheumatoid arthritis in New Zealand and the US, however, no recent development has been reported. Phase I development in chronic lymphocytic leukaemia was being conducted in Italy, Spain, Israel, Latvia, and the UK. However, no recent reports of development had been identified.

IL-6, produced by synovial tissue macrophages, fibroblasts and lipopolysaccharide-stimulated synovial fluid monocytes, induces an acute-phase inflammatory response. In chronic inflammation, it has both inflammatory and anti-inflammatory effects. Synovial fluid levels of IL-6 are elevated in patients with rheumatoid arthritis, and correlate with clinical and laboratory markers of disease activity [2] .

As at December 2018, no recent reports of development had been identified for phase-I development in Juvenile-rheumatoid-arthritis in Russia (SC, Injection), Mexico (SC, Injection), Canada (SC, Injection), Brazil (SC, Injection), Australia (SC, Injection), Argentina (SC, Injection).

As at June 2019, no recent reports of development had been identified for phase-I development in Polymyalgia-rheumatica (First-line therapy, In the elderly, In adults) in France (IV, Infusion).

Company Agreements

In the first half of 2009, Chugai Pharmaceutical entered into a licensing agreement with ChoongWae Corporation (later JW Pharmaceutical) to grant rights to develop and market tocilizumab in South Korea for the RA indication.

In the first quarter of 2003, Chugai Pharmaceutical and Roche formed an agreement to co-develop and co-promote tocilizumab. In May 2007, Chugai decided not to exercise its optional right to co-promote tocilizumab in the US, Italy and Spain. However, the company retained marketing rights in Japan, South Korea and Taiwan, and will co-promote the product in France, Germany, and the UK with Roche. Profits will be shared by the two companies in proportion to their co-promotion effort. Roche will co-develop and promote tocilizumab worldwide, except in Japan, South Korea and Taiwan. This agreement includes the rights to patents and trademarks for tocilizumab; in return, Roche will make milestone and royalty payments [3] [4] .

Roche previously acquired a majority share in Chugai Pharmaceutical in October 2002. Nippon Roche was merged into Chugai, which is Roche's exclusive pharmaceutical representative in Japan. The relationship between Chugai and Roche has been defined through a jointly agreed governance agreement, by which Chugai will be an autonomously managed company. Chugai is now Roche's exclusive pharma representative in Japan and will have rights to develop and market Roche products in Japan. As part of the transaction, Roche gained rights of first refusal for licensing, marketing or co-developing any Chugai products which are available for partnering.

Chugai entered into a toll manufacturing and supply agreement with Genentech (Roche) in July 2008. According to the agreement, Genentech will manufacture tocilizumab bulk drug substance at its cell culture facilities in Vacaville, California. Chugai Pharma Manufacturing Co., a wholly-owned subsidiary of Chugai, will also continue to produce tocilizumab bulk drug substance at its Utsunomiya plant in Japan. The agreement was executed after a detailed analysis revealed a location risk with all manufacturing processes being performed at a single plant [5] .

In May 2000, Chugai and the US company Protein Design Labs reached an agreement whereby Chugai will receive non-exclusive, worldwide licences for an undisclosed number of its antibody targets under Protein Design Labs' antibody humanisation patents. One of the targets included is the human interleukin-6 receptor. Chugai will pay Protein Design Labs $US6.04 million in signing and licensing fees. Chugai will also pay annual maintenance fees and royalties on any future product sales.

Protein Design Labs has since changed its name to PDL BioPharma [6] .

Key Development Milestones

Intravenous formulation

COVID-2019 Infections

In May 2020, Genentech initiated the phase III EMPACTA trial to evaluate the safety and efficacy of tocilizumab compared with a placebo in combination with standard of care in hospitalised patients with COVID-19 pneumonia (ML42528; NCT04372186). The randomised, double-blind, placebo-controlled, multicenter study will enrol approximately 375 patients in the US [7] [8] .

In May 2020, Roche in collaboration with Gilead Sciences initiated the phase III REMDACTA trial to evaluate the safety and efficacy of Actemra/RoActemra plus remdesivir, versus placebo plus remdesivir in hospitalised patients with severe COVID-19 pneumonia. The randomised, double-blind trial intends to enroll approximately 450 patients in the US, Canada and Europe [9] .

In April 2020, Chugai Pharmaceutical filed a clinical trial notification with the Pharmaceuticals and Medical Devices Agency today to conduct a phase III clinical trial of intravenous tocilizumab (Actemra, 80 mg, 200 mg, and 400 mg) for the treatment of hospitalized patients with severe COVID-19 pneumonia in Japan [10] [11] .

In March 2020, Roche in collaboration with the Biomedical Advanced Research and Development (BARDA) initiated the phase III COVACTA trial to evaluate the safety and efficacy of intravenous tocilizumab with standard of care in hospitalised adult patients with severe COVID-19 pneumonia (NCT04320615; EudraCT2020-001154-22; WA42380). The double-blind, randomised trial intends to recruit approximately 450 patients in the US, France, Italy, Netherland, Spain, Denmark, Germany, UK [7] [10] [12] [13] . First patient in the trial was enrolled in April 2020. Earlier, in the same month, the US FDA approved to conduct the phase III COVACTA trial for the treatment of hospitalised patients with severe COVID-19 pneumonia. The planned phase III COVACTA clinical trial in collaboration with the Biomedical Advanced Research and Development (BARDA) intends to evaluate the safety and efficacy of intravenous tocilizumab with standard of care in hospitalised adult patients with severe COVID-19 pneumonia [14] .

In April 2020, Roche and University Hospital Inselspita initiated the phase II CORON-ACT trial to assess the safety and efficacy of tocilizumab for the treatment of patients with COVID-2019 infections (NCT04335071; 2020-00691; 2020DR2044). The primary endpoint of trial is to determine the number of patient with ICU admission after seven days, number of patients with iintubation and number of deaths. The randomised, double-blind, controlled trial intends to enrol approximately 100 patients in Switzerland [15] .

Rheumatoid arthritis

IV tocilizumab has been approved in the US for the treatment of moderate-to-severe rheumatoid arthritis (RA) in patients who have not adequately responded to TNF inhibitors. The candidate is also approved in this indication, in combination with methotrexate, in the EU. Tocilizumab has been launched in Japan, Australia, Brazil and India for the treatment of RA and has been approved in Canada and South Korea. The antibody has also been approved in Switzerland for the treatment of moderately severe-to-severe active RA in adults who have not responded adequately to disease-modifying antirheumatic drugs (DMARDs) or tumour necrosis factor (TNF) inhibitors. The drug is marketed as RoActemra® in Switzerland and in the EU [16] [17] [18] [19] .

Genentech submitted a supplemental BLA (sBLA) for tocilizumab to the US FDA in December 2011, seeking to remove the condition that the agent can only be used in patients "who have had an inadequate response to one or more tumour necrosis factor antagonist therapies" from the current indication (patients with moderately to severely active RA) [20] . The amendment would see tocilizumab approved for the treatment of adults with RA who have not responded to DMARDs, or were intolerant of the agents. The sBLA was accepted for review by the FDA in February 2012, and was approved in October of the same year. The product's approved indication was expanded to include treatment of patients with moderate to severe RA who have had an inadequate response to one or more DMARDs [21] [22] .

Japan was the first market worldwide to gain access to tocilizumab in April 2008, when it was approved by the Japanese Ministry of Health, Labour and Welfare (MHLW) for the treatment of RA. Approval in Japan was initially conditional, requiring that all patients were monitored for efficacy and tolerability. Interim post-marketing data from patients with juvenile RA were submitted to the Japanese MHLW in August 2010. These data were sufficient to lift the Japanese MHLW's condition of continued monitoring of tocilizumab. Additional post-marketing data from the FIRST BIO study in biologics-naive patients with RA were presented at the 16th Annual Congress of the European League Against Rheumatism (EULAR - 2015) in June 2015 [23] [24] [25] .

Approval in the US and the EU was based on five multinational, phase III trials of tocilizumab, either alone or in combination with methotrexate and/or other DMARDs; the largest clinical programme of a biologic in RA. These trials are the RADIATE, OPTION, TOWARD, AMBITION and LITHE trials [17] [18] . Tocilizumab was approved in January 2010 by the US FDA, for the treatment of adults with moderate-to-severe RA who had not responded adequately to TNF inhibitors. Tocilizumab is approved for use as a monotherapy, or in combination with a disease-modifying agent such as methotrexate. Launch occurred later in January 2010 [17] [16] . In January 2009, the European Commission approved tocilizumab in combination with methotrexate, for the treatment of adults with moderate-to-severe RA who were unresponsive or intolerant to previous DMARD or anti-TNF therapies. The approval included a clause for use of tocilizumab as monotherapy in cases where methotrexate treatment is intolerable or inappropriate [18] [26] . In mid-2012, Roche filed an application in the EU for a line extension for tocilizumab as monotherapy for RA in patients unresponsive to or intolerant of methotrexate, based on the outcomes of the ADACTA trial. Approval was obtained in the fourth quarter of 2012. Treatment with tocilizumab, either alone or in combination with methotrexate, is reimbursed by the Scottish Medicines Consortium [27] .

Roche has reported that tocilizumab is approved in China for the treatment of rheumatoid arthritis [28] .

In September 2015, the UK National Institute for Health and Clinical Excellence (NICE) issued a Final Appraisal Determination, recommending use of tocilizumab monotherapy on the National Health Services (NHS), for the treatment of patients with severe rheumatoid arthritis who are intolerable to or do not wish to take methotrexate or DMARDs. NICE, in February 2012, recommended use of tocilizumab in patients who have failed DMARDs, but have not received anti-TNF therapies. The guidance included specific circumstances for use, and is only applicable if tocilizumab is provided with the agreed discount under the patient access scheme. Recommendations by NICE are based on data from the phase IV ADACTA study [27] [29] .

In January 2016, the UK's NICE issued a final draft guidance recommending the use of tocilizumab in combination with methotrexate and also as monotherapy in patients with severe rheumatoid arthritis [30] [31] .

In June 2010, the European Commission extended tocilizumab's indications to include prevention of structural joint damage progression and improvement in physical function in patients with RA, when administered in combination with methotrexate. This followed on from the EMA's CHMP recommendation in April 2010, and the decision was supported by positive 2-year data from the phase III LITHE trial [32] [33] [34] . US FDA approval for this label extension was granted in January 2011 [35] . The supplemental BLA was submitted to the US FDA in March 2010 [36] .

In July 2012, Roche completed a phase IIIb trial that evaluated the safety and efficacy of tocilizumab in combination with methotrexate in patients with active rheumatoid arthritis who have an inadequate response to non-biologic disease-modifying antirheumatic drugs (ML25536; NCT01353859). The open-label, non-randomised, single-group trial was initiated in March 2011, and recruited 39 patients in Indonesia [37] .

In July 2015, Roche completed a phase III study that evaluated efficacy and safety of tocilizumab in patients with severe rheumatoid arthritis being treated with a TNF inhibitor and experiencing a Disease activity score28 ESR > 3.2 (133239; UKCRN14117; 2017). The trial was initiated in August 2013 and enrolled 160 patients in the United Kingdom [38] .

In February 2014, Roche completed a phase III study which assessed the efficacy and safety of tocilizumab, with or without rituximab, in patients with rheumatoid arthritis (NCT01332994). Rituximab was administered if patients proved unresponsive to tocilizumab therapy. A total of 519 patients were recruited in Germany [39] .

Roche initiated a registrational phase III trial in October 2011 to investigate tocilizumab alone or in combination with methotrexate in patients with RA who have an inadequate response to methotrexate (NCT01399697). The double-blind, randomised study is being conducted in Spain and aims to enrol 258 patients [40] . A similar trial was completed in 77 patients in Austria (ML27837; NCT01587989; 2011-001863-39) [41] .

Roche completed an open-label phase III trial that investigated the efficacy and tolerability of tocilizumab, with and without methotrexate, in patients with moderate-to-severe RA who had an inadequate response to a DMARD (NCT01254331). The trial enrolled 51 patients in Tunisia [42] .

The phase III REMISSION study included 120 patients with active RA that responded inadequately to disease-modifying anti-rheumatic drugs (NCT01610791). The single-arm, open-label study was conducted in Morocco; all patients received tocilizumab 8 mg/kg/week for 24 weeks. The primary outcome was tolerability [43] .

In September 2011, Roche completed the ROSE (Rapid Onset and Systemic Efficacy) phase III trial of tocilizumab versus placebo in combination with DMARDs in patients with moderate-to-severe active RA (NCT00531817). The trial was conducted in the US and Puerto Rico and enrolled 619 patients; its initiation date was in September 2007 [44] .

ChoongWae Pharma completed a phase III trial of tocilizumab in patients with moderate-to-severe RA in November 2010 (NCT01211834). The randomised, double-blind, placebo-controlled trial involved 90 patients in South Korea. Endpoints included measures of efficacy and safety [45] .

Roche completed a phase III trial of tocilizumab in patients with moderate or severe RA unresponsive to DMARDs or anti-TNF therapy, in April 2012 (NCT00977106; TORPEDO). The trial enrolled 103 patients in France [46] .

Roche has completed a Philippines-based phase III trial in patients with moderate-to-severe RA (NCT00848120) [47] .

Genentech (a member of the Roche group) conducted a head-to-head trial that compared tocilizumab monotherapy with adalimumab monotherapy in patients with RA who had an inadequate response to DMARDs. The multinational trial (ADACTA; NCT01119859) enrolled 326 patients from centres in Australia, Belgium, Brazil, Czech Republic, England, Finland, Germany, Greece, Mexico, Norway, Portugal, Spain, Sweden, Switzerland, Turkey, and the USA. Results have been reported. Patients who received tocilizumab as a single agent (without other DMARDs) had a significantly greater improvement in disease activity (assessed as DAS28 score reduction) after 24 weeks, compared with adalimumab [48] [49] [50] [51] .

Roche completed a phase III trial in May 2010 of tocilizumab in patients with RA who have had an inadequate response to non-biologic DMARDs (NCT00810277; ML22012; 2008-004126-16 ). The open- label, single-arm study assessed the safety and efficacy of tocilizumab in patients with moderate-to-severe active RA. Patients received IV infusion of tocilizumab 8 mg/kg every 4 weeks for a total of 6 infusions, either as monotherapy or in combination with their current non-biologic DMARDs. The study enrolled 14 patients in Finland and was initiated in November 2008 [52] .

Roche completed a phase III trial in Saudi Arabia in March 2013 in 28 patients with RA who had had an inadequate response to DMARDs or anti-TNF (NCT01326962). Patients received tocilizumab at a dose of 8 mg/kg (to a maximum of 800mg) intravenously every four weeks for a total of six infusions. The primary endpoints were change in disease activity score, the proportion of patients achieving remission and time to remission, assessed at 24 weeks [53] .

The single-arm, phase III PICTURE trial was initiated in February 2010 to assess tocilizumab alone or in combination with methotrexate in patients with moderate-to-severe RA (ML22725; NCT01063062). The open-label, 24-week trial enrolled 56 patients in Egypt and was completed in April 2011 [54] .

The phase III ALABASTER trial was initiated in February 2011 to investigate the tolerability and efficacy of tocilizumab + methotrexate in patients with moderate-to-severe RA with an inadequate response to DMARDs. The primary outcome is the incidence of adverse events, which will be assessed at 24 weeks. The trial is being conducted in Bosnia-Herzegovina has completed enrolment of 71 patients (NCT01235507) [55] .

Roche completed a phase III trial in August 2010 comparing the safety and efficacy, in terms of reduction of signs and symptoms, of tocilizumab versus placebo, both in combination with DMARDs, in patients with RA who have an inadequate response to DMARDs (NCT00773461). The randomised, double-blind trial, initiated in October 2008, enrolled 260 patients in China. Patient enrolment was completed in February 2010 [56] .

The completed ACT-SURE phase III trial assessed the safety, tolerability and efficacy of tocilizumab (administered by IV infusion) monotherapy, or combination therapy with non-biologic DMARDs, in patients with severe active RA who had an inadequate response to prior non-biologic DMARD or anti-TNF therapy (NCT00750880; MA21573). The trial enrolled 1697 patients in the EU, Turkey, Switzerland, the US, Canada and Australia, and preliminary results have been presented [57] [58] [59] . In April 2012, Roche completed a phase III extension trial to the MA21573 study, that evaluated the safety, tolerability and efficacy of tocilizumab monotherapy, or combination therapy with non-biological disease-modifying antirheumatic drugs (DMARDS), in patients with moderate to severe active rheumatoid arthritis (NCT00883753; EudraCT2008-006924-68; ACTRN12609000747224; 083928; MA22460). Patients who completed the 24-week MA21573 study and had at least a moderate response, were eligible to enter the extension trial. A total of 934 patients received tocilizumab 8 mg/kg IV every four weeks for an anticipated 1-2 year duration in Austria, Australia, Canada, Czech Republic, France, Greece, Hungary, Italy, the Netherlands, Poland, Portugal, Romania, Saudi Arabia, Spain and the UK [60] .

An additional phase III trial assessing the safety, tolerability and efficacy of tocilizumab in patients with active RA that has not responded adequately to background non-biologic DMARDs, was completed in August 2014 (ML25095; NCT01245439). The trial was initiated in September 2011 and enrolled 69 patients in Turkey [61] .

Roche has completed in a phase III study investigating the effects of tocilizumab for 1-2 years on lipids, arterial stiffness and markers of atherogenic risk in patients with moderate-to-severe RA (NCT00535782). In Part 1, patients were randomised to receive tocilizumab or placebo every 4 weeks in combination with methotrexate. In an open-label Part 2, patients received tocilizumab plus methotrexate. The study enrolled 132 patients in the US, Canada, Puerto Rico and the UK [62] . A phase III trial investigated the effect of tocilizumab and DMARDs on improving fatigue and anaemia in patients with moderate-to-severe RA (NCT00951275). The trial enrolled 105 patients in Italy and was completed in January 2012 [63] .

Two long-term extension trials are underway in 2500 patients who participated in the phase III OPTION, TOWARD, RADIATE and AMBITION trials. Patients in the extension trials received tocilizumab 8mg/kg every 4 weeks for up to 2.5 years (GROWTH95 and GROWTH96). An interim analysis showed that in all 3 patient populations (DMARD-IR [inadequate response], anti-TNF-IR and DMARD-naive) treated with tocilizumab, long-term efficacy was maintained, as measured by ACR response rates and DAS28 scores [64] [19] . Data from the long-term extension follow-up of the AMBITION trial were presented [65] .

The phase III LITHE study (tociLIzumab safety and THE prevention of structural joint damage; NCT00106535) indicated that patients treated with tocilizumab in combination with methotrexate had significantly less damage to their joints at three years, compared with control patients who received methotrexate alone [66] [67] [32] [33] [34] [68] [69] .

In September 2014, Roche completed an extension study (EudraCT2005-002909-23; NCT00720798) to evaluate the long-term efficacy and safety of tocilizumab in patients who have completed treatment in core studies (NCT00106522, NCT00106574 and NCT00109408) in adults with rheumatoid arthritis. The randomised, open-label trial was initiated in September 2005 and enrolled 2067 patients who received tocilizumab monotherapy or combination therapy with standard anti-rheumatic drugs [70] .

A phase III study in South Africa, completed by Roche in the second half of 2011, assessed the long-term efficacy of tocilizumab in combination with DMARDs in patients with RA (NCT01214733). Patients who had completed two phase III studies in South Africa (NCT00106535 and NCT00720798) were eligible to participate; the trial enrolled 31 participants [71] .

The phase III AMBITION (Actemra versus Methotrexate double-Blind Investigative Trial In mONotherapy, NCT00109408) trial, met its primary endpoint of non-inferiority of tocilizumab 8mg/kg compared with methotrexate. The AMBITION trial enrolled 673 patients with moderate-to-severe RA in 18 countries. Efficacy was evaluated using the American College of Rheumatology score, the Disease Activity Score, and EULAR response criteria [72] [73] [74] [75] .

The phase III TOWARD trial (Tocilizumab in cOmbination With traditional DMARD therapy, NCT00106574) was conducted in 1216 patients with active, moderate-to-severe RA who had an inadequate response to previous DMARD therapy. It met its primary endpoint of significant improvement in disease signs and symptoms [76] [77] .

Roche conducted the RADIATE (RheumAtoiD ArthritIs Study in Anti-TNF FailurEs, NCT00106522) trial in 498 patients with moderate-to-severe RA who failed to respond to previous anti-TNF therapy. Efficacy was measured using the American College of Rheumatology (ACR) score, the Disease Activity Score (DAS28), and EULAR response criteria. The trial was conducted in 13 countries, including the US. Positive results have been reported [78] .

In January 2007, positive results were reported from OPTION (TOcilizumab Pivotal Trial in Methotrexate Inadequate respONders, NCT00106548), a multinational phase III trial in 623 patients, where treatment with tocilizumab resulted in a significant improvement in the signs and symptoms of RA at week 24 compared with standard treatment with methotrexate. The trial met its primary endpoint [79] [80] [81] .

Results from the phase III ACT-RAY and ACT-STAR trials evaluating tocilizumab monotherapy in patients with moderate-to-severe RA were presented in November 2011 [82] . The ACT-RAY trial was completed in January 2013 and evaluated the efficacy and tolerability of tocilizumab with or without methotrexate in patients with moderate-to-severe active rheumatoid arthritis who were previously treated with methotrexate (MA21488; NCT00810199). The trial enrolled 556 patients in the US, Brazil, Croatia, Israel, Norway, Russia, Serbia, Thailand and in countries in the EU. The trial began in March 2009 [83] . The ACT-STAR trial evaluated the safety, tolerability and efficacy of tocilizumab in patients with moderate-to-severe RA, who were unable to tolerate or had inadequate response to DMARD therapy (NCT00891020). The trial enrolled 889 patients in the US [84] .

In April 2006, Chugai Pharmaceutical completed a phase III trial that evaluated the clinical efficacy and safety of tocilizumab in a double-blind, parallel-group, controlled study using tocilizumab or methotrexate (MTX) in rheumatoid arthritis (RA) patients with MTX administered (MRA213JP; NCT00144521). The randomised, double-blind, parallel, prospective trial was initiated in February 2004 and enrolled 125 patients in Japan [85] .

In February 2006, Chugai Pharmaceutical completed the phase III SAMURAI trial that evaluated the clinical efficacy and tolerability of tocilizumab, patients with RA are randomized to receive either tocilizumab or conventional DMARDs. This trial will compare the effects of tocilizumab and standard disease-modifying antirheumatic drugs (DMARDs) on disease progression (MRA012JP; NCT00144508; JapicCTI050016). The open, parallel, prospective, randomised trial was initiated in March 2003 and enrolled 306 patients in Japan [86] .

Roche is conducting a prospective observational study to evaluate the safety and efficacy of tocilizumab on the use of glucocorticoids in patients with moderate-to-severe RA treated with standard of care (NCT01564901). The study is taking place in Spain and will aim to recruit 120 patients [87] . Roche is also conducting another observational study in patients with RA who are receiving tocilizumab (NCT01565122). Approximately 70 patients will be recruited in Finland [88] .

Before August 2018, University of Nebraska in collaboration with Genentech, withdrew a phase II trial prior to enrolment due to lost of funding (READ-4; 594-15; NCT02511067). The single blind trial was designed to evaluate the safety, tolerability and efficacy of ranibizumab and tocilizumab in eyes with diabetic macular oedema, in the US [89] .

In September 2019, Chugai Pharmaceutical completed the phase II T-ReX trial, that evaluated whether low disease activity would be sustained with reducing and stopping methotrexate in patients with rheumatoid arthritis treated with tocilizumab (R000024483; UMIN000021247). The open-label trial was initiated in July 2016 and enrolled 53 patients in Japan [90] .

In September 2013, Roche completed a phase II trial that investigated the incidence of infusion-related reactions of tocilizumab when given over 31 min compared with 60 min in patients with moderate to severe active rheumatoid arthritis (ACT-FAST; ML27901; EudraCT2011-002363-15; NCT01468077). The open-label, randomised trial, which began in August 2011, enrolled 43 patients in Denmark and Iceland [91] .

In April 2008, Roche completed a two-arm drug interaction study that assessed the pharmacokinetics of tocilizumab in combination with simvastatin and methotrexate in patients with rheumatoid arthritis (NCT00365001; PDO-WP18663; WP18663). The open, parallel, prospective, randomised trial was initiated in November 2005 and enrolled 23 patients in the US and New Zealand [92] .

Early rheumatoid arthritis

In September 2014, the European Commission approved tocilizumab for use in treatment of patients with early stage rheumatoid arthritis not previously treated with methotrexate. The EMA's Committee for Medicinal Products for Human Use issued a positive opinion for use of tocilizumab in this patient population, in July 2014. The approval was based on results from the phase III FUNCTION study [93] [94] . Tocilizumab was filed for approval in the EU for the treatment of early-stage rheumatoid arthritis, according to the Roche pipeline as of October 2013.

In January 2015, Health Canada approved the use of intravenous and subcutaneous formulations of tocilizumab in adult patients with early moderate to severe RA. The approval was based on results from the phase III FUNCTION study [95] .

In January 2014, Roche completed a randomised, double-blind, placebo-controlled phase III trial that assessed the safety and efficacy of tocilizumab and methotrexate (monotherapy and combination therapy) in patients with early moderate-to-severe RA (WA19926; FUNCTION; NCT01007435). Tocilizumab was dosed every 4 weeks. The primary outcome measure was DAS28 remission (<2.6) at week 24. Secondary outcome measures were measured up to week 52. This trial enrolled 1128 patients from Europe, the US, China, South America, Canada, Australia, Singapore, Hong Kong, South Africa, Thailand, Israel, New Zealand and the Philippines [96] . Initial results have been presented [65] . An extension of the NCT01007435 was completed in May 2016, in Brazil (NCT01668966) [97] . Another open-label extension trial was completed in December 2014 in Hungary and enrolled 12 patients (ML28146; EudraCT2011-006125-14; FUNCTION LTE; NCT01649804) [98] . An extension trial was completed in Russia in June 2015 and enrolled 49 patients (NCT01664598) [99] . The trial was completed in Macedonia in April 2015 and enrolled 13 patients (NCT01730456) [100] . The extension to NCT01007435 trial was also completed in France, in June 2015 (NCT01655381) [101] and Poland (NCT01665430) [102] and enrolled 15 and 38 patients, respectively. In February 2018, the company terminated the phase III extension trial in Poland (NCT01665430), due to market authorization of tocilizumab for the study population. Roche also completed a phase III trial, in September 2014, that compared the efficacy with regard to sustained remission and safety of tocilizumab and methotrexate, in combination or as monotherapy, in treatment-naïve patients with early rheumatoid arthritis (U-ACT-EARLY; ML22497; EudraCT2009-013316-12; NCT01034137). The randomised, double-blind, placebo-controlled trial enrolled 317 patients in the Netherlands [103] . In November 2017, data from the trial was presented at the 81st American College of Rheumatology and the 52nd Association of Rheumatology Health Professionals Annual Scientific Meeting (ACR/ARHP-2017) [104] [105] . An extension of this trial (U-Act-After; NCT01918267) was initiated in early rheumatoid arthritis in the Netherlands [106] .

In June 2019, Roche presented data from a clinical study at the 20th Annual Congress of the European League Against Rheumatism (EULAR-2019), which analysed the changes in adipokines and body composition during tocilizumab treatment in patients with rheumatoid arthritis. The 12 month multi-center, open-label study enrolled 107 patients [107] [108] .

Juvenile rheumatoid arthritis (also known as juvenile idiopathic arthritis)

The US FDA approved tocilizumab in April 2013 for the treatment of polyarticular juvenile idiopathic arthritis in children from the age of two years with active disease, given alone or in combination with methotrexate [109] . Tocilizumab was previously approved by the US FDA, in April 2011, for the treatment of active systemic juvenile idiopathic arthritis (sJIA) in patients two years of age and older administered alone or in combination with methotrexate [110] [111] . It has also been approved in Mexico for the same indication [112] .

In October 2013, Health Canada approved tocilizumab for the treatment of polyarticular juvenile idiopathic arthritis in children from the age of two years with active disease, given alone or in combination with methotrexate. Tocilizumab was previously approved by Health Canada, in January 2012, for the treatment of active systemic juvenile idiopathic arthritis (sJIA) in patients two years of age and older administered alone or in combination with methotrexate. The expanded approval was based on data from the phase III CHERISH trial [113] .

The EMA approved tocilizumab in June 2013 for the treatment of polyarticular juvenile idiopathic arthritis in patients aged 2 years or older who had not responded adequately to methotrexate therapy. The approval was based on data from the phase III CHERISH trial [28] . This followed a positive opinion from the CHMP for this indication in April 2013 [114] . Previously, the European Commission granted marketing authorisation for tocilizumab, alone or in combination with methotrexate, for the treatment of active sJIA in August 2011 in patients aged 2 years and above who had responded inadequately to previous therapy with NSAIDs and systemic corticosteroids [115] . Earlier, in October 2010, Roche had filed regulatory applications for tocilizumab in sJIA in the EU and US; subsequently the CHMP adopted a positive opinion in May 2011 [116] .

In October 2015, the UK's National Institute for Health and Clinical Excellence (NICE) issued the final draft guidance provisionally recommending tocilizumab as one of the treatment options for juvenile idiopathic arthritis [117] . Earlier, in December 2011, the UK's National Institute for Health and Clinical Excellence (NICE) had published final guidance recommending tocilizumab for the treatment of sJIA in patients aged 2 years and older, where specific previous treatments were not satisfactory, if the manufacturer makes tocilizumab available with the discount agreed as part of a patient access scheme [118] [119] .

Tocilizumab received conditional approval from the Japanese Ministry of Health, Labour and Welfare (MHLW) for the treatment of systemic-onset and polyarticular-course juvenile idiopathic arthritis in April 2008; approval was contingent on continued monitoring of patients for efficacy and tolerability. The MHLW subsequently removed the condition for continued monitoring of patients with polyarticular-course juvenile idiopathic arthritis based on favourable interim post-marketing surveillance data. As of August 2010, the surveillance and enrolment of systemic-onset juvenile idiopathic arthritis (sJIA) patients was still ongoing [24] [25] .

On 31 July 2012, the US FDA granted orphan designation for tocilizumab in the treatment of patients aged 16 years and below with polyarticular-course juvenile idiopathic arthritis [120] .

In June 2019, updated results from long-term extension study in Juvenile rheumatoid arthritis were presented at 20th Annual Congress of the European League Against Rheumatism (EULAR-2019) [121] . In October 2018, interim adverse events data from a long-term extension study in Juvenile rheumatoid arthritis were presented at the 82nd American College of Rheumatology and the 52nd Association of Rheumatology Health Professionals Annual Scientific Meeting (ACR/ARHP - 2018). The data suggested that tocilizumab continued to have an acceptable tolerability profile with no new safety concerns [122] .

Roche has completed the phase III CHERISH trial, which investigated the efficacy and tolerability of tocilizumab in combination with concomitant NSAIDs, corticosteroids and methotrexate for the treatment of juvenile rheumatoid arthritis (WA19977; NCT00988221; EudraCT2009-011593-15). The trial design included a 24-week randomised, placebo-controlled withdrawal part with a 16-week open-label lead-in phase, and a 64-week open-label follow-up part. The trial enrolled 188 patients in the US, the EU, Argentina, Australia, Brazil, Canada, Mexico, Peru and Russia [123] . In addition, enrolment has been completed in the following extension trials of CHERISH in patients with polyarticular juvenile RA. The long-term tolerability of tocilizumab was investigated over 3 years in 11 patients in Brazil (NCT01727986) [124] . A study in Poland and Russia that enrolled 41 participants, aged 2 years and older, has been terminated (NCT01575769) [125] . Six patients have been enrolled in a trial in Germany (NCT01667471) [126] . In January 2014, the company completed a trial in France which enrolled seven patients with juvenile idiopathic arthritis (NCT01673919) [127] .

In August 2014, Roche completed the randomised, two-part phase III TENDER trial evaluating the efficacy and safety of tocilizumab in patients less than 2 years old with systemic juvenile RA (sJIA) who have an inadequate clinical response to NSAIDs and corticosteroids (WA18221, EudraCT2007-000872-18; NCT00642460). In part 1 of the trial, patients were randomised 2:1 to receive tocilizumab 8 or 12 mg/kg, or placebo, every 2 weeks for 12 weeks. Stable NSAIDs and methotrexate were continued throughout the study. After 12 weeks of double-blind treatment, all patients will have the option to enter part 2 of the study, and receive open-label treatment with tocilizumab for a further 92 weeks. The trial was initiated in May 2008 and enrolled 112 patients in the US, Canada, Mexico, Argentina, Brazil, Australia, Czech Republic, Denmark, Germany, Greece, Belgium, Italy, the Netherlands, Poland, Slovakia, Spain, Sweden, the UK and Norway [128] . In November 2009, Roche reported that the trial had met its primary endpoint [129] [130] . Interim results showed that tocilizumab gave high efficacy in improving the signs and symptoms of sJIA, and was been well-tolerated in children [131] [132] [129] . The company reported two-year efficacy and tolerability data [133] . The trial data supported the regulatory approval of tocilizumab for the treatment of systemic juvenile idiopathic arthritis [134] .

In July 2017, Roche completed a phase I trial that evaluated the pharmacokinetics, pharmacodynamics, efficacy, and safety of tocilizumab, in patients with active systemic juvenile idiopathic arthritis (sJIA) (less than 2 years old) (NP25737; NCT01455701; EudraCT2015-000435-33). The open-label trial was initiated in October 2012 and enrolled 11 patients in the US, Argentina, Belgium, Canada, Germany, Hungary, Poland, France, the UK, and Spain [135] . In June 2017, the company reported the pharmacokinetics, pharmacodynamics , efficacy, and safety data of the trial at the 18th Annual Congress of the European League Against Rheumatism (EULAR-2017) [134] . In October 2018, Roche presented updated adverse events data following completion of the optional extension period (OEP) from the trial at the 82nd American College of Rheumatology and the 52nd Association of Rheumatology Health Professionals Annual Scientific Meeting (ACR/ARHP-2018) [136] .

Chronic lymphocytic leukaemia

In September 2018, Roche discontinued the phase I study designed to evaluate the safety of intravenous tocilizumab plus standard of care premedication, administered prior to obinutuzumab plus chlorambucil regimen, in patients with untreated B-cell chronic lymphocytic leukaemia as the premedication with toilizumab was unlikely to reduce the risk of IRR (BO29448; EudraCT2014-002815-40; NCT02336048). The randomised,double-blind trial was initiated in June 2015 and enrolled 38 patients in the UK, Spain, Italy, Latvia and Israel. In December 2018, safety and pharmacokinetic data from the trial were presented at the 60th Annual Meeting and Exposition of the American Society of Hematology (ASH-Hem-2018) [137] [138] .

Cytokine release syndrome (drug hypersensitivity in development table)

Chugai Pharmaceutical, in March 2019, received a regulatory approval from the Ministry of Health, Labour and Welfare (MHLW) for Actemra® (tocilizumab) intravenous infusion (80, 200, and 400mg) for an additional indication of cytokine release syndrome (CRS) induced by tumor-specific T cell infusion therapy and an additional dosing regimen for cytokine release syndrome (CRS). The approval was based on the results of two global phase II studies conducted by Novartis that evaluated efficacy and safety of CAR-T cell therapy in patients with blood cancers by administering tocilizumab as monotherapy or combination therapy with corticosteroids or other treatments to patients with severe CRS [139] . Earlier, in May 2018, Chugai Pharmaceuticals submitted a regulatory application to the Japanese Ministry of Health, Labour and Welfare (MHLW) for the approval of an additional indication of cytokine release syndrome (CRS) induced by treatment with CAR-T cell therapy for tocilizumab intravenous infusion (80, 200, and 400mg). The application was supported by the results of phase II global studies conducted by Novartis to evaluate the efficacy and safety of CAR-T cell therapy [140] .

In August 2017, the US FDA approved intravenous tocilizumab for the treatment of CAR T cell-induced cytokine release syndrome (CRS) in ≥ 2 year old patients. The regulatory application was granted priority review status. The approval was based on retrospective analysis of pooled data from clinical trials of CAR T cell therapies for blood cancers. In a study, resolution of CRS occurred within 14 days in an independent cohort of 15 patients with CART T cell-induced CRS [141] .
Tocilizumab was granted orphan drug designation by the US FDA for the treatment of CAR T cell-induced CRS [141] .

In June 2018, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended an extension to the therapeutic indication for tocilizumab to include the treatment of CAR-T cell induced cytokine release syndrome in adults and paediatric patients 2 years of age and older [142] .

Familial mediterranean fever

In April 2018, Roche in collaboration with University Hospital Tuebingen initiated a phase II trial to evaluate the efficacy of tocilizumab in patients with active familial mediterranean fever (EudraCT2016-004505-13; NCT03446209; TOFFIFE; TOFFIFE1-1). The double-blind, parallel, prospective, randomised trial is enrolling approximately 30 patients in Germany [143] .

Giant lymph node hyperplasia (Castleman's disease)

Tocilizumab injection was launched as Actemra® 200 for intravenous infusion in the treatment of giant lymph node hyperplasia in June 2005; this followed approval by the Japanese Ministry of Health, Labour and Welfare in April 2005 and regulatory filing in April 2003. A condition of approval required the continued monitoring of efficacy and safety of tocilizumab in patients with giant lymph node hyperplasia [24] [144] [145] .

Tocilizumab completed phase II development for giant lymph node hyperplasia in Japan in 2002, where it has been granted orphan drug status.

The drug was undergoing phase I development for Castleman's disease with Chugai BioPharmaceuticals in the US and was undergoing phase II development with Chugai Pharma Europe in the EU; however, development has been discontinued in these regions.

Adult onset Still's disease

In May 2109, Chugai Pharmaceutical announced that Japanese Ministry of Health, Labour and Welfare has approved tocilizumab intravenous Infusion 80 mg, 200 mg, and 400 mg for the treatment of adult onset Still's disease in patients who have not responded sufficiently to existing therapies [146] . The regulatory application for the same was submitted in May 2018. The application was supported by clinical data from an investigator initiated trial of tocilizumab in patients with adult onset Still's disease. The placebo-controlled, randomized, double-blinded study validated efficacy and safety of tocilizumab in patients with inadequate responses to treatment with corticosteroids. The study was conducted by Keio University Hospital [147] .

Ankylosing spondylitis

Roche discontinued development of tocilizumab for the treatment of ankylosing spondylitis in the third quarter of 2011 [148] .

Two phase III trials evaluating the safety and efficacy of tocilizumab in patients with ankylosing spondylitis were terminated in December 2011 due to lack of efficacy (NCT01209702 and NCT01209689). The first randomised, double-blind, parallel, phase III study was to enrol approximately 502 patients who have had an inadequate response to previous TNF antagonist therapy. The similarly designed seamless additional phase III study was to enrol approximately 250 patients who have failed treatment with non-steroidal anti-inflammatory drugs and are naïve to tumour necrosis factor (TNF) antagonist therapy. Recruitment began in the US in December 2010, with further sites planned for Canada, Lithuania, and Slovakia [149] [150] .

Pancreatic cancer

Chugai was conducting phase I/II development of tocilizumab for the treatment of unresectable pancreatic cancer, in Japan. However, development in this indication was discontinued in July 2012, due to difficulties in evaluating safety and efficacy responses.

Myositis

In July 2019, Genentech in collaboration with the University of Pittsburgh completed a phase II trial that assessed the efficacy of tocilizumab in the treatment of patients with polymyositis and dermatomyositis (0039599; NCT02043548). The randomised, double-blind trial was initiated in October 2014 and enrolled 36 patients in the US [151] .

Urogenital cancer

In April 2019, Sanofi and Roche initiated the phase-Ib/II MORPHEUS mUC trial to evaluate the efficacy and safety of multiple immunotherapy-based treatment combinations containing tocilizumab, linagliptin, niraparib, isatuximab, atezolizumab, Isatuximab and Hu5F9 G4 in patients with locally advanced or metastatic urothelial carcinoma after failure with platinum-containing chemotherapy (NCT03869190; WO39613; EudraCT2017-004634-28). The open-label, randomised trial is enrolling approximately 305 patients in Spain and South Korea and may extend to France, Greece and the US [152] .

Subcutaneous formulation

Rheumatoid arthritis

The US FDA approved a subcutaneous formulation of tocilizumab, in October 2013, for the treatment of adults with moderate to severe rheumatoid arthritis (RA) who have received one or more DMARD. Tocilizumab SC is approved as a monotherapy or in combination with methotrexate or other non-biological DMARD. A prefilled syringe injection formulation is available in the US. Approval was based data from on the pivotal phase III SUMMACTA and BREVACTA studies [153] . In February 2013, the US FDA accepted a BLA, submitted in December 2012 by Genentech, for a subcutaneous formulation of tocilizumab for the treatment of adult RA. A 10-month review period was scheduled based on the Prescription Drug User Fee Act (PDUFA) [154] .

In November 2018, the US FDA approved ACTPen™ 162 mg/0.9 mL, a single-dose prefilled autoinjector for tocilizumab (Actemra®), as an additional formulation for adult patients with moderate to severe active rheumatoid arthritis who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs (DMARDs), and for adult patients with giant cell arteritis (GCA). ACTPen was also approved to be administered by caregivers to patients, aged two years and older, with active polyarticular juvenile idiopathic arthritis or active systemic juvenile idiopathic arthritis. The product approval was based on results from two studies, including data from an observational phase IV study in patients with RA, and data from another open-label, randomised, two-period, crossover phase I study of Actemra 162 mg SC via the ACTPen in 188 healthy volunteers [see below] [155] .

Subcutaneous tocilizumab was approved in the EU in April 2014 as a monotherapy and as part of combination therapy for moderate to severe RA in patients who have responded inadequately or are intolerant to other treatments. The product is available in a prefilled syringe [156] . The MAA was filed in the EU in December 2012, following the release of positive results from two registrational studies (SUMMACTA and BREVACTA). In December 2013, Roche reported that the European Commission's Committee for Medicinal Products for Human Use (CHMP) had granted a positive opinion recommending approval of the product for the treatment of moderate to severe RA in patients who have responded inadequately, or are intolerant of DMARDs or TNF-alpha inhibitors [157] .

In May 2018, the EMA approved ACTPen™ 162 mg/0.9 mL, a single-dose prefilled autoinjector for tocilizumab (Actemra®), as an additional formulation for patients with moderate to severe active rheumatoid arthritis, and giant cell arteritis (GCA) [155] .

In June 2017, Chugai obtained approval for additional dosage of tocilizumab (162mg weekly dose) and reduction in dose interval to one week from the Ministry of Health, Labour and Welfare in Japan for patients with rheumatoid arthritis who inadequately respond to the currently approved every other week dosing regimen, based on the results from MRA231JP trial [see below]. The application was filed in August 2016 [158] [159] .

In May 2013, Chugai launched a SC injection formulation of tocilizumab administered at two-week interval in Japan for the treatment of RA that does not respond sufficiently to one or more existing therapies. The marketing application was submitted in March 2012 and approval was obtained in March 2013. The product is listed on the Japanese National Health Insurance reimbursement schedule. The SC formulation is available in Japan as a 162mg syringe and as a 162mg auto-injector [160] [161] .

In May 2014, Health Canada approved a subcutaneous formulation of tocilizumab for use as monotherapy and combination therapy in the treatment of adults with moderately to severe RA who have inadequate responses to one or more DMARDs and/or TNF antagonists. This formulation will be available in Canada in June. The approval was based on the pivotal phase III SUMMACTA and BREVACTA trials [162] .

In November 2013, Chugai submitted an application for approval of a SC formulation of tocilizumab for rheumatoid arthritis in Taiwan.

In July 2015, Roche initiated a phase IV trial to evaluate rheumatoid arthritis activity using DAS28 in patients treated with subcutaneously administered tocilizumab (NCT02534311). The primary endpoint will be average change from baseline in DAS28, assessed up to week 24 or week 48. This observational trial was designed to enrol approximately 60 patients in Slovakia [163] .

In May 2017, Roche initiated a phase III trial to evaluate the efficacy and safety of subcutaneous tocilizumab (162 mg) given as monotherapy and in combination with methotrexate versus methotrexate given as monotherapy, in patients with moderate to severe active rheumatoid arthritis who have inadequate response to current disease modifying anti-rheumatic drug therapy (YA29359; NCT03155347). The study comprises a 24-week double-blind treatment phase, followed by a 24-week extension phase. This randomised, double-blind, parallel-group trial is enrolling 425 patients in China [164] .

Chugai Pharmaceuticals initiated a clinical trial in August 2016, met the primary endpoint of superiority of weekly dose of tocilizumab to every other week dose, which was defined by change in DAS28-ESR score from baseline (MRA231JP). The randomised, double-blind trial verified efficacy and safety of the weekly dose of Actemra 162mg subcutaneous injection, comparing to the every other week dosing regimen in patients with rheumatoid arthritis who inadequately respond to the every other week dose of Actemra 162mg subcutaneous injection [159] .

A registrational phase III study which compared the efficacy and safety of SC versus IV tocilizumab in patients with moderate-to-severe active RA met its primary endpoint (SUMMACTA; NCT01194414) [165] . The SC formulation of tocilizumab showed comparable efficacy compared with the IV formulation [166] . Patients were randomised to receive either SC tocilizumab 162mg weekly or IV tocilizumab 8 mg/kg every 4 weeks during the double-blind period of 24 weeks. Results from the 24 week period were first reported in July 2011 [167] . A small phase III extension trial in France evaluated the safety and efficacy of SC tocilizumab in 11 patients with RA who had completed the core 97-week SUMMACTA trial (NCT01734993) [168] .

Roche initiated a phase III trial to investigate efficacy and safety of subcutaneous tocilizumab, both as a monotherapy and/or in combination with methotrexate and other non-biologic DMARDs, in patients with active rheumatoid arthritis who were not previously treated with tocilizumab (TOSCARA; EudraCT2013-002150-79; NCT02031471). A total of 57 patients were enrolled; patients received weekly administration of subcutaneous tocilizumab 162mg. The primary end point was changes in disease activity score - erythrocyte sedimentation rate (DAS28-ESR) score, assessed at week 24 from baseline. The trial was conducted in Belgium and Luxembourg, and was completed in September 2015 [169] .

In May 2017, Chugai completed a phase III trial that evaluated the efficacy, safety and pharmacokinetics of treatment with 162mg tocilizumab given weekly versus every other week in patients with rheumatoid arthritis (JapicCTI142505). Change in DAS28 was evaluated as the primary endpoint measure in the trial. The randomised, double-blind, parallel-group trial was initiated in February 2014 and enrolled 42 patients in Japan. Chugai Pharmaceutical, in November 2016, presented efficacy data from the phase III trial of subcutaneous tocilizumab in patients with rheumatoid arthritis, at the 80th American College of Rheumatology and the 51st Annual Meeting of the Association of Rheumatology and Health Professionals (ACR-ARHP-2016) [170] [171] .

In October 2016, Roche completed a phase III trial that evaluated the safety and efficacy of tocilizumab subcutaneous alone or in combination with non-biologic disease modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis patients in Latin America with an inadequate response to non-biologic DMARDs (NCT02011334; ML28700). The open-label, non-randomised, single-group trial was initiated in July 2014 and enrolled 285 patients in Argentina, Brazil, Colombia, Dominican Republic, Mexico and Venezuela [172] .

A phase III trial of SC tocilizumab in combination with traditional DMARDs was completed in November 2013 and met its primary endpoint (BREVACTA; NA25220; EudraCT2010-019912-18; NCT01232569) [173] . The randomised, double-blind trial investigated the efficacy and tolerability of tocilizumab 162mg given every 2 weeks, compared with placebo, in patients with moderate-to-severe active RA who had an inadequate response to DMARDs alone. A total of 656 patients was enrolled in the US, Argentina, Australia, Brazil, Bulgaria, Canada, Colombia, Greece, Guatemala, Hungary, Israel, Malaysia, Mexico, New Zealand, Phillipines, Russia, South Africa, Spain, Switzerland, Thailand and Poland. The primary endpoint was the ACR20% response rate at 24 weeks. All patients will receive tocilizumab in a 72-week open-label extension [174] .

In September 2016, Roche completed a phase III trial, that investigated the efficacy and tolerability of tocilizumab in patients with active rheumatoid arthritis who were naive to tocilizumab and who have had an inadequate response to non-biologic DMARDs (ML28691; EudraCT2013-002007-34; NCT02046616). The non-randomised, open-labelled trial was initiated in May 2014, and enrolled 133 patients in Denmark, Finland, Norway and Sweden [175] .

In December 2015, Roche completed the phase III TOSCA trial of tocilizumab that evaluated the efficacy and safety of tocilizumab as a monotherapy or in combination with non-biologic DMARDs in patients with moderate to severe RA who had an inadequate response to non-biologic or biologic DMARDs (NCT02001987; ML28693). Patients received once-weekly tocilizumab (162mg) for up to 76 weeks. The two part, open label, single group study was initiated in February 2014 and enrolled 139 patients in France [176] . In June 2017, data from the trial were presented at the 18th Annual Congress of the European League Against Rheumatism (EULAR-2017) [177] [176] .

Two extension studies of BREVACTA and SUMMACTA were initiated to assess the long-term efficacy and safety of SC tocilizumab. An open-label two-year phase III study was completed in June 2014, and was conducted at multiple sites across the US and Puerto Rico in 218 patients who had completed the extension phases of the previous trials (ML28338; NCT01662063) [178] . The second study was completed in April 2015, which was a 72-week, roll-over extension study evaluating the long-term administration of SC tocilizumab (ML28488; EudraCT2012-002632-87; NCT01772316). Patients were continued on their stable dose of DMARDs throughout the duration of the trial of 2 years. The study was initiated in December 2012 and enrolled 47 patients in Spain [179] .

In November 2013, Roche initiated a phase III trial to investigate the safety, efficacy, tolerability and non-progression of structural joint damage following tocilizumab SC in patients with moderate to severe active rheumatoid arthritis (Ac-Cute; NCT01951170; ML28703). The non-randomised, open-label study enrolled 52 patients in Australia, and was completed in August 2015 [180] .

In July 2016, Roche completed a phase III trial that evaluated the efficacy and safety of SC tocilizumab, in monotherapy or in combination with methotrexate and/or other disease-modifying anti-rheumatic drugs (DMARDs), in patients with moderate-to-severe active rheumatoid arthritis (NCT01941940). This open-label trial was initiated in September 2013 and enrolled 227 patients in Italy [181] .

In October 2016, Roche completed the phase III COMP-ACT trial that evaluated the safety and efficacy of tocilizumab plus continued methotrexate versus tocilizumab alone following discontinuation of methotrexate in patients with rheumatoid arthritis (NCT01855789; ML28776). The randomised, double-blind trial enrolled 718 patients in the US [182] . In November 2017, the company presented positive results at the 81st American College of Rheumatology and the 52nd Association of Rheumatology Health Professionals Annual Scientific Meeting (ACR/ARHP-2017). In June 2018, results from an MRI sub-study form the trial were presented at the 19th Annual Congress of the European League Against Rheumatism (EULAR-2018) [183] [184] .

Roche, in August 2016, completed a phase III study that investigated the efficacy and safety of tocilizumab as monotherapy or in combination with methotrexate or other non-biologic disease-modifying antirheumatics (DMARDs) in patients with severe rheumatoid arthritis and an inadequate response to tumour necrosis factor inhibitors (NCT02046603; EudraCT2013-000054-22). The study was initiated in March 2014, and enrolled 162 patients in the UK [185] .

In July 2016, Roche completed a second phase III trial of tocilizumab that evaluated the safety and efficacy of tocilizumab as monotherapy and/or combined with methotrexate or other non-biologic DMARD drugs in patients with rheumatoid arthritis (EudraCT2013-000359-42; NCT01941095; ML28695). The non-randomised, open-label trial was initiated in September 2013 and enrolled 100 patients in Greece [186] .

Roche, in May 2016, completed the open-label phase IIIb OSCAR trial that investigated the tolerability and efficacy of tocilizumab in patients with rheumatoid arthritis who have had an inadequate response to non-biologic disease modifying anti-rheumatic drugs (DMARDs) (ML28702; EudraCT2013-000342-19; NCT01987479). Tocilizumab was administered as monotherapy or in combination with methotrexate or other non-biologic DMARDs. A total of 150 patients were enrolled in the Netherlands [187] . In March 2016, the company completed a similar phase IIIb trial in Ireland, Portugal and Spain (NCT01995201; EudraCT2013-002429-52). The study enrolled 401 patients [188]

Chugai has completed a phase IIIb study (NCT01258712; MRA230TW) and a long-term extension thereof (NCT01347983; MRA230TW EX) in Taiwan. Together these studies compared the efficacy and tolerability of SC tocilizumab + IV methotrexate with IV methotrexate + placebo in patients with moderate-to-severe RA. The randomised parent trial began in December 2010 and enrolled 136 patients; the long-term extension trial began in May 2011, and enrolled 80 patients [189] [190] .

A phase III trial to investigate the efficacy of SC tocilizumab in patients with rheumatoid arthritis, was completed in July 2015 (NCT01988012). The study enrolled 101 patients in Israel [191] .

In June 2016, Roche completed a phase I trial that assessed the bioequivalence of tocilizumab 162mg SC injection, using a pre-filled syringe-needle safety device (PFS-NSD) and a single injection via an autoinjector (AI-1000 G2), in healthy volunteers (WA30003; NCT02678988). The randomised, two-period crossover, open-label trial enrolled 188 volunteers in the US [192] .

Roche completed a phase I trial which compared the bioavailability of subcutaneous tocilizumab given by auto-injector versus pre-filled syringe in volunteers in February 2012 (NCT01418989). The randomised, parallel-assignment, open-label study involved 238 volunteers in France [193] .

Roche has completed a phase I trial of the SC formulation of tocilizumab to assess the pharmacokinetics, pharmacodynamics, efficacy and safety of the formulation in combination with methotrexate and folic acid in 29 patients with RA (NCT00965653). The trial was conducted in Canada, Spain, and New Zealand. Initial results show SC tocilizumab is well tolerated [194] [195] [196] .

Schnitzler's-syndrome

Roche, in collaboration with Charite University, Berlin completed the phase II TOCISCH trial that evaluated efficacy and safety of tocilizumab in patients with active schnitzler's syndrome (NCT03046381; TOCISCH; EudraCT2016-003828-23; ML39310). The priamry endpoint of the trial was to dettermine physician global assessment from baseline aseline versus week 20. The open-label trial was initiated in July 2017 and recruited 12 patients in the US [197] .

Juvenile rheumatoid arthritis

In September 2018, the US FDA approved SC tocilizumab, either alone or in combination with methotrexate, for the treatment of active systemic idiopathic arthritis (sJIA) in patients two years of age older. The approval was based on data from the phase I JIGSAW 118 trial [see below]. [198] . In May 2018, the US FDA approved SC tocilizumab, either alone or in combination with methotrexate, for the treatment of active polyarticular juvenile idiopathic arthritis (PJIA) in patients two years of age older [199] . The approval was based on data from the phase I JIGSAW 117 trial [see below].

In September 2018, Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion for the subcutaneous formulation of tocilizumab for the treatment of active systemic juvenile idiopathic arthritis (sJIA) in patients one year of age and older. The drug can be given alone or in combination with methotrexate in patients with sJIA. The CHMP opinion is based on data from the WA28118 study (see below). The efficacy of SC drug in children one to 17 years of age is based on PK exposure and extrapolation of established efficacy of tocilizumab IV in sJIA patients and tocilizumab SC in patients with rheumatoid arthritis [200] .

In April 2018, the European Commission approved label expansion for subcutaneous formulation of tocilizumab to include the indication juvenile idiopathic polyarthritis (pJIA) in patients two years of age and older, who have responded inadequately to previous therapy with methotrexate. Earlier, in February 2018, CHMP granted a positive opinion based on data from WA28117 and WA19977 trials (EMA Website, September 2018) [201] .

In June 2014, Roche initiated a long-term phase I trial to evaluate the safety and efficacy of SC tocilizumab 162mg in patients with polyarticular-course and systemic juvenile idiopathic arthritis (WA29231; NCT02165345). Enrolment of approximately 96 subjects is underway in the US, Germany, Spain, Canada, Italy and the United Kingdom [202] .

Roche, in May 2016, completed a phase Ib trial of subcutaneous tocilizumab for the treatment of poly-articular-course juvenile idiopathic arthritis (JIGSAW 117; WA28117; EudraCT2012-003486-18; NCT01904279). This open-label trial was initiated in July 2013, and assessed the pharmacokinetics, pharmacodynamics and safety of the compound in 52 subjects, aged one to 17 years, in the US, Argentina, Australia, Brazil, Canada, France, Germany, Italy, Mexico, Russia, Spain, Poland and the UK. Safety data from the trial were released by the company in May 2018 [199] [203] .

In June 2017, Roche completed a phase I trial, which evaluated the pharmacokinetics, pharmacodynamics and safety of subcutaneous tocilizumab in patients with systemic juvenile idiopathic arthritis (JIGSAW118; WA28118; EudraCT2012-003490-26; NCT01904292). The trial was initiated in August 2013 and enrolled 51 patients in Italy, the UK, the US, Argentina, Australia, Brazil, Canada, France, Germany, Mexico, Russia and Spain. In November 2017, the company presented data from the trial at the 81st American College of Rheumatology and the 52nd Association of Rheumatology Health Professionals Annual Scientific Meeting (ACR/ARHP-2017) [204] [205] . In June 2018, safety, pharmacokinetics and pharmacodynamic data presented at the 19th Annual Congress of the European League Against Rheumatism (EULAR-2018) [206] .

Early rheumatoid arthritis

In January 2015, Health Canada approved the use of intravenous and subcutaneous formulations of tocilizumab in adult patients with early moderate to severe RA. The approval was based on results from the phase III FUNCTION study [see above] [95] .

Osteoarthritis

Roche, in collaboration with Assistance Publique - Hôpitaux de Paris, initiated a phase III trial to evaluate the efficacy of tocilizumab on pain relief in approximately 90 patients with refractory hand osteoarthritis in France in November 2016 (P120206; NCT02477059). The trial was completed in February 2019 [207] .

Polymyalgia rheumatica

In October 2014, Chugai Pharmaceutical, in collaboration with University Hospital, Brest completed a phase I trial, which evaluated the safety and efficacy of tocilizumab as a first line therapy, in the treatment of patients with polymyalgia rheumatic (NCT01713842; RB 11-075 TENOR). The open label trial, which was initiated in July 2012, enrolled 21 patients in France. Results from the trial were presented at the 20th Annual Congress of the European League Against Rheumatism (EULAR-2019), in June 2019 [208] [209] .

Systemic scleroderma (SSc)

As at July 2019, development of tocilizumab for the treatment of systemic scleroderma had been discontinued (Chugai Pharmaceutical pipeline, July 2019).

In March 2016, the Ministry of Health, labour and Welfare of Japan granted orphan drug designation to tocilizumab for treatment of patients with systemic scleroderma [210] .

Regulatory submissions for tocilizumab in the treatment of systemic scleroderma [systemic sclerosis] are expected in 2017 or beyond, according to Roche's pipeline in January 2015.

The US FDA granted tocilizumab Breakthrough Therapy designation for the treatment of systemic sclerosis in June 2015. The designation was granted on the basis of the phase II/III faSScinate trial [see below] [211] [212] .

In August 2017, Chugai initiated a phase III trial to evaluate long-term safety, efficacy, pharmacodynamics of subcutaneous tocilizumab in patients with systemic sclerosis who participated in WA29767 study [see below] (JapicCTI-173760). The open-label, single-arm trial will enrol approximately 18 patients in Japan [213] .

In February 2019, Roche completed a phase III trial that evaluated the efficacy and safety of tocilizumab in patients with systemic sclerosis (focuSSed; WA29767; NCT02453256; EudraCT2015-000424-28). Evaluation of the change in modified Rodnan skin score was the primary endpoint of the trial. The randomised, double blind, placebo control trial was initiated in November 2015, and enrolled 212 patients in the US, Denmark, Hungary, Portugal and Spain, Canada, Argentina, the UK, Belgium, Brazil, Bulgaria, Croatia, Greece, Italy, Lithuania, Japan, Mexico, Netherlands, Poland, Puerto Rico, Romania, South Africa, Switzerland, France, Ireland and Germany. In June 2019, the company presented efficacy and safety data at the 20th Annual Congress of the European League Against Rheumatism (EULAR-2019) [214] [211] [212] [215] .

The faSScinate trial did not meet the primary endpoint of improvement in skin thickening at 24 weeks, which was assessed by the Rodnan skin score (NCT01532869; EudraCT2011-001460-22). In June 2015, Roche completed this phase II/III trial of subcutaneous tocilizumab in patients with systemic scleroderma). In the double-blind trial 87 patients were randomised to receive tocilizumab 162mg or placebo, weekly for 48 weeks. From weeks 49 to 96, all patients were to receive open-label tocilizumab 162mg weekly. The trial was initiated in March 2012 and enrolled patients in the US, Canada, France, Germany and the UK [216] . The study indicated continued improvement in skin thickening between weeks 24 and 48, with comparable adverse events in both groups [211] [212] . In November 2016, the company presented data from the open-label treatment duration of the faSScinate study [217] .

Large vessel

vasculitis (giant cell arteritis and Takayasu arteritis): In August 2017, Japanese Ministry of Health, Labour and Welfare, approved tocilizumab 162mg syringe, for subcutaneous injection, for the treatment of large vessel vasculitis (LVV) including, Takayasu arteritis and giant cell arteritis (GCA). The approval was based on the results from the phase III MRA632JP trial conducted in patients with Takayasu arteritis and GiACTA trial conducted in GCA patients [see below]. Chugai Pharmaceutical filed the application in November 2016 [218] [219] .

In June 2014, tocilizumab received orphan drug designation from Ministry of Health, Labour and Welfare, Japan [218] .

Takayasu arteritis

Chugai Pharmaceuticals, in February 2019, completed the phase III TOCITAKA trial that evaluated the efficacy and tolerance of tocilizumab in takayasu arteritis (EudraCT2013-005039-26; NCT02101333; P130404). The primary end point of the trial was to determine the number of good responders without prednisone after 6-months tocilizumab treatment. The open-label trial was initiated in June 2014 and recruited 15 participants in France [220]

In January 2018, Chugai Pharmaceutical completed a phase III study that evaluated the safety, efficacy, pharmacokinetics and pharmacodynamics of subcutaneous tocilizumab in patients with Takayasu arteritis (MRA632JP; JapicCTI-142616). The double-blind, open, parallel, prospective, randomised trial was initiated in June 2014 and enrolled 36 patients, aged 12 years and older in Japan. Following the completion of the double-blind study, long-term safety and efficacy will be evaluated in an open-label design [221] .

Pulmonary

arterial hypertension: In February 2018, Roche completed the TRANSFORM-UK phase II trial, which evaluated the safety and efficacy of tocilizumab in group 1 pulmonary arterial hypertension patients (NCT02676947; PO2060). The open-label trial was initiated in January 2016, and enrolled 29 patients in the UK [222] . In May 2018, data were presented at the 114th International Conference of the American Thoracic Society (ATS-2018) [223] .

Giant cell arteritis

In September 2017, the European Commission approved subcutaneous tocilizumab, in all member states of the EU along with Norway, Iceland and Liechtenstein, for the treatment of patients with giant cell arteritis (GCA). The approval was based on the results of the phase III GiACTA trial [see trial below] [224] . In July 2017, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending approval of tocilizumab (Actemra®/RoActemra®) for the treatment of GCA [225] .

In April 2018, tocilizumab was recommended by NICE for the treatment of giant cell arteritis in adult patients [226] .

In May 2017, the Medsafe approved subcutaneous tocilizumab in New Zealand, for the treatment of patients with GCA. The approval was based on the positive outcome of the phase III GiACTA study [see trial below] [225] .

The US FDA approved Actemra® (tocilizumab) subcutaneous injection for the treatment of GCA, in May 2017. The approval was based on the data of the phase III GiACTA study evaluating Actemra in patients with GC [227] . In January 2017, Genentech reported that the US FDA accepted its sBLA for tocilizumab for the treatment of giant cell arteritis. The FDA also granted a Priority Review designation to the sBLA. The designation was granted based upon the positive results from the phase III GiACTA study [see below] [228] .

In November 2017, Health Canada approved tocilizumab (Actemra®) subcutaneous injection for the treatment of adult patients with giant cell arteritis. The approval was based on the outcome of the phase III GiACTA trial [229] .

Genentech reported in October 2016 that the US FDA granted Breakthrough Therapy designation to tocilizumab for the treatment of giant cell arteritis, based on the results of the global phase III GiACTA study [230] .

In June 2018, Roche completed the phase III GiACTA trial that met its primary and key secondary endpoint, demonstrating that tocilizumab, initially in combination with a six month steroid (glucocorticoid) taper, enabled significantly more patients to achieve sustained disease remission and also significantly reducing steroid exposure compared with steroids alone (WA28119; Eudra2011-006022-25; NCT01791153). The trial evaluated the efficacy and safety of tocilizumab, in patients with giant cell arteritis. The randomised, double-blinded trial was initiated in July 2013, which enrolled 251 patients in the US, Canada, UK, Austria, Belgium, Denmark, France, Germany, Italy, Netherlands, Poland, Portugal, Spain, Sweden and Norway [231] [232] . Positive results were released in July 2017, and were also presented at the 2016 American College of Rheumatology (ACR) and Association for Rheumatology Health Professionals (ARHP) Annual Meeting [233] [234] . In November 2016, data from an ongoing 104-week open label extension study from GiACTA to quantify tocilizumab’s long-term safety and maintenance of efficacy beyond one year, and any potential long-term steroid sparing effects were presented at the 80th American College of Rheumatology (ACR) and Association for Rheumatology Health Professionals (ARHP) Annual Meeting (ACR/ARHP- 2016) [235] . Updated data from the trial presented at the 20th Annual Congress of the European League Against Rheumatism (EULAR-2019) in June 2019 [236] [237] [238] . Later, in November 2019, 3-year results from the trial were presented at the 83rd American College of Rheumatology and the 54th Association of Rheumatology Health Professionals Annual Scientific Meeting (ACR/ARHP-2019) [239] [240]
[241] .

In August 2019, Hoffmann-La Roche completed the long-term extension study of study WA28119 phase III trial which investigated the long-term safety of SC tocilizumab in participants with giant cell arteritis, who subsequently have flare or persisting disease activity (ML39425; EudraCT2016-002716-41; NCT03202368). The open label trial was initiated in October 2017 and enrolled three patients in France [242] .

In September 2015, University Hospital Inselspital, in collaboration with Roche and the University of Bern, completed the randomised, double-blind phase II trial that assessed the efficacy of tocilizumab plus glucocorticoids, when compared with placebo plus glucocorticoids, in patients with giant cell arteritis (168/10; NCT01450137). The primary endpoint was the proportion of patients that achieved complete remission at 12 weeks. The trial was initiated in September 2011 and enrolled 30 patients in Switzerland [243] .

In August 2019, Roche initiated a phase I trial to evaluate the safety, pharmacokinetic and pharmacodynamics of tocilizumab administered intravenously in patients with giant cell arteritis (WP41152; EudraCT2018-004718-17; NCT03923738). The open label trial intends to enrol approximately 25 patients in Switzerland [244] .

Healthy volunteers trials

In January 2017, Herlev Hospital in collaboration with Celgene, initiated the phase II PACTO trial to evaluate whether tocilizumab in combination with gemcitabine or nab-paclitaxel is more efficacious than gemcitabine or nab-paclitaxel alone (GI1612; EudraCT2016-000643-13; NCT02767557). The randomised, parallel-assignment trial intends to enrol approximately 140 patients in Denmark [245] .

In June 2016, Chugai and Roche completed a phase I trial that evaluated the bioequivalence, immunogenicity, safety and tolerability following single dose of tocilizumab 162mg SC injection, derived from drug substance manufactured using the current commercial product and the new product process, in healthy volunteers (JapicCTI-163150). The open-label, randomised, two-stage, two-period cross-over trial was initiated in February 2016, and enrolled 74 volunteers in Japan [246] .

Other investigator-sponsored trials

In July 2018, Barrow Neurological Institute and Genentech completed a phase II study, that evaluated the safety and efficacy of intravenous tocilizumab in patients with amyotrophic lateral sclerosis (TCZALS-001; NCT02469896). The study was initiated in November 2015 and enrolled 22 subjects in the US [247] .

In December 2015, Hospital for Special Surgery in collaboration with Genentech completed a phase IIa trial of tocilizumab in the treatment of polymyalgia rheumatica (NCT01396317). The trial was initiated in July 2011 and enrolled 10 patients in the US [248] .

In December 2014, Brian Miller of Georgia Regents University completed an open-label phase I trial that assessed the safety and efficacy of adjunctive tocilizumab in patients with schizophrenia receiving a stable dose of antipsychotic medications (Pro00000405; NCT01696929). The trial enrolled 8 patients in the US. The trial began in September 2012 [249] .

Discontinued indications

Tocilizumab was in phase I development for the treatment of systemic lupus erythematosus (SLE), multiple myeloma, and Crohn's disease. However, development has been discontinued in these indications.

Labelling information

The US approved label for tocilizumab carries a black boxed warning regarding the risk of serious infections, such as tuberculosis, bacterial, invasive fungal, viral, and other opportunistic infections, that may lead to hospitalisation or death [250] .

Patent Information

Chugai and the US company Protein Design Labs reached an agreement in May 2000, whereby Chugai will receive non-exclusive, worldwide licences for an undisclosed number of its antibody targets under Protein Design Labs' antibody humanisation patents. One of the targets included is the human interleukin-6 receptor. Chugai will pay Protein Design Labs $US6.04 million in signing and licensing fees. Chugai will also pay annual maintenance fees and royalties on any future product sales.

In January 2006, Protein Design Labs changed its name to PDL BioPharma [6] .

Drug Properties & Chemical Synopsis

  • Route of administration IV, SC
  • Formulation Infusion, Injection, unspecified
  • Class Anti-inflammatories, Antineoplastics, Antirheumatics, Antivirals, Immunotherapies, Monoclonal antibodies, Skin disorder therapies
  • Target Interleukin 6 receptor; Interleukin Receptor
  • Mechanism of Action Immunosuppressants; Interleukin 6 receptor antagonists
  • WHO ATC code

    A07E (Intestinal Antiinflammatory Agents)

    J05 (Antivirals for Systemic Use)

    L04A-C07 (Tocilizumab)

    M01 (Antiinflammatory and Antirheumatic Products)

  • EPhMRA code

    A7E (Intestinal Anti-Inflammatory Agents)

    J5 (Antivirals for Systemic Use)

    L1G (Monoclonal Antibody Antineoplastics)

    L4X (Other Immunosuppressants)

    M1 (Anti-Inflammatory and Anti-Rheumatic Products)

    M5 (Other Drugs for Disorders of the Musculo-Skeletal System)

    N7 (Other CNS Drugs)

  • Chemical name Immunoglobulin G1, anti-(human interleukin 6 receptor) (human-mouse monoclonal MRA heavy chain), disulfide with human-mouse monoclonal MRA κ-chain, dimer
  • CAS Registry Number 375823-41-9

Biomarkers Sourced From Trials

Indication Biomarker Function Biomarker Name Number of Trials

adenocarcinoma

not specified

IL6

1

advanced breast cancer

Exclusion

HER2

1

advanced breast cancer

Inclusion

HER2

1

advanced breast cancer

Outcome Measure

HER2

1

amyotrophic lateral sclerosis

Outcome Measure

IL6

ATPase, Ca++ transporting, type 2C, member 1

1

1

ankylosing spondylitis

Outcome Measure

Ubiquinone-2

interleukin 6 receptor

IL6

CRP

1

1

1

1

chronic lymphocytic leukaemia

Outcome Measure

SAA

interleukin 6 receptor

IL6

Ferritin

CRP

1

1

1

1

1

cytokine release syndrome

not specified

IL12B

IL12A

IL1 beta

IL1 alpha

1

1

1

1

cytokine release syndrome

Exclusion

CD19

1

cytokine release syndrome

Inclusion

IL6

IFN-gamma

CD19

1

1

1

cytokine release syndrome

Outcome Measure

TNF-alpha

IL8

IL6

IL5

IL4

IL2

IL13

IL10

IFN-gamma

Ferritin

CD25

1

1

1

1

1

1

1

1

1

1

1

dermatomyositis

not specified

PM/Scl-100 auto-antibodies

Mi-2 antibodies

Jo-1 Auto-antibodies

IL6

anti-TIF1-gamma

anti-SRP

1

1

1

1

1

1

diabetic macular oedema

not specified

A1C

1

Erdheim-Chester disease

not specified

IL6

1

fibrous dysplasia of bone

Outcome Measure

CTx

CRP

1

1

giant cell arteritis

not specified

ER alpha

1

giant cell arteritis

Inclusion

CRP

1

giant cell arteritis

Outcome Measure

interleukin 6 receptor

IL6

CRP

1

1

2

graft-versus-host disease

Outcome Measure

BAFF

1

haemophagocytic lymphohistiocytosis

not specified

IL12B

IL12A

IL1 beta

IL1 alpha

1

1

1

1

haemophagocytic lymphohistiocytosis

Inclusion

IL6

IFN-gamma

1

1

haemophagocytic lymphohistiocytosis

Outcome Measure

TNF-alpha

IL8

IL6

IL5

IL4

IL2

IL13

IL10

IFN-gamma

Ferritin

CD25

1

1

1

1

1

1

1

1

1

1

1

HIV infections

Inclusion

CD4

1

HIV infections

Outcome Measure

Ki67

CRP

1

1

joint disorders

Inclusion

metaxin 1

1

joint disorders

Outcome Measure

Rheumatoid factor

metaxin 1

CRP

bestrophin 1

1

1

1

1

juvenile rheumatoid arthritis

Inclusion

CRP

1

juvenile rheumatoid arthritis

Outcome Measure

Rheumatoid factor

PDS5 cohesin associated factor B

Kell blood group, metallo-endopeptidase

interleukin 6 receptor

IL6

Ferritin

CRP

1

1

1

2

3

1

9

major depressive disorder

not specified

IL6

1

male breast cancer

Exclusion

HER2

1

male breast cancer

Inclusion

HER2

1

male breast cancer

Outcome Measure

HER2

1

myocardial infarction

Exclusion

IL6

CRP

1

1

myocardial infarction

Inclusion

Troponin T, cardiac

1

myocardial infarction

Outcome Measure

Troponin T, cardiac

TNF-alpha

IL6

IL18

CRP

CKM

CKB

BNP

2

1

1

1

2

1

1

2

ovarian cancer

Outcome Measure

VEGF-A

p53

IL8

IL6

1

1

1

1

ovarian cancer

Safety

VEGF-A

p53

IL8

IL6

1

1

1

1

pancreatic cancer

not specified

IL6

1

polymyalgia rheumatica

not specified

Rheumatoid factor

CRP

CCP antibodies

1

1

1

polymyalgia rheumatica

Outcome Measure

TGF-beta

Pyridinoline

IL6

1

1

2

polymyositis

not specified

PM/Scl-100 auto-antibodies

Mi-2 antibodies

Jo-1 Auto-antibodies

IL6

anti-TIF1-gamma

anti-SRP

1

1

1

1

1

1

Pulmonary arterial hypertension

Outcome Measure

BNP

1

renal transplant rejection

Exclusion

Creatinine

1

renal transplant rejection

Outcome Measure

Anti-HLA antibodies

1

rheumatoid arthritis

not specified

TNF-alpha

FasL

Fas cell surface death receptor

2

1

1

rheumatoid arthritis

Exclusion

metaxin 1

group-specific component (vitamin D binding protein)

GBA

2

1

1

rheumatoid arthritis

Inclusion

Z-DNA binding protein 1

TNF-alpha

metaxin 1

IL6

group-specific component (vitamin D binding protein)

GBA

CRP

1

1

2

1

1

1

3

rheumatoid arthritis

Outcome Measure

Z-DNA binding protein 1

WAS/WASL interacting protein family, member 1

VEGF-C

VEGF-A

Uric acid

Ubiquinone-2

tumor necrosis factor superfamily member 13

TNF-alpha

TGF-beta

Tetrahydrofuran

T-box 1

Survivin

STAT3

Soluble transferrin receptor

Sclerostin

SAA

RORC

Rheumatoid factor

PINP

PIIINP

PGR

NPY

Neprilysin

natriuretic peptide receptor 1

metaxin 1

MCP1

MAPK1

Malondialdehyde

Leucyl-phenylalanine

L-selectin

L-Cysteine

Kell blood group, metallo-endopeptidase

interleukin 6 receptor

interleukin 23 receptor

IL8

IL6

IL4

IL23

IL2

IL17

IL10

IL1 beta

IL1 alpha

IFN-gamma

IFN-alpha 2

Hydrocortisone

hyaluronan synthase 2

growth hormone 1

group-specific component (vitamin D binding protein)

GM-CSF

GBA

gamma-glutamyltransferase light chain 1

formyl peptide receptor 1

Ferritin

Dehydroepiandrosterone

CTx

CRP

chromosome 16 open reading frame 70

Chemerin

CD63

CD45

CD4

CD38

CD27 molecule

CD24

CD19

CCP antibodies

C-C motif chemokine ligand 8

bestrophin 1

BAFF

B2M

Annexin A5

Androstenedione

ALT

adrenoceptor alpha 1D

Adiponectin

Adenosine triphosphate

ACTH

8

1

2

2

2

1

1

4

1

1

4

1

1

1

1

1

1

11

1

1

1

1

1

1

3

2

1

1

1

1

1

1

14

1

1

9

1

1

1

3

2

2

1

1

1

1

1

1

1

1

1

1

1

1

1

2

82

1

1

1

1

1

2

2

1

2

5

1

9

2

1

1

1

1

1

1

1

1

schizoaffective disorder

not specified

TNF-alpha

1

schizoaffective disorder

Outcome Measure

IL6

fibroblast growth factor 9

1

1

schizophrenia

not specified

TNF-alpha

IL6

Hydrocortisone

CRP

1

1

1

1

schizophrenia

Outcome Measure

IL6

fibroblast growth factor 9

1

1

systemic scleroderma

not specified

interleukin 6 receptor

1

systemic scleroderma

Inclusion

Mental retardation, X-linked, with short stature

1

systemic scleroderma

Outcome Measure

Mental retardation, X-linked, with short stature

interleukin 6 receptor

IL6

CRP

1

1

2

1

type 1 diabetes mellitus

Inclusion

C-peptide

1

type 1 diabetes mellitus

Outcome Measure

C-peptide

A1C

1

1

Biomarker

Drug Name Biomarker Name Biomarker Function
Tocilizumab - Roche A1C Outcome Measure
ACTH Outcome Measure
Adenosine triphosphate Outcome Measure
Adiponectin Outcome Measure
ALT Outcome Measure
Androstenedione Outcome Measure
Annexin A5 Outcome Measure
Anti-HLA antibodies Outcome Measure
anti-SRP not specified
anti-TIF1-gamma not specified
ATPase, Ca++ transporting, type 2C, member 1 Outcome Measure
B2M Outcome Measure
BAFF Outcome Measure
bestrophin 1 Outcome Measure
BNP Outcome Measure
C-C motif chemokine ligand 8 Outcome Measure
C-peptide Inclusion, Outcome Measure
CCP antibodies Outcome Measure
CD19 Exclusion, Inclusion, Outcome Measure
CD24 Outcome Measure
CD25 Outcome Measure
CD27 molecule Outcome Measure
CD38 Outcome Measure
CD4 Inclusion, Outcome Measure
CD45 Outcome Measure
CD63 Outcome Measure
Chemerin Outcome Measure
chromosome 16 open reading frame 70 Outcome Measure
CKB Outcome Measure
CKM Outcome Measure
Creatinine Exclusion
CRP Exclusion, Inclusion, Outcome Measure
CTx Outcome Measure
Dehydroepiandrosterone Outcome Measure
ER alpha Outcome Measure
Fas cell surface death receptor not specified
FasL not specified
Ferritin Outcome Measure
fibroblast growth factor 9 Outcome Measure
formyl peptide receptor 1 Outcome Measure
GLP-1 Outcome Measure
GM-CSF Outcome Measure
group-specific component (vitamin D binding protein) Outcome Measure
growth hormone 1 Outcome Measure
HER2 Exclusion, Inclusion, Outcome Measure
hyaluronan synthase 2 Outcome Measure
Hydrocortisone Outcome Measure
IFN-gamma Inclusion, Outcome Measure
IL1 alpha Outcome Measure
IL1 beta Outcome Measure
IL10 Outcome Measure
IL12A not specified
IL12B not specified
IL13 Outcome Measure
IL17 Outcome Measure
IL18 Outcome Measure
IL2 Outcome Measure
IL23 Outcome Measure
IL4 Outcome Measure
IL5 Outcome Measure
IL6 Exclusion, Inclusion, Outcome Measure, Safety
IL8 Outcome Measure, Safety
interleukin 23 receptor Outcome Measure
interleukin 6 receptor Outcome Measure
Jo-1 Auto-antibodies not specified
Kell blood group, metallo-endopeptidase Outcome Measure
Ki67 Outcome Measure
L-Cysteine Outcome Measure
L-selectin Outcome Measure
Leucyl-phenylalanine Outcome Measure
Malondialdehyde Outcome Measure
MCP1 Outcome Measure
Mental retardation, X-linked, with short stature Inclusion, Outcome Measure
metaxin 1 Exclusion, Inclusion, Outcome Measure
Mi-2 antibodies not specified
natriuretic peptide receptor 1 Outcome Measure
Neprilysin Outcome Measure
NPY Outcome Measure
p53 Outcome Measure, Safety
PGR Outcome Measure
PIIINP Outcome Measure
PINP Outcome Measure
PM/Scl-100 auto-antibodies not specified
Rheumatoid factor Outcome Measure
RORC Outcome Measure
SAA Outcome Measure
Sclerostin Outcome Measure
Soluble transferrin receptor Outcome Measure
Survivin Outcome Measure
T-box 1 Outcome Measure
Tetrahydrofuran Outcome Measure
TGF-beta Outcome Measure
TNF-alpha Inclusion, Outcome Measure
Troponin T, cardiac Inclusion, Outcome Measure
tumor necrosis factor superfamily member 13 Outcome Measure
Ubiquinone-2 Outcome Measure
Uric acid Outcome Measure
VEGF-A Outcome Measure, Safety
VEGF-C Outcome Measure
villin 1 not specified
WAS/WASL interacting protein family, member 1 Outcome Measure
xenotropic and polytropic retrovirus receptor 1 Outcome Measure
Z-DNA binding protein 1 Inclusion, Outcome Measure
For more detail, check out BiomarkerBase: the leading source of information about biomarkers used in drug development and diagnostic tests, tracking a comprehensive list of biomarker uses worldwide by over 800 companies

Development Status

Summary Table

Indication Qualifier Patient Segment Phase Countries Route / Formulation Developers Event Date
Adult-onset Still's disease - Treatment-experienced Registered Japan IV / Infusion Chugai Pharmaceutical 23 May 2019
Amyotrophic lateral sclerosis - - Phase II USA IV / Infusion Roche 01 Nov 2015
Ankylosing spondylitis - - Discontinued (III) USA, United Kingdom IV / Infusion Roche 13 Oct 2011
COVID 2019 infections in combination with remdesivir Combination therapy Phase III Canada, Europe, USA IV / unspecified Roche 28 May 2020
COVID 2019 infections in hospitalised adult patients with severe COVID-19 pneumonia - Phase III Denmark, France, Germany, Italy, Netherlands, Spain, USA, United Kingdom IV / unspecified Biomedical Advanced Research and Development Authority, Roche 08 Apr 2020
COVID 2019 infections - - Phase II Switzerland IV / unspecified Roche 26 Apr 2020
Chronic lymphocytic leukaemia - Combination therapy, First-line therapy No development reported (I) Israel, Italy, Latvia, Spain, United Kingdom IV / Infusion Roche 28 Oct 2018
Crohn's disease - - Discontinued (II) Japan IV / Injection Chugai Pharmaceutical 27 Oct 2009
Dermatomyositis - Treatment-experienced Phase II USA IV / Infusion Roche, University of Pittsburgh 01 Oct 2014
Drug hypersensitivity cytokine release syndrome induced by treatment with CAR-T cell therapy - Marketed Japan IV / Infusion Chugai Pharmaceutical 26 Mar 2019
Drug hypersensitivity CART cell-induced cytokine release syndrome - Registered USA IV / Injection Roche 30 Aug 2017
Drug hypersensitivity CART cell-induced cytokine release syndrome In adolescents, In adults, In children Preregistration European Union IV / Injection Roche 29 Jun 2018
Familial Mediterranean fever - - Phase II Germany IV / Infusion Roche, University Hospital Tubingen 23 Apr 2018
Giant cell arteritis - Combination therapy Marketed United Kingdom SC / Injection Roche 01 Apr 2018
Giant cell arteritis - Combination therapy Registered Japan SC / Injection Chugai Pharmaceutical 25 Aug 2017
Giant cell arteritis - Combination therapy Registered Canada, European Union, Iceland, Liechtenstein, New Zealand, Norway, USA SC / Injection Roche 02 Nov 2017
Giant cell arteritis - Combination therapy Phase II Switzerland SC / Injection Roche, University of Bern, University Hospital Inselspital 30 Sep 2011
Giant cell arteritis - - Phase I Switzerland IV / Infusion Roche 05 Aug 2019
Giant lymph node hyperplasia - - Marketed Japan IV / Injection Chugai Pharmaceutical 13 Jun 2005
Giant lymph node hyperplasia - - Discontinued (I) USA IV / Injection Chugai Pharmaceutical, Roche 27 Oct 2009
Juvenile rheumatoid arthritis juvenile idiopathic polyarthritis (pJIA) - Marketed Austria, Belgium, Czech Republic, Denmark, Finland, France, Germany, Greece, Hungary, Ireland, Netherlands, Norway, Poland, Portugal, Spain, Sweden, United Kingdom SC / Injection Roche 13 Apr 2018
Juvenile rheumatoid arthritis Systemic onset and polyarticular juvenile idiopathic arthritis - Marketed Japan IV / Infusion Chugai Pharmaceutical, Roche 16 Apr 2008
Juvenile rheumatoid arthritis Systemic onset and polyarticular juvenile idiopathic arthritis Systemic onset - Marketed Argentina, Australia, Austria, Canada, Czech Republic, Greece, Hong Kong, Hungary, India, Israel, Malaysia, Mexico, Myanmar, Netherlands, New Zealand, Philippines, Spain, Switzerland, Thailand, USA, United Kingdom IV / Infusion Roche 09 Apr 2015
Juvenile rheumatoid arthritis In active polyarticular juvenile idiopathic arthritis (PJIA) and active systemic juvenile idiopathic arthritis (sJIA) patients Combination therapy Registered USA SC / Injection Roche 14 May 2018
Juvenile rheumatoid arthritis juvenile idiopathic polyarthritis (pJIA) juvenile idiopathic polyarthritis - Registered European Union, Iceland, Liechtenstein SC / Injection Roche 12 Apr 2018
Juvenile rheumatoid arthritis - - Phase III Brazil, Norway, Peru, Russia IV / Infusion Roche 19 Nov 2009
Juvenile rheumatoid arthritis Systemic or polyarticular-course juvenile idiopathic arthritis - No development reported (I) Argentina, Australia, Brazil, Canada, Mexico, Russia SC / Injection Roche 28 Dec 2018
Multiple myeloma - - Discontinued (II) France IV / Injection Chugai Pharmaceutical 27 Oct 2009
Osteoarthritis Hand osteoarthritis Treatment-experienced Phase III France IV / Infusion Assistance Publique Hopitaux de Paris, Roche 27 Nov 2016
Pancreatic cancer - - Discontinued (I/II) Japan IV / Injection Chugai Pharmaceutical 26 Jul 2012
Polymyalgia rheumatica - - Phase II USA IV / Infusion Hospital for Special Surgery, Roche 01 Jul 2011
Polymyalgia rheumatica - First-line therapy, In adults, In the elderly No development reported (I) France IV / Infusion Chugai Pharmaceutical 28 Jun 2019
Polymyositis - Treatment-experienced Phase II USA IV / Infusion Roche, University of Pittsburgh 01 Oct 2014
Pulmonary arterial hypertension - - Phase II United Kingdom IV / unspecified Roche 01 Jan 2016
Rheumatoid arthritis - Late-stage disease, Mid-stage disease Marketed Ireland, Switzerland SC / Injection Roche 31 Mar 2015
Rheumatoid arthritis - Combination therapy, Monotherapy, Treatment-resistant Marketed USA SC / Injection Roche 04 Feb 2014
Rheumatoid arthritis - - Marketed South Korea IV / Infusion JW Pharmaceutical 08 Apr 2015
Rheumatoid arthritis - Combination therapy, Monotherapy, Treatment-experienced Marketed United Kingdom SC / Injection Roche 28 Apr 2014
Rheumatoid arthritis - Late-stage disease, Mid-stage disease Marketed Argentina, Australia, Austria, Belgium, Canada, Chile, China, Czech Republic, Denmark, Finland, Greece, Hong Kong, Hungary, India, Indonesia, Ireland, Israel, Malaysia, Myanmar, Netherlands, Norway, Philippines, Poland, Portugal, Russia, Singapore, Spain, Sweden, Switzerland, Thailand, Turkey, Ukraine, Vietnam IV / Infusion Roche 09 Apr 2015
Rheumatoid arthritis - Treatment-resistant Marketed Japan SC / Injection Chugai Pharmaceutical 24 May 2013
Rheumatoid arthritis - Late-stage disease, Mid-stage disease Marketed Brazil, France, Germany, Japan, Mexico, New Zealand, USA, United Kingdom IV / Infusion Chugai Pharmaceutical, Roche 15 May 2014
Rheumatoid arthritis - Early-stage disease Registered Canada SC / Injection Chugai Pharmaceutical, Roche 08 Jan 2015
Rheumatoid arthritis - Combination therapy, Late-stage disease, Mid-stage disease, Monotherapy, Treatment-resistant Registered Canada SC / Injection Roche 08 May 2014
Rheumatoid arthritis - Early-stage disease Registered Canada, European Union IV / Infusion Chugai Pharmaceutical, Roche 08 Jan 2015
Rheumatoid arthritis - - Preregistration Taiwan SC / Injection Chugai Pharmaceutical 30 Nov 2013
Rheumatoid arthritis - Late-stage disease, Mid-stage disease Phase III Croatia, Serbia IV / Infusion Roche 01 Mar 2009
Rheumatoid arthritis moderate-to-severe Treatment-experienced Phase III Denmark, Finland, Norway, Spain, Sweden SC / Injection Roche 01 May 2014
Rheumatoid arthritis - Monotherapy, Treatment-experienced Phase III China SC / Injection Roche 18 May 2017
Rheumatoid arthritis - Early-stage disease Phase III Argentina, Brazil, Colombia, Guatemala, Macedonia, Mexico, Panama, Peru, Puerto Rico IV / Infusion Roche 31 Oct 2009
Rheumatoid arthritis - Late-stage disease, Mid-stage disease Phase III Argentina, Australia, Belgium, Bosnia-Herzegovina, Brazil, Colombia, Guatemala, Hong Kong, Israel, Luxembourg, Mexico, New Zealand, Peru, Philippines, Puerto Rico, Russia, Singapore, South Africa, Thailand SC / Injection Roche 01 Feb 2014
Rheumatoid arthritis - Early-stage disease Phase III Australia, China, Hong Kong, Israel, New Zealand, Philippines, Russia, Singapore, South Africa, Thailand, Turkey, USA IV / Infusion Chugai Pharmaceutical, Roche 31 Oct 2009
Rheumatoid arthritis moderate-to-severe Combination therapy, Monotherapy, Treatment-resistant Phase III Argentina, Brazil, Colombia, Dominican Republic, Mexico, Venezuela SC / Injection Roche 01 Jul 2014
Rheumatoid arthritis - Combination therapy, Late-stage disease, Mid-stage disease Phase III Malaysia, Panama SC / Injection Roche 01 Mar 2011
Rheumatoid arthritis - Combination therapy, Treatment-experienced Phase III China SC / Injection Roche 18 May 2017
Rheumatoid arthritis - - Phase II Japan SC / Injection Chugai Pharmaceutical 22 Jul 2016
Rheumatoid arthritis - Late-stage disease, Mid-stage disease No development reported (III) Egypt, Morocco, Saudi Arabia IV / Infusion Roche 09 Apr 2015
Rheumatoid arthritis - Combination therapy, In adults, In the elderly, Treatment-experienced No development reported (I) New Zealand, USA IV / Infusion Roche 04 Nov 2017
Schnitzler syndrome - Treatment-experienced Phase II Germany SC / Injection Charite - Universitatsmedizin Berlin, Roche 19 Jul 2017
Systemic lupus erythematosus - - Discontinued (I) Japan IV / Injection Chugai Pharmaceutical, Roche 27 Oct 2009
Systemic scleroderma - - Discontinued (III) Argentina, Belgium, Bulgaria, Canada, Croatia, Denmark, France, Germany, Greece, Hungary, Ireland, Italy, Japan, Lithuania, Mexico, Netherlands, Poland, Portugal, Puerto Rico, Romania, South Africa, Spain, Switzerland, USA, United Kingdom SC / Injection Roche 25 Jul 2019
Urogenital cancer - Combination therapy, Late-stage disease, Metastatic disease, Second-line therapy or greater Phase I/II South Korea, Spain IV / Infusion Roche 30 Apr 2019
Vasculitis Takayasu arteritis In adolescents, In adults, In children, In the elderly Registered Japan IV / Injection Chugai Pharmaceutical 25 Aug 2017
Vasculitis Takayasu arteritis - Phase III France SC / Injection Assistance Publique Hopitaux de Paris, Chugai Pharmaceutical 10 Jun 2014

Orphan Status

Indication Patient Segment Country Organisation Event Date
Drug hypersensitivity - USA Roche 30 Aug 2017
Giant lymph node hyperplasia - Japan Chugai Pharmaceutical 14 Mar 2008
Systemic scleroderma - Japan Chugai Pharmaceutical 17 Mar 2016
Vasculitis - Japan Chugai Pharmaceutical 01 Jun 2014

Commercial Information

Involved Organisations

Organisation Involvement Countries
Osaka University Originator Japan
Chugai Pharmaceutical Originator Japan
Osaka University Owner Japan
Chugai Pharmaceutical Owner Japan
JW Pharmaceutical Licensee South Korea
Roche Licensee World
University Hospital Tubingen Collaborator Germany
Hospital for Special Surgery Collaborator USA
University Hospital Inselspital Collaborator Switzerland
Gilead Sciences Collaborator USA
Charite - Universitatsmedizin Berlin Collaborator Germany
Keio University Collaborator Japan
University of Bern Collaborator Switzerland
Assistance Publique Hopitaux de Paris Collaborator France
University of Pittsburgh Collaborator USA
Biomedical Advanced Research and Development Authority Collaborator USA
University Hospital, Brest Collaborator

Brand Names

Brand Name Organisations Indications Countries
ACTPen Roche Giant cell arteritis, Juvenile rheumatoid arthritis, Rheumatoid arthritis USA
Actemra Roche, Chugai Pharmaceutical Rheumatoid arthritis, Giant lymph node hyperplasia, Juvenile rheumatoid arthritis, Giant cell arteritis Canada, Japan, USA, World
RoActemra Roche Rheumatoid arthritis, Giant cell arteritis European Union, Switzerland, USA

Credit Suisse Market Status

Indication Region Company Phase Expected Launch Year Probability of Success% Patent Expiry Year Expected Generic Entry Last Update
Rheumatoid Arthritis ex US Chugai, Roche Marketed 2009 100 2017 01 Jan 2022 02 Apr 2020
Rheumatoid Arthritis Japan Chugai, Roche Marketed 2005 100 2012 - 02 Apr 2020
Rheumatoid Arthritis US Chugai, Roche Marketed 2010 100 2019 01 Jan 2023 02 Apr 2020
Vasculitis ex Japan (50% US) Chugai, Roche Marketed 2017 100 2017 - 02 Apr 2020

Credit Suisse Financial Forecast

Indication Region 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 Last Update
Rheumatoid Arthritis ex US 774 884 970 979 1014 1014 912 821 739 665 02 Apr 2020
Rheumatoid Arthritis Japan 287 310 346 398 417 426 417 417 417 334 02 Apr 2020
Rheumatoid Arthritis US 654 771 850 930 1050 1150 1150 1350 1450 1600 02 Apr 2020
Vasculitis ex Japan (50% US) 0 0 50 150 300 450 550 650 650 520 02 Apr 2020
Total 1715 1965 2216 2457 2781 3040 3029 3238 3256 3119

Scientific Summary

  • Adverse Events Occasional: Anaphylaxis; Diarrhoea; Elevated liver enzymes; Gastrointestinal perforations; Headache; Hyperlipidaemia; Hypersensitivity; Hypertension; Infections; Nasopharyngitis; Nausea; Neutropenia; Respiratory tract infections; Thrombocytopenia
    Rare: Abscess; Osteomyelitis; Pleurisy; Sepsis; Septicaemia

Pharmacokinetics

In the phase Ib GALACTA trial, in previously untreated patients with chronic lymphocytic leukaemia (CLL) and comorbidities, tocilizumab (TCZ) exposure was lower on average than in rheumatoid arthritis patients of equivalent weight treated with the dose of 8 mg/kg (mean Cmax 154 verus 193µg/mL) [137] [138] .

In a long term safety and efficacy phase I study in 52 patients with juvenile rheumatoid arthritis, median Cmin was similar between BW groups and higher than with tocilizumab (TCZ) IV with median Cmin of 3.2 μg/mL for 10 mg/kg <30kg BW and 7.3 μg/mL for 8 mg/kg ≥30kg BW. Adequate exposure from SC doses was seen. Median Cmax was lower from SC than IV dosing. Cmax was 62.4 μg/mL and 29.7 μg/mL in the <30kg BW and ≥30kg BW groups, respectively. AUC12 weeks was 2998 μg/mL and 1933 μg/mL in the <30kg BW and ≥30kg BW groups, respectively [253] [202] .

In an open-label dose-escalation study in patients with rheumatoid arthritis who received tocilizumab up to 162mg QW, Cmax and AUC was 4.9 µg/mL and 444 µg hr/mL at 81mg, and 10.9 µg/mL and 2300 µg hr/mL at 162mg after 1st administration [257] .

Results of an open-label phase I NP25737 trial in patients (n = 11) less than 2 years old with active systemic juvenile idiopathic arthritis (sJIA) demonstrated that serum tocilizumab concentrations, estimated using population pharmacokinetics analysis, peaked immediately after infusion, median (range) maximum concentration was 282 (195-347) μg/mL, steady state reached by week 12, and median trough concentration was 34.3 μg/mL (range 19.2-59.7 μg/mL). Peak and trough exposures were within the exposure range in older children (244 [109-382] to 54.3 [10.9-117] μg/mL) [134] [135] .

Treatment with tocilizumab demonstrated similar median steady state Cmin for patients <30 kg body weight (BW) receiving tocilizumab 162 mg every two weeks and those ≥30 kg BW receiving tocilizumab 162 mg once a week in a phase I trial. Ninety five percent (49/51) of patients treated with tocilizumab subcutaneous had steady state Cmin higher than the 5th percentile achieved with tocilizumab intravenous. Median and range of AUC2weeks were similar for both weight groups. Median Ctrough between both body weight groups (<30 kg and ≥30 kg) was similar, and higher Ctrough compared with tocilizumab intravenous in both BW categories. Cmax and AUC12weeks were higher in the <30 kg BW than the ≥30 kg BW tocilizumab subcutaneous group. Consistent with subcutaneous vs intravenous administration, median Cmax from SC dosing was lower than with IV dosing in both BW groups. The results were reported from 52 systemic Juvenile Idiopathic Arthritis patients aged between 1 to 17 years enrolled in a open-label phase I trial [206] [204] [205] .

Three year results from the phase III GiACTA trial demonstrated that treatment with Tocilizumab (TCZ) during the first 4 weeks of dosing, TCZ C trough levels were comparable in the TCZ break group and the part 1 prednisone taper (TCZ- QW) group and part 2 [240] [238]

Adverse Events

Rheumatoid arthritis

Post-marketing analyses

no new safety issues were observed in a 3-year postmarketing study toclizumab in 5573 Japanese patients with rheumatoid arthritis. The incidence of fatal events, malignancies, cardiac dysfunction, gastrointestinal perforation, and serious infections did not increase over time [23] .

The overall incidence of adverse reactions to tocilizumab was 37.9% in an interim analysis of a Japanese postmarketing surveillance study in 3881 patients with moderate to severe rheumatoid arthritis; of these events, 8.0% were reported as serious. The most frequently observed adverse events overall were abnormal laboratory test results and infections, and the most frequently occurring serious events were infections, including pneumonia. The safety profile of tocilizumab was similar to that observed in clinical trials [24] .

Pooled analyses

over an average treatment duration of more than 3.5 years, tocilizumab was not associated with any new safety signals, and the overall safety profile was consistent with prior experience. The most common serious adverse events were infections (4.6 per 100 patient years). These results were from a pooled analysis of safety data from five pivotal phase III trials (LITHE, OPTION, AMBITION,TOWARD, RADIATE) and two long-term extension studies (GROWTH95 and GROWTH96) [82] [268] .

A pooled analysis of the phase III OPTION and TOWARD trials demonstrated tocilizumab (8 mg/kg) in combination with disease-modifying anti-rheumatic drugs (DMARDs) was safe and well-tolerated in patients with moderate-to-severe rheumatoid arthritis. The analysis included 1 008 patients who were treated with an intravenous infusion of tocilizumab every four weeks plus DMARDs administered weekly, and 618 control patients. The proportion of patients experiencing at least one adverse event was 72.1% and 61.8%, at least one serious adverse event were 6.6% and 4.9% and those experiencing a serious infection were 2.8% and 1.6%, in the tocilizumab and control groups respectively. The rate of infections per 100 patients was 116.6 for tocilizumab and 95.5 for control. The most common adverse events (tocilizumab vs control) were upper respiratory tract infections (8.3% vs 6.6%), headache (5.4% vs 4.0%), hypertension (4.8% vs 3.2%), rash (3.2% vs 1.1%) and pruritus (1.8% vs 0.6%). Increases from <200 mg/dL fasting total cholesterol at baseline to ≥240 mg/dL were seen in 5.6% of tocilizumab and 1.0% of control patients. Non-haematological neoplasms occurred in 0.1% and 0.3% of the tocilizumab and control groups respectively. Withdrawals due to adverse events were 4.4% and 2.1% of patients for tocilizumab and control respectively. A sub analysis of these studies which grouped patients according to age (<65 years vs ≥65 years) showed tocilizumab to be safe and well-tolerated regardless of patient age [277] [278] .

According to pooled clinical trial data, the serious adverse events associated with tocilizumab were serious infections, gastrointestinal perforations and hypersensitivity, including anaphylaxis [275] .

Combined analysis of three clinical studies (two phase III and one phase II) indicated that tocilizumab was well tolerated by among patients with rheumatoid arthritis. The most commonly reported adverse events were infections (i.e. primarily aggravated rheumatoid arthritis infections), anaphylaxis and allergic hypersensitivity. Recipients also had transiently mild elevations in lipid and liver function tests that returned to near-baseline within 8 weeks of the last tocilizumab infusion [290] .

In two studies (BP19461 and WP18633) it was shown that absolute neutrophil counts decreased to their lowest point 3 to 5 days following administration with tocilizumab (2-28 mg/kg) in healthy subjects. After this time, neutrophils recovered towards baseline dose-dependently. Patients with rheumatoid arthritis showed a similar pattern following administration of tocilizumab [261] .

Rates of gastrointestinal perforations that occurred in patients with rheumatoid arthritis who were receiving tocilizumab were analysed using the tocilizumab worldwide RA clinical trials database. Results of the analysis showed that most patients who experienced gastrointestinal perforation were also receiving corticosteroids, NSAIDS, and methotrexate [262] .

Phase IV

tocilizumab and adalimumab were associated with similar rates of adverse events in the multinational, phase IV, head-to-head, randomised, double-blind ADACTA trial conducted in 326 patients with moderate to severely active rheumatoid arthritis. The most commonly reported adverse events included upper respiratory tract infections and nasopharyngitis. Included patients had intolerance to methotrexate or were deemed inappropriate candidates for continued methotrexate therapy. Patients had not previously received biologic therapies [27] [49] [50] .

Phase III

in the phase III ACT-STAR study in 883 patients with moderate to severe RA who had exhibited inadequate clinical response on their current non-biologic or biologic DMARDs, rates of serious adverse events (SAEs) were comparable among patients on monotherapy (5.8%), tocilizumab 4 mg/kg plus a DMARD (8%), or tocilizumab 8 mg/kg plus a DMARD (8.4%). The most common SAEs were serious infections in patients who received monotherapy (2.9%), tocilizumab 4/8 mg/kg plus a DMARD (3.6%), and 8 mg/kg of tocilizumab plus a DMARD (3.9%). A subset analysis of 552 patients with moderate to severe RA who exhibited inadequate clinical response to at least one tumour necrosis factor (TNF) blocker showed the rate of SAEs among patients taking a concomitant DMARD were comparable (7.4% in the 4 mg/kg group and 7.9% in the 8 mg/kg group), but lower in those taking tocilizumab alone (4.6%) [82] .

Of 1681 evaluable patients with RA who received tocilizumab alone or in combination, 12.8% withdrew from the phase III ACT-SURE study; 4.8% because of safety-related reasons, with infection the primary reason for withdrawal (1.1% of patients). Patients were inadequate responders to prior DMARD therapy, anti-TNF therapy or recently switched from anti-TNF therapy. In the DMARD-inadequate responders, adverse events, serious adverse events and serious infections were slightly lower than patients who had prior anti-TNF therapy. Tocilizumab 8 mg/kg was intravenously administered alone or in combination with DMARDs q4w, for 24 weeks [57] .

Tocilizumab monotherapy had similar adverse event profile as that of tocilizumab plus methotrexate in patients with moderate to severe RA in the phase IIIb ACT-RAY study (NCT00810199). Rates of events per 100 patient years in the mono versus combination therapy were: adverse events 467 versus 491; serious adverse events 18 versus 21; serious infections 6 versus 6 [82] [112] .

The most common adverse events were nausea, headache, nasopharyngitis, diarrhoea, and upper respiratory tract infection in the phase III RADIATE trial in 499 patients with moderate-to-severe rheumatoid arthritis. Adverse events occurred in 84%, 87%, and 81% in the tocilizumab 8mg/kg, tocilizumab 4mg/kg, and control groups, respectively. Serious adverse events occurred in 6%, 7%, and 11%, respectively. Serious infections occurred in 5%, 2%, and 3%, respectively [274] [73] [78] .

In the phase III TOWARD trial in 1216 patients with rheumatoid arthritis, the most common adverse events were upper respiratory tract infections, headache, nasopharyngitis and hypertension. Serious infections were reported in some patients [285] .

Tocilizumab was well tolerated by patients with moderate to severe RA in the phase III LITHE study. In this randomised trial, 1190 patients (ITT population) received either tocilizumab (4 mg/kg or 8 mg/kg, one infusion every four weeks for 1 year) in combination with methotrexate (weekly) or placebo infusions every four weeks plus methotrexate weekly. The most common adverse events were serious infections, malignancies and solid cancers [66] [270] [269] [273] [283] [284] .

In a multicentre study, 164 patients aged ≥ 20 years with rheumatoid arthritis were randomised to receive IV tocilizumab 4 mg/kg (n = 55) or 8 mg/kg (55), or placebo, every 4 weeks for 3 months. Adverse events occurred in 51%, 59% and 56% of high-dose tocilizumab, low-dose tocilizumab and placebo recipients, respectively [306] .

In an open-label extension of a double-blind trial, 142 patients with rheumatoid arthritis received intravenous tocilizumab 8 mg/kg/dose, every 4 weeks, for a median period of 17 months (21 months maximum). In the double-blind phase, patients had received placebo or tocilizumab 4 or 8 mg/kg/dose for 3 months. Tocilizumab was generally well tolerated with long-term treatment; 11% of patients withdrew due to adverse events. Cholesterol levels increased from 185 mg/dL at baseline to 225 mg/dL at 12 months; however, no cardiovascular events occurred [309] .

In a randomised, double-blind, parallel-group study (the CHARISMA study), 359 patients with active rheumatoid arthritis received either methotrexate alone, tocilizumab alone, or tocilizumab plus methotrexate for 16 weeks. The dose of methotrexate was 10-25 mg/week. Tocilizumab was administered as 2, 4 or 8 mg/kg by IV-infusion once every 4 weeks. Tocilizumab was generally well-tolerated. 33 patients withdrew from the study because of adverse events. Serious treatment-related adverse events in tocilizumab recipients were: foot abscess (1), osteomyelitis (1), chest infection (1), pleurisy (1), septicaemia (1), sepsis (1) and joint infection (1). There were five cases of hypersensitivity at low doses of tocilizumab. Tocilizumab increased levels of alanine aminotransferase, aspartate aminotransferase, total cholesterol, high-density lipoprotein cholesterol and triglycerides; the Atherogenic index did not change [299] .

Results from a 52-week phase III trial conducted in 302 patients with rheumatoid arthritis demonstrated overall incidences of adverse events (including laboratory abnormalities) of 96% and 87% in patients treated with tocilizumab (8 mg/kg, every 4 weeks) or conventional DMARDs, respectively. No tuberculosis was observed [292] .

Results from a phase III trial in 125 patients with rheumatoid arthritis who had inadequate response to methotrexate treatment showed that the incidence of adverse events was 91.8% and 71.9% for tocilizumab (8 mg/kg every 4 weeks for 24 weeks) and methotrexate, respectively. There were 4 cases of serious adverse events in the tocilizumab group and 3 cases in the methotrexate group [291] [85] .

In the OPTION trial in 623 patients with moderate-to-severe rheumatoid arthritis, the adverse events profile was similar between tocilizumab 8mg/kg, tocilizumab 4mg/kg, and methotrexate only. Serious infections were reported by 6 patients in the 8mg/kg group, 3 patients in the 4mg/kg group, and 2 patients in the methotrexate group [288] .

In the AMBITION trial, the most common adverse events in patients receiving tocilizumab were upper respiratory tract infections, headache, gastrointestinal disorders and nasopharyngitis. The incidence of AEs was similar; 80% and 78% in the tocilizumab and methotrexate groups respectively. Serious AEs and serious infections were higher in the tocilizumab group compared to methotrexate; 4% and 3% vs 1.4% and 0.7% respectively. ALT increased from normal at baseline to >3 times the upper limit of normal in 4% and 2% of patients in the methotrexate and tocilizumab groups respectively. Total cholesterol increased from <200 to ≥240mg/dL in 13% and <1% of patients in the tocilizumab and methotrexate groups respectively. No grade 4 neutropenia occurred [271] [72] [74] [64] .

Phase II

Results from a phase II trial of 359 patients with rheumatoid arthritis showed that tocilizumab was generally well tolerated in patients with rheumatoid arthritis. Serious treatment-related adverse events included infections (n = 5), hypersensitivity (5), foot abscess (1), osteomyelitis (1), chest infection (1), pleurisy (1), septicaemia (1), sepsis (1), and joint infection (1) [299] .

Forty five patients with clinically active rheumatoid arthritis were randomised to receive a single dose of IV tocilizumab 0.1 mg/kg (n = 9), 1 mg/kg (9), 5 mg/kg (9) or 10 mg/kg (7), or placebo. There were no significant differences in the incidence or type of adverse events between the tocilizumab groups and the placebo group, according to the researchers. Specific antibodies against tocilizumab were not detected in any of the patients who received active treatment [300] .

In an open-label trial, 15 patients with active rheumatoid arthritis received IV tocilizumab at 2 mg/kg/dose (n = 5), at 4 mg/kg/dose (5), or at 8 mg/kg/dose, once every two-weeks for 24 weeks. Some of the researchers were affiliated with Chugai Pharmaceutical, which provided financial support for the study. Tocilizumab was generally well tolerated, although increased blood cholesterol levels were observed in 10/15 (67%) patients. None of the fifteen patients developed antinuclear, anti-DNA or anti-tocilizumab antibodies [302] [297] .

Rheumatoid arthritis - SC formulation

Phase III

Interim results from a phase III registrational trial demonstrated that subcutaneously injected tocilizumab (162 mg Q2W) and intravenously infused tocilizumab (8 mg/kg Q4W), administered over 24 weeks, had similar clinical safety profiles [167] .

The safety profile of subcutaneously administered tocilizumab administered every week (TCZ-SC qw) was comparable to that administered every two weeks (TCZ-SC q2w) in a phase III trial in 43 patients with rheumatoid arthritis. Adverse events were experienced by 71.4% and 66.7% of patients in the TCZ-SC qw and TCZ-SC q2w groups, respectively. One patient in each group experienced ≥ 1 serious adverse event. There was 1 death in the TCZ-SC qw group [170] [171] .

In the phase III TOSCA trial, subcutaneous tocilizumab, at 162 mg, at 24weeks, demonstrated a comparable safety profile as a montherapy and in combination with methotrexate, in patients with rheumatoid arthritis who had previous inadequate responses to DMARDs and/or biologic therapy. 27.9% of patients receiving > 5 mg corticosteroids at baseline decreased the daily dose ≤ 5 mg/d/eq.pred. (30.1% in mono TCZ and 26.7% in combo). Out of 16.5% who discontinued the trial, 13.0% did so for lack of efficacy and 52.1% for safety reasons. 95.7% of patients experienced at least one adverse event and 10.1% at least one serious AE and similar rates were observed between groups. Death of a patient, unrelated to the treatment, occurred following a septic shock after surgery for gastric volvulus. In the open-label trial, 139 patients were enrolled [176] [177] .

Phase I/II

Tocilizumab subcutaneous injection was well tolerated up to 162mg QW in an open-label dose escalation study, with no serious adverse events or injection site reactions reported [257] .

Rheumatoid arthritis - SC versus IV formulation

Phase III

A study conducted in Japan has demonstrated the clinical safety profile of SC tocilizumab was consistent with the safety profile of IV tocilizumab in patients with RA [303] .

Juvenile rheumatoid arthritis

Post-marketing analyses

An interim analysis of a Japanese postmarketing study (n = 106) showed that adverse events occurred in 41.7% of patients with polyarticular-course juvenile idiopathic arthritis (pJIA) after treatment with tocilizumab. Of the patients experiencing an adverse event, 10.7% were serious. The most frequently reported adverse event overall was infection [24] .

Results from the 12-week main evaluation period (MEP) and the optional extension period (OEP) (until 52 weeks from baseline or 2 years of age reached) of an open-label phase I (NP25737) trial of tocilizumab (TCZ) in patients (n = 11) less than 2 years old with active systemic juvenile idiopathic arthritis (sJIA) showed that during the OEP, long-term treatment with TCZ was well tolerated in sJIA patients aged <2 years without any additional safety signals were reported in the OEP. Of 11 pts enrolled in the MEP, 7 entered the OEP and received ≥1 dose of TCZ. Ten of eleven (90.9%) patients showed ≥1 AEs which were mild or moderate and unrelated to TCZ. The most common AEs reported were were upper respiratory tract infection (6/11; 54.5%) and neutropenia , hypersensitivity, neutropenia, viral upper respiratory tract infection, rash and vomiting (each 3/11; 27.3%). Number of patients who reported serious AEs were 5/11 (45.5%) of whom 2 during the OEP (transaminases increased, histiocytosis hematophagic), 3 during the MEP (3 hypersensitivity events), and 2 during safety follow-up of the MEP (sJIA flare, hand-foot-and-mouth disease). Number of patients who reported withdrawal due to AEs were 5/11 (45.5%) of whom during the OEP, one patient withdrew because of a serious AE related to increased transaminases; during the MEP, three patients withdrew because of serious hypersensitivity reactions to TCZ and one because of thrombocytopenia. Dose modification required due to AEs in 5/11 patients (1 in the MEP, 4 in the OEP) mostly because of infections, neutropenia, and elevated liver enzymes which were mild or moderate in intensity. There were not death reported post treatment with tocilizumab [136] [134] [135] .

Phase III

Infections were the most common adverse events over a treatment period of 40 weeks in the phase III CHERISH trial of tocilizumab in patients with polyarticular juvenile idiopathic arthritis. The trial enrolled patients aged 2-17 years with active disease for at least 6 months who had not responded to treatment with methotrexate. Tocilizumab was administered monthly at doses of 8 mg/kg (body weight ≥30kg) or 10 mg/kg (body weight <30kg). Decreases in white blood cell counts and platelet counts were also observed, plus elevations in ALT and AST liver enzymes [28] .

Tocilizumab was associated 4 serious adverse events in patients with systemic-onset juvenile idiopathic arthritis in the phase III TENDER trial (NCT00642460). These were angioedema and urticaria (1), varicella (1), and bacterial arthritis (1), all of which resolved without sequelae.The overall safety profile was consistent with previously reported data from other trials. Patients (n=108) were randomised to tocilizumab 8 or 12mg/kg (depending on weight), or placebo [131] [130] . At two years, in the intent-to-treat population, 47 serious adverse events were reported in 35 patients with systemic juvenile idiopathic arthritis; 15 of the events were considered at least remotely related to tocilizumab. In total 22 serious infections were reported in 20 patients; 8 infections were considered related to tocilizumab and all but 1 fatal streptococcus infection resolved [133] .

Subcutaneous administration of tocilizumab in a phase I trial was generally safe and well tolerated. Most patients reported had ≥1 adverse events (AE; n=50; 98%). Commonly reported adverse events were viral upper respiratory tract infection (25.5%), neutropenia (25.5%), and cough (23.5%). Nine serious adverse events were occurred in seven patients (13.7%; 19.3/100 PY); 5 were infections, all in the <30 kg group. Two deaths were occurred, both in the <30 kg group. Injection site reactions were occurred in 21 patients (41%); most were mild and none led to treatment interruption or withdrawal. The results were reported from 52 systemic Juvenile Idiopathic Arthritis patients aged between 1 to 17 years enrolled in a open-label phase I trial [206] [204] [205]

Crohn's disease

In a pilot study, 36 patients with active Crohn's disease were randomised into 1 of 3 treatment groups, in which each group received 6 IV infusions 2 weeks apart: tocilizumab 8 mg/kg alone or placebo, or alternate biweekly IV infusions of tocilizumab and placebo. The incidence of adverse events was similar in all treatment groups [295] .

Healthy volunteers

Results from a study in 121 healthy subjects who received either tocilizumab (10 mg/kg or 20 mg/kg), moxifloxacin (400mg), or placebo showed that there were no QT prolonging effects of clinical concern by tocilizumab [263] .

Giant cell arteritis

Results from the phase III GiACTA study demonstrate that tocilizumab had a generally well tolerated adverse events (AEs) profile and the safety profile of the tocilizumab groups was generally consistent with the documented safety profile of tocilizumab in other indications. Incidence of AEs was similar in the 4 treatment arms. No deaths or new vision loss incidents were reported over the period of observation. Fewer patients reported serious adverse events in the tocilizumab weekly (15%) and biweekly groups (14.3%) than in the placebo combined with a 26-week steroid taper regimen (22%) and placebo combined with a 52-week steroid taper regimen groups (25.5%). The data was obtained from 251 patients randomised 1:1:2:1 to four groups: a, short-course prednisone (26-week prednisone taper + weekly subcutaneous [SC] placebo); B, long-course prednisone (52-week prednisone taper + weekly SC placebo); C, weekly SC TCZ 162 mg + 26-week prednisone taper; D, every other week SC TCZ 162 mg + 26-week prednisone taper [233] [256] [238] . Updated results from part-2 study showed rates of serious adverse events per 100 patient-years over 3 years (double-blind period + part 2) were comparable for patients who never received tocilizumab (23.2) and who received ≥ 1 dose of tocilizumab (25.4), and rates of serious infections were 4.6 and 3.5 per 100 patient-years, respectively. No new safety signals were observed with tocilizumab exposure in glucocorticoid patients during the three-year study. Results were reported from 215 of 250 patients enrolled in the study [237] .

Vasculitis (Takayasu Arteritis):

In a phase III study of tocilizumab in takayasu arteritis, adverse events were reported in 77.8% tocilizumab-treated and 61.1% placebo-treated patients respectively. No fatalities were observed in the study, but serious AEs were observed in 1 and 2 patients in tocilizumab and placebo groups respectively [255] [221] .

Systemic scleroderma:

In the phase II/III faSScinate study it was observed that rates of serious adverse events (95% CI) per 100 patient-years (PY) were 76.1 (50.6, 110.0) in placebo patients and 66.7 (42.3, 100.1) in tocilizumab patients and were 36.0 (18.0, 64.4) in placebo-to-tocilizumab converted patients and 16.5 (5.4, 38.5) in patients continuing on tocilizumab in the OL period. Rates (95% CI)/100PY of serious infections in the double-blind period were 10.9 (3.0, 27.9) in placebo patients and 34.8 (18.0, 60.8) in tocilizumab patients. In the open-label phase, they were 19.6 (7.2, 42.7) in placebo-to-tocilizumab patients and 0.0 (0.0, 12.2) in tocilizumab patients. No deaths were observed in the open-label phase of the study, whereas 4 deaths had occurred in the double-blind phase, out of which 3 were in tocilizumab and 1 in placebo-treated patients [217] [216] .

Safety results were consistent with Cx of systemic sclerosis and the established tocilizumab (TCZ) safety profile; SAEs were reported by 17% of placebo patients and 13% of TCZ patients; serious infections were reported by 7% and 2% of patients, respectively [214] [215] .

Rheumatoid arthritis

In the priliminary data from the phase III trial comparing the tocilizumab monotherapy against combination therapy demonstrated a consistent safety profile with no new safety signals observed. The most common SAE was infection, occurring in 4.1% of patients. Tocilizuamb combination therapy had greater frequency of AEs, SAEs and serious infections than monotherapy arm [308] [182] .

In a phase Ib trial, subcutaneous tocilizumab was found to be safe, and the safety profile was consistent with subcutaneous tocilizumab IV, except for the occurrence of injection site reactions (ASRs) and neutropenia. During the study, a higher frequency of ISRs (28.8%) was observed in patients with polyarticular juvenile idiopathic arthritis, compared to that of patients treated with tocilizumab SC for approved indications. The ISRs were mild in severity and patient(s) did not withdrew from the study due to ISRs. A decrease in neutrophil count of below 1 × 109 per L was observed in 15.4% patients, and the event was more frequent in patients less than 30 kg (25.9%) compared to patients at or above 30 kg (4.0%). The open-label trial enrolled 52 patients [199] [203] .

Pulmonary arterial hypertension

Phase II:

Treatment with intravenously administered tocilizumab was generally well tolerated in patients (n=29) with pulmonary arterial hypertension, in the TRANSFORM-UK phase II trial. Six patients were withdrawn prior to drug administration; one chest infection, one exacerbation of co-morbid disease, 4 at baseline right heart catheterisation. Tocilizumab was discontinued in four patients due to serious adverse events, including urosepsis, clinical worsening, chest pain and peripheral arterial embolus. Vomiting occurred in one patient and was classified as a suspected unexpected serious adverse reaction. No deaths were reported from the trial [223] [222] .

Juvenile rheumatoid arthritis:

Results from an ongoing three-year, long-term extension (LTE) of two 52-week, open-label studies in patients with systemic juvenile idiopathic arthritis (sJIA) and polyarticular juvenile idiopathic arthritis (pJIA), showed that tocilizumab had an acceptable tolerability profile with no new safety concerns. Most of the adverse events (AEs) were grade 1 or 2. Grade ≥3 AEs were reported by 10/44 (20.8%) pJIA and 4/38 (10.5%) sJIA patients. The most commonly reported AE was nasopharyngitis in both pJIA (17/44 [38.6%]) and sJIA (11/38 [28.9%]). Other AEs reported in ≥15% of the patients included arthralgia, vomiting, diarrhoea, gastroenteritis, cough, pyrexia, headache, and oropharyngeal pain in pJIA, and upper respiratory tract infection, pyrexia, arthralgia cough and rash in sJIA patients. There were no opportunistic infections and AESIs were consistent with the 52-week data. In six pJIA patients (13.6%) and seven sJIA patients (18.4%), neutropenia AEs were reported. In pJIA patient population, 5/44 (11.4%) experienced SAEs (furuncle, pneumonia, appendicitis, eye pain/headache, infectious mononucleosis). However, out of these, only pneumonia was considered treatment related. Of sJIA pts, 2/38 (5.3%) experienced SAEs (pneumonia, craniocerebral injury from a fall) but neither of these was considered treatment related. Neutralizing anti-TCZ antibodies were observed in two pJIA patients (4.7%) and none of the sJIA patients. There were no deaths reported. Results were reported from (n = 44) pJIA and (n = 38) sJIA patients [121] [122] [202] .

Chronic lymphocytic leukaemia

In the phase Ib GALACTA trial, in previously untreated patients (pts) with chronic lymphocytic leukemia (CLL) and comorbidities, infusion-related reactions occurred in 72% patients in the tocilizumab (TCZ) arm and in 77% patients from the placebo (PLB) arm. Grade ≥3 IRRs were experienced by 44% patients in the TCZ arm and 31% patients in the PLB arm. Three patients in the TCZ arm and one patient in the PLB arm discontinued treatment due to IRRs. Of the 19 patients with measurable TCZ levels, no marked differences in exposure were seen based on IRR intensity. Use of a single 8 mg/kg dose of TCZ prior to the first dose of obinutuzumab was feasible, but did not prevent IRRs in this patient population [137] [138] .

Pharmacodynamics

Summary

HPM-1 inhibited the proliferation of exogenously stimulated T cells as well as production of IgG indicating that hPM-1 binds to and blocks cynomolgus monkey IL-6 receptors [304] . hPM-1 exhibited antitumour activity in human myeloma mouse xenografts with similar efficacy to that of the original mouse monoclonal antibody used against human IL-6 receptors [307] .

Purified lamina propria cells from patients with Crohn's disease (CD) and/or patients with ulcerative colitis produced greater levels of interleukin (IL)-6 and the soluble IL-6 receptor (sIL-6R) than cells from controls. This led to activation of a pathway resulting in induction of anti-apoptotic genes. Treatment of CD4+ T cells with tocilizumab resulted in the cells undergoing apoptosis. In mice, tocilizumab showed beneficial effects in murine models of chronic intestinal inflammation. Tocilizumab suppressed colitis activity in T-cell reconstituted severe combined immunodeficient (SCID) mice and significantly reduced colonic inflammation in mice with colitis due to IL-10 deficiency and mice with trinitrobenzene sulfonic acid-induced colitis. Further studies in mice showed that blockade of the IL-6 signalling pathway also induced apoptosis in lamina propria CD4+ T cells in vivo. The researchers concluded that "specific targeting of IL-6 signaling pathway may be a new way to treat CD and may provide a new approach for the treatment of other autoimmune diseases, such as rheumatoid arthritis, that are accompanied by increased production of IL-6" [301] .

In an open-label dose-escalation study in patients with rheumatoid arthritis who received tocilizumab up to 162mg QW, CRP decreased after single dose within first week for all three dose groups. However, baseline levels returned for patients in the 81mg Q2W dose group from Week 2, 3, 5, 7 and 9, just before the injection. Mean CRP decreased slowly following the switch to 81mg QW at week 9. At 162 mg Q2W, CRP returned to baseline at the end of week 3. Mean CRP decreased progressively beyond ULN and remained over the period of this study following repeated administration. In the 162mg QW group, the CRP decreased below ULN at the end of Week 1 and was maintained [257] .

Following administration of tocilizumab 8 mg/kg, serum IL-6 levels were increased from baseline at day 3. However, following this initial increase, serum IL-6 levels gradually decreased with repeated tocilizumab treatment. Serum soluble IL-6R (sIL-6R) levels also significantly increased following tocilizumab administration at 14 days. Through gel filtration chromatography, it was shown that over 95% of the increased sIL-6R existed as an immune complex with tocilizumab. Inflammation markers such as CRP were normalised when free tocilizumab was detected in the serum. This phase I/II study examined serum levels of IL-6 after multiple infusions of tocilizumab in patients with rheumatoid arthritis [293] .

Toclizumab inhibited joint space narrowing and the increased expression of cartilage matrix-degrading enzymes and oxidative stress in a murine model of cartilage degradation in arthritis [23] .

Results of an open-label phase I NP25737 trial of tocilizumab in patients (n = 11) less than 2 years old with active systemic juvenile idiopathic arthritis (sJIA) observed that the mean±SD soluble IL-6 receptor levels were 47.65±16.40 ng/mL at baseline and 927.83±148.07 ng/mL at day 71. CRP levels were 250.81±425.11 mg/L and 2.80±3.56 mg/L, respectively. ESR levels were 59.40±27.47 mm/h and 2.00±1.00 mm/h, respectively [134] [135] .

In a phase I trial, treatment with tocilizumab subcutaneous resulted in consistent changes in pharmacodynamic parameters for tocilizumab-naive patients with those previously observed for tocilizumab intravenous. Changes in interleukin-6, C-reactive protein, and erythrocyte sedimentation rate were similar for both weight groups. The results were reported from 52 systemic Juvenile Idiopathic Arthritis patients aged between 1 to 17 years enrolled in a open-label phase I trial [206] [204] [205]

Transcriptomic analysis of samples from patients of rheumatoid arthritis demonstrated that tocilizumab enabled the identification of eight transcripts (CLU, F13A1, ITGA2B, ITGB3, SELP, SNCA, SPARC, TREML1) whose relative abundances were significantly reduced at T3m and genes linked with the pro-inflammatory role of platelets were down regulated [252] [176] .

Three year results from the phase III GiACTA trial demonstrated that patients who experienced lare while on Tocilizumab (TCZ) had low levels of CRP and ESR. In part 2 of the trial, TCZ C trough and PD biomarkers after the first initial 4 doses were comparable at steady state to the values at the end of part 1. Patients who experienced lare while not receiving TCZ had higher levels of CRP and ESR compared to those who experienced lare on TCZ, where lares occurred despite low levels of these inflammatory markers [240] [238]

Therapeutic Trials

Tocilizumab treatment of 20mg in seven patients with giant lymph node hyperplasia caused an immediate alleviation of fever and malaise. C-reactive protein (CRP), fibrinogen and anaemia started to improve within 24 hours. Improvements were observed in CRP levels, fibrinogen, thrombocytosis and serum amyloid A protein within one month in most cases. Haemoglobin, albumin and immunoglobulin levels improved more gradually over a 3- to 4-month period. There were also dramatic improvements in lymphadenopathy in all patients. Patients who had amyloidosis and renal function abnormalities had improvements in serum creatinine and urine protein. Tomographical scans confirmed the disappearance of pathologically significant visceral lymph nodes in all patients. Histopathological analysis showed reduced follicular hyperplasia and vascularity after tocilizumab. The therapeutic effects of tocilizumab did not diminish even after continuous 11-month treatment. Termination of therapy resulted in recurrence of fever, malaise and anaemia within two weeks and treatment with prednisolone had no effect. Readministration of tocilizumab however was as effective as first treatment course [298] .

Cytokine release syndrome (drug hypersensitivity)

Retrospective analysis of pooled data from clinical trials of CART T cell therapies in paediatric and adult patients (n = 45) with life-threatening CRS demonstrated that tocilizumab, with or without high-dose corticosteroids, resolved CRS within 14 days in 31 patients (69%; 95% CI: 53%–82%) [141] .

Results from the phase III COMP-ACT trial in 296 randomised patients assessing patient related outcomes between patients with rheumatoid arthritis who achieved low disease activity with tocilizumab + methotrexate and then continued or discontinued methotrexate showed that The mean changes in patient global assessment of disease activity (PtGA), pain, Health Assessment Questionnaire Disability Index (HAQ-DI )and Functional Assessment of Chronic Illness Therapy (FACIT)-fatigue scores from Week 24 to Weeks 40 were similar between the TCZ + MTX and TCZ-MONO groups. The difference (95% CI) between TCZ-MONO and TCZ+MTX group for Week 24 to 52 for PtGA measure was 4.14 (-0.56, 8.84), pain was 4.69 (0.14, 9.24), HAQ-DI score was 0.01 (-0.08, 0.10) and FACIT-Fatigue score was -1.82 (-3.69, 0.06), respectively. The proportion of patients with HAQ-DI measure < 0.5, showing difference (95% CI) between both the groups was -5.4 (-16.7, 5.8) for Week 24, -3.2 (-15.0, 8.6) for Week 40 and -5.1 (-17.3, 7.0) for Week 52, respectively. Out of the 296 patients who achieved DAS28 ≤ 3.2 at week 24, 79 were enrolled in the MRI sub-study (41 with combination therapy and and 38 with monotherapy). Between TCZ+MTX and TCZ-MONO cohorts, the mean changes from week 24 to 40 in bone erosion, synovitis, osteitis and cartilage loss scores were not significantly different. Also, no significant differences were observed between the groups in the proportion of patients with no progression in each outcome measure (range, 89.7% to 97.4% with TCZ+MTX and 87.9% to 100.0% with TCZ-MONO) [183] [184] [182] .

Vasculitis (Takayasu arteritis):

In a phase III study of tocilizumab in patients with takayasu arteritis, it was observed that in the intention-to-treat (ITT) population, 8 tocilizumab-treated and 11 placebo-treated patients relapsed. Relapse-free at week 24 were estimated to be 50.6% and 22.9% respectively. There was no statistical difference between groups for time to first relapse with a hazard ratio of 0.41 [95.41% CI: 0.15, 1.10]; p = 0.0596. In the per-protocol population, for relapse criteria, the hazard ratio was 0.34 and p = 0.0345 [95.41% CI: 0.11, 1.00] in the favour of tocilizumab. Tocilizumab showed favourable trend in objective systemic symptoms, subjective systemic symptoms, elevated inflammation markers, vascular lesions, and ischaemic symptoms accompanied by organ lesions (ITT population) [255] [221] .

In a pilot study, 36 patients with active Crohn's disease were randomised into 1 of 3 treatment groups, in which each group received 6 IV infusions 2 weeks apart: tocilizumab 8 mg/kg alone or placebo, or alternate biweekly IV infusions of tocilizumab and placebo. At 12 weeks, the clinical response rate (defined as a reduction from baseline in Crohn's Disease Activity Index [CDAI] score of ≥ 70) was achieved by significantly more patients in the group that received only tocilizumab and by those who received tocilizumab plus placebo, compared with the placebo-only group (80% and 42% vs 31%, respectively). Corresponding rates of remission (CDAI score of < 150) were 20%, 25% and 0%, respectively [295] .

Rheumatoid arthritis

Post-marketing analyses

following once a month treatment with 8mg/kg toclizumab, the CDAI remission rate and HAQ-DI remission rate of biologics-naive patients with rheumatoid arthritis at one year were 36.8% and 65%, respectively. A total of 839 Japanese patients with RA were included in this post-marketing analyses [23] .

Tocilizumab therapy markedly improved the disease activity score-28 (DAS28) from a baseline level of 5.53 to 3.00 at week 28 in a postmarketing surveillance study in 2072 patients with moderate to severe rheumatoid arthritis (RA). The disease remission rate was 45.0% at week 28. These interim data were collected in patients who were enrolled between April 2008 and July 2009, in Japan [24] .

Pooled analyses

after 48 weeks of treatment, tocilizumab was associated with disease remission in more than one third of patients who had previously failed disease modifying antirheumatic drugs (regardless of prior treatment history or disease duration). This was the main finding from a pooled analysis of data from five pivotal phase III trials (LITHE, OPTION, AMBITION,TOWARD, RADIATE) and two long-term extension studies (GROWTH95 and GROWTH96) [268] .

In data from two long term extension studies (GROWTH95, GROWTH96), the percentage of patients treated with tocilizumab who achieved remission from rheumatoid arthritis increased from 27% after 2 years to 62% after 3.4 years [267] . In an analysis of patients in the GROWTH95, GROWTH96 and the open-label phase of LITHE, efficacy during long-term tocilizumab treatment was demonstrated by increasing numbers and/or proportions of patients achieving ACR50/70, LDA, and DAS28 remission until at least week 96, which were maintained in patients who reached week 192 (3.7 years) [258] .

A pooled analysis of the phase III OPTION and TOWARD trials demonstrated the efficacy of tocilizumab (8 mg/kg) in combination with disease-modifying anti-rheumatic drugs (DMARDs) in patients with moderate-to-severe rheumatoid arthritis. The analysis included 1 008 patients who were treated with an intravenous infusion of tocilizumab every four weeks plus DMARDs administered weekly, and 617 control patients. At week 24, ACR20, ACR50 and ACR70 response rates were 60.3, 38.9 and 20.8% in patients on tocilizumab, compared with 25.1, 9.6 and 2.6%, respectively, in the control group (all p < 0.0001). The individual ACR score parameters significantly improved from baseline to week 24 in patients on tocilizumab compared with patients on control. A significantly greater reduction in disease activity score-28 (DAS28) was observed in patients receiving tocilizumab compared with control (3.30 vs 1.35) at week 24 and DAS28 remission was seen in 29.7% of the tocilizumab group compared with 2.7% for the control. Tocilizumab also demonstrated an early onset of response with 7.1% of patients showing DAS28 remission at week four vs 0.7% for the control group. Good to moderate EULAR response was achieved by week two in 64.1% of patients on tocilizumab vs 17.2% for the control group; by week 24 the respective proportions of patients was 79.7% and 36.6%. A sub analysis of these studies which grouped patients according to age (<65 years vs ≥65 years) showed tocilizumab to be effective in the treatment of rheumatoid arthritis regardless of patient age [278] [276] [280] .

A combined analysis of three clinical studies (two phase III and one phase II) indicated that tocilizumab was associated with consistently improved remission rates among patients with rheumatoid arthritis compared with conventional methotrexate or placebo. In a 52-week phase III study (n = 302), ACR70 and ACR20 responses were achieved by 43.3% and 89.2% tocilizumab (8 mg/kg) recipients versus corresponding values of 5.5% and 35.2% for methotrexate recipients; DAS28 (Disease Activity Score) remission was achieved in 58.6% of tocilizumab recipients compared with 3.4% of those on methotrexate. Similarly in a second phase III trial (n = 125), the percentage of patients treated with tocilizumab (8 mg/kg) versus methotrexate who achieved ACR70 and ACR20 responses at 24 weeks were 27.9% versus 4.7% and 80.3% versus 25.0%, respectively; DAS28 remission was attained in 41% versus 1.6% of tocilizumab versus methotrexate recipients. In a phase II study (n = 163) that compared tocilizumab with placebo for 12 weeks, 16.4% and 18.2% of tocilizumab (8 mg/kg) recipients achieved ACR70 and DAS28, respectively; conversely, no patients achieved ACR70 or DAS28 in the control group [290] .

Post-hoc analysis using data from patients who took part in 4 phase III clinical trials and who had previous inadequate responses to DMARDs or TNF-α inhibitors showed that some patients required >12 weeks of treatment with tocilizumab before clinical benefit was achieved. A post-hoc analysis of the phase III AMBITION trial showed similar results. For example, 40% of patients (who were ACR20 non-responders at week 12) achieved ACR20 at week 24 [265] [264] .

Phase IV

DAS28 scores were reduced from baseline to a greater extent with tocilizumab than with adalimumab at 24 weeks (primary endpoint) in the multinational, phase IV, head-to-head, randomised, double-blind ADACTA trial conducted in 326 patients with moderate to severely active rheumatoid arthritis (DAS28 score reduction of 3.3 vs 1.8, respectively; p<0.0001). Tocilizumab was also associated with better ratings on ACR20, 50 and 702 responses (65%, 47% and 33% vs 49%, 28% and 18%, respectively) as well as DAS28 remission (40% vs 11%, respectively; p<0.0001) and low disease activity. The observed differences were all statistically significant. Included patients had intolerance to methotrexate or were deemed inappropriate candidates for continued methotrexate therapy. Patients had not previously received biologic therapies [48] [49] [50] .

Phase III

in the FUNCTION phase III trial, data showed that tocilizumab 8 mg/kg, with or without methotrexate, was superior to methotrexate alone in achieving disease remission at week 24, as measured by DAS28<2.6. Treatment with tocilizumab plus methotrexate also resulted in statistically significant improvements in the signs and symptoms of RA and physical function, and a reduction in structural joint damage at 52 weeks (secondary endpoints). Tocilizumab alone demonstrated superiority to methotrexate alone in achieving disease remission at week 24; statistical significance was not met, but clinically meaningful improvements were noted in RA signs and symptoms at week 24 and structural joint damage inhibition to week 52. The trial enrolled patients with early rheumatoid arthritis who had not previously received methotrexate [65] .

In the phase III ACT-STAR study in 883 patients with moderate to severe RA who had exhibited inadequate clinical response on their current non-biologic or biologic DMARDs, efficacy rates, measured by a DAS28 score of less than 2.6, were similar between those who received monotherapy (15.7%), tocilizumab 4/8 mg/kg (17.6%), and tocilizumab 8 mg/kg (22.8%) [82] .

In preliminary results of the ACT-SURE phase IIIb trial (n = 1697), tocilizumab as monotherapy or in combination with DMARDs was effective for the treatment of patients with RA who had prior inadequate response to DMARD and/or anti-TNF therapy, or patients who switched to tocilizumab without anti-TNF treatment washout (NCT00750880). Disease activity score 28 (DAS28) remission occurred in 24%-38%, and 49%-62% of patients at week-8 and -24, respectively. At week 24, DAS28 values were 2.34 in DMARD-inadequate response patients, 2.83 in previous anti-TNF users and 2.76 in recent anti-TNF users. DAS28 remission was achieved in 49.8% of tocilizumab monotherapy recipients; respective ACR20/50/70 responses at 24 weeks were 66.9%, 43.5% and 23.8%. Patients were treated with IV tocilizumab (8 mg/kg) q4w alone, or in combination with DMARDs, for 24 weeks [57] .

Tocilizumab monotherapy was as effective as tocilizumab plus methotrexate in patients with moderate to severe RA in the phase IIIb ACT-RAY study (NCT00810199). At week 24, DAS28<2.6 remission rate was 35% and 40% in the mono- and combination therapies, respectively (primary endpoint). This trial enrolled 556 biologic-naïve patients with inadequate response to methotrexate [82] [112] .

Long-term efficacy data (up to 3.5 yrs) in 3986 patients (from several phase III trials) showed that tocilizumab was efficacious in patients with rheumatoid arthritis. In patients who were inadequate responders to DMARDs, increased numbers of patients achieved ACR50 and ACR70 up to weeks 72 and 96, respectively and also achieved maintenance of ACR70 for 24 consecutive weeks. The proportions of patients who achieved outcomes increased further, or were maintained, with continued tocilizumab treatment up to week 180. In patients who were inadequate responders to anti-TNF, proportions of patients who achieved outcomes increased or were maintained with continued tocilizumab treatment [266] .

Three-year data the phase III LITHE study demonstrated that a significantly higher percentage of patients experienced no radiographic progression of joint damage following treatment with tocilizumab (8 mg/kg and 4 mg/kg) plus methotrexate compared with methotrexate alone (67, 69% vs 51% of patients). A greater proportion of patients experienced remission (DAS28 score<2.6) following three years tocilizumab (8 mg/kg) treatment compared with two years of treatment (57% vs 54% of patients). At three years, compared with methotrexate, tocilizumab (4 or 8 mg/kg) + methotrexate significantly improved physical function (assessed using the change from baseline in the mean area under the Health Assessment Questionnaire Disability Index) by 37%, compared with 34% at two years. The LITHE study recruited 1196 patients with moderate to severe RA who had an inadequate response to methotrexate [66] [268] [260] [34] [64] [269] [272] [283] [284] .

Tocilizumab monotherapy was superior to methotrexate and significantly reduced RA signs and symptoms compared with methotrexate in the AMBITION trial. Patients (n = 673) in this study were randomised to receive either tocilizumab 8 mg/kg, IV every four weeks plus placebo capsules weekly or placebo infusions every four weeks plus methotrexate weekly. In the tocilizumab arm, 70%, 44% and 28% of the patients achieved ACR20, ACR50 and ACR70, respectively, compared with 53%, 34% and 15% in the methotrexate arm. Disease remission was achieved by 34% of the patients in the tocilizumab group compared with 12% of patients treated with methotrexate. Additionally a higher proportion of the tocilizumab group achieved a significant EULAR response by the second week of the trial. The odds of achieving DAS28 remission were >5x higher and good/moderate EULAR response was >4x higher with tocilizumab compared with methotrexate [271] [271] [72] [73] [74] . Long-term extension (LTE) follow-up of the AMBITION trial showed high remission rates and improvements in disease activity lasting for up to 4.6 years. Upon entry to the LTE study, DMARDs including methotrexate, were added in 43% of patients (n=104) who did not achieve a 50% reduction in swollen joint count (SJC) and tender joint count (TJC) from baseline. Fifty-seven percent of patients (n=139) continued receiving tocilizumab alone. The number of patients achieving remission continued to increase or were maintained over time, and by week 240, 66.7% of patients achieved remission (as measured by DAS28<2.6). Disease activity, as measured by SJC and TJC continued to decline or was maintained up to week 240 (reduction from 19.0 SJC; 32.5 TJC at start of trial, to 1.8 SJC; 3.8 TJC at week 240) [65] .

Tocilizumab (8mg/kg q4w) in combination with traditional disease modifying drugs (DMARDs) improved rheumatoid arthritis signs and symptoms at week 24 in the phase III TOWARD trial when compared with DMARDs alone. ACR20, 50 and 70 scores were achieved by 60.8%, 37.6% and 20.5%, respectively, of patients treated with tocilizumab compared with 24.5%, 9.0% and 2.9%, respectively, of patients receiving placebo. Disease remission occurred in 30% of patients receiving tocilizumab compared with 3.4% of patients treated with placebo. This trial, conducted in 1216 patients with active, moderate to severe rheumatoid arthritis who had inadequate response to previous DMARD therapy, evaluated tocilizumab using the ACR score assessment method [285] [286] [76] [281] .

Tocilizumab significantly improved the signs and symptoms of rheumatoid arthritis (RA) compared with control, in patients with moderate to severe RA enrolled in the phase III OPTION trial. Patients treated with tocilizumab 4 mg/kg or 8 mg/kg every 4 weeks plus methotrexate or placebo weekly. Patients treated with tocilizumab 8 mg/kg plus methotrexate achieved significant improvements in ACR20, 50 and 70 scores at week 24 of 59%, 44% and 22%, respectively. Patients treated with tocilizumab 4 mg/kg plus methotrexate achieved improvements in ACR20, 50 and 70 scores at week 24 of 48%, 32% and 12%, respectively, while patients treated with methotrexate only achieved ACR70 and 50 scores of 2% and 11%, respectively. Reductions in DAS of 3.43 for the 8 mg/kg group, 2.68 for the 4mg/kg group and 1.55 for the methotrexate group were observed from week 2 onwards. Remission was achieved in 28% of patients in the 8mg/kg group, 14% of patients receiving tocilizumab 4 mg/kg and 1% of patients receiving methotrexate only. A good/moderate EULAR response was seen in 79.5% of patients receiving the higher dose of tocilizumab, 61.9% of patients receiving the 4mg/kg dose, and 34.8% of patients receiving methotrexate only. Improvements from baseline were noted in the 8mg/kg group, 4mg/kg group and methotrexate group in the Health Assessment Questionnaire score (-0.55 points, -0.52 points, and -0.34 points, respectively), the Functional Assessment of Chronic Illness Therapy-Fatigue scale ( 8.60 points, 7.29 points, and 4.01 points, respectively), the Short Form 36 Health Survey physical component (9.5 points, 9.7 points, and 5.0 points, respectively), and the Short Form 36 Health Survey mental component (7.3 points, 5.7 points, and 2.7 points, respectively). Patients receiving the higher dose of tocilizumab also showed a rapid normalisation of C-reactive protein (CRP) levels, lower fatigue scores, and improved haemoglobin levels [289] [288] [287] .

Of the 623 patients with rheumatoid arthritis enrolled in the OPTION trial, 416 patients with an inadequate response to methotrexate were included in a phase III 24-week randomised placebo-controlled study. Patients were randomised to receive an infusion of tocilizumab at 8mg/kg plus methotrexate, 4 mg/kg plus methotrexate, or placebo plus methotrexate (10-25mg weekly) every 4 weeks for 20 weeks with final follow-up at week 24. Serum biomarkers of bone formation (osteocalcin and type I collagen N-propeptide, PINP), bone resorption [cathepsin-K (CTX-I) and MMP (ICTP)-mediated type I collagen fragments], cartilage metabolism (type IIA collagen N-propeptide, PIIANP and type II collagen helical peptide, Helix-II) and matrix-metalloprotease-3 (MMP-3) were measured at baseline and after 4, 16 and 24 weeks. At week 24, for the evaluated biochemical marker subset, ACR20/50/70 responses were observed respectively in 64/47/23% of patients in the tocilizumab 8mg/kg group, 49/31/14% in the 4mg/kg group, and 26/9/3% in the control group. Tocilizumab combined with methotrexate induced an increase in bone formation markers which was significant compared with control at 4 weeks for PINP (p<0.01 for both doses). Tocilizumab plus methotrexate also induced a significant decrease in CTX-I and ICTP and a marked dose-dependent reduction of PIIANP, Helix-II and MMP-3. Patients receiving tocilizumab at 4 or 8 mg/kg with and ACR 50 response had a larger decrease in ICTP 9 (median: -18.5 versus -5.0%, p<0.01), Helix-II (-54.3 versus -38.9%, p<0.01) and MMP-3 (median: -63.0 versus -28.5%, p<0.001) than non-responders [279] .

In the phase III RADIATE trial, treatment with tocilizumab plus methotrexate resulted in significant clinical benefits compared with methotrexate monotherapy in patients who had failed to respond adequately to anti-TNF therapies alone. Patients (n = 499) in this placebo-controlled, double-blind study were randomised to receive tocilizumab 4 or 8 mg/kg, IV, plus methotrexate every four weeks or placebo infusions plus methotrexate weekly for 24 weeks. Of the patients treated with tocilizumab 8 mg/kg and methotrexate, 50%, 29% and 12% achieved ACR20, ACR50 and ACR70, respectively, compared with 10%, 4% and 1%, respectively, of patients treated with placebo + methotrexate. Additionally, significant clinical benefits were seen in the subgroup analysis of difficult-to-treat patients who had received up to three anti-TNF therapies that failed. Disease remission was seen in 30% of the patients treated with tocilizumab + methotrexate, compared with 1.6% of patients in the methotrexate only group. Withdrawal or the need for rescue therapy occurred in 25%, 34%, and 60% of patients treated with tocilizumab 8 mg/kg, tocilizumab 4 mg/kg, methotrexate alone (control group), respectively [274] [73] [78] [282] .

Results from a phase III trial conducted in Japan in 302 patients with rheumatoid arthritis demonstrated that there was statistically significant less radiographic joint destruction in patients who received tocilizumab (8 mg/kg, IV-infusion) every 4 weeks for 52 weeks, compared with the control group of patients (who received single or combination DMARDs). ACR response rates were also higher in patients who received tocilizumab compared with the control group [292] .

Results from a phase III trial in 125 patients in Japan with rheumatoid arthritis who had inadequate response to methotrexate treatment showed that tocilizumab (8 mg/kg every 4 weeks for 24 weeks) achieved statistically significantly higher response rates than methotrexate. ACR20, ACR50, and ACR70 response rates were 80.3, 49.2 and 29.5 for tocilizumab, compared with 25.0, 10.9, and 6.3 for methotrexate [291] [85] .

Phase II

there appeared to be a relationship between response to tocilizumab therapy and serum IL-6 levels in patients with rheumatoid arthritis. Serum IL-6 levels decreased significantly from baseline in patients who achieved an American College of Rheumatology 70% (ACR70) response criteria, but did not change in those who did not achieve an ACR70 response. Treatment response was sustained for up to 22 months after treatment withdrawal in five patients. This double-blind, parallel, phase II study randomised 109 patients with rheumatoid arthritis [294] .

In a multicentre study, 164 patients aged ≥ 20 years with rheumatoid arthritis were randomised to receive IV tocilizumab 4 mg/kg (n = 55) or 8 mg/kg (55), or placebo, every four weeks for three months. C-reactive protein levels were normalised in 76%, 26% and 1.9% of patients receiving high- and low-dose tocilizumab, and placebo, respectively. A significantly greater proportion of patients in the high-dose tocilizumab group had an improvement in disease activity of ≥ 20% according to American College of Rheumatology criteria (ACR20), compared with the placebo group (78% vs 11%). The ACR20 rate in the low dose tocilizumab group (57% of patients) was significantly greater than that of the placebo group, but significantly lower than that of the high-dose group. ACR50 and ACR70 responses were achieved by 40% and 16.4% of patients, respectively, in the high-dose tocilizumab group; corresponding values were 25.9% and 20.4% in the low-dose tocilizumab group, and 1.9% and 0% in the placebo group. Similarly, 91% of high-dose tocilizumab recipients achieved a "good or moderate" DAS28 rating (Disease Activity Score in 28 joints), compared with 72% and 19% of low-dose tocilizumab and placebo recipients, respectively. The level of rheumatoid factors decreased significantly in the high-dose tocilizumab group from 345.5 IU/mL at baseline to 235.6 IU/mL at 12 weeks; there was a non significant decrease in the low-dose tocilizumab group and an increase in the placebo group. There were significant increases in haemoglobin, osteocalcin and PICP (C-terminal type I procollagen propeptide) levels, and significant decreases in platelet, fibrinogen, serum amyloid A, urinary pyridinoline and deoxypyridinoline levels in the tocilizumab groups, but not in the placebo group [306] .

Forty five patients with clinically active rheumatoid arthritis were randomised to receive a single dose of IV tocilizumab 0.1 mg/kg (n = 9), 1 mg/kg (9), 5 mg/kg (9) or 10 mg/kg (7), or placebo. A significantly greater proportion of patients in the tocilizumab 5 mg/kg group, compared with the placebo group, achieved American College of Rheumatology (ACR) 20% response criteria at week 2 (primary endpoint). The significant treatment difference between the tocilizumab 5 mg/kg and placebo groups was maintained until week 8. A similar treatment benefit was observed in the tocilizumab 10 mg/kg group at week 6. The researchers noted that erythrocyte sedimentation rates and C-reactive protein levels in the tocilizumab 5 mg/kg and 10 mg/kg groups decreased within a week of drug administration and were maintained within the normal range for approximately 4 weeks [300] .

In an open-label trial, 15 patients with active rheumatoid arthritis received IV tocilizumab at 2 mg/kg/dose (n = 5), at 4 mg/kg/dose (5), or at 8 mg/kg/dose, once every 2 weeks for 24 weeks. Some of the researchers were affiliated with Chugai Pharmaceutical, which provided financial support for the study. At 24 weeks, the proportions of patients who achieved a 20%, 50% or 70% improvement from baseline in American College of Rheumatology score were > 80%, 33%, and 13%, respectively. All three treatment groups experienced significant improvements from baseline in C-reactive protein levels, erythrocyte sedimentation rates, swollen joint counts, physician and patient global assessments and pain scores. Tender joint counts only improved significantly in patients who received tocilizumab 8 mg/kg/dose. Patients in this dosage group also had significant reductions in rheumatoid factor at 14 weeks [297] .

In a randomised, double-blind, parallel-group study (the CHARISMA study), 359 patients with active rheumatoid arthritis received either methotrexate alone, tocilizumab alone, or tocilizumab plus methotrexate for 12 weeks, with endpoints measured at 16 weeks. The dose of methotrexate was 10-25 mg/week. Tocilizumab was administered as 2, 4 or 8 mg/kg by IV-infusion once every four weeks. Tocilizumab alone and in combination with methotrexate was more effective than methotrexate alone in the treatment of rheumatoid arthritis, as determined by American College of Rheumatology (ACR) 20% response criteria. Significantly more patients receiving tocilizumab 4 or 8 mg/kg/dose every 4 weeks achieved an ACR 20% response than patients receiving methotrexate (61% and 63% versus 41% of patients; p < 0.05) [299] .

In an open-label extension of a double-blind trial, 142 patients with rheumatoid arthritis received intravenous tocilizumab 8 mg/kg/dose, every 4 weeks, for a median period of 17 months (21 months maximum). In the double-blind phase, patients had received placebo or tocilizumab 4 or 8 mg/kg/dose for 3 months. After 12 months, 83%, 52% and 26% of patients achieved American College of Rheumatology 20%, 50% and 70% response criteria, respectively. In 93% of patients, C-reactive protein was normalised [309] .

Rheumatoid arthritis - SC formulation

Phase III

the international phase III SUMMACTA and BREVACTA trials both met their primary endpoints of ACR20 response criteria at 24 weeks, in patients receiving traditional DMARDs. The SUMMACTA trial investigated the efficacy of weekly subcutaneous injections of tocilizumab compared with 4-weekly intravenous injections in a total of 1262 patients. The results demonstrated that SC tocilizumab was statistically noninferior to IV tocilizumab, in terms of the proportion of patients who met the ACR20 response criteria at 24 weeks. In the BREVACTA trial, 656 patients were randomised to SC tocilizumab every 2 weeks or placebo, in addition to background DMARDS. The proportion of patients who met the ACR20 response criteria at 24 weeks was significantly greater in the tocilizumab group than the placebo group. The SUMMACTA and BREVACTA trials enrolled patients who had moderate-to-severe rheumatoid arthritis with an inadequate response to DMARDs alone [173] [166] .

In the phase III TOSCA trial, subcutaneous tocilizumab, at 162 mg, was effective as a montherapy and in combination with methotrexate, in patients with rheumatoid arthritis who had previous inadequate responses to DMARDs and/or biologic therapy. At week-24, DAS28 score variation vs baseline was -3.1 (p < 0.0001); -3.0 in mono TCZ vs -3 .1 in combo TCZ (p = 0.76). The proportion of patients who achieved DAS28 remission was 51.1% [41.9% in mono vs 55.2% in combo (p = 0.14)]. CDAI remission was achieved in 17% patients [16% in mono vs 17% in combo (p=0.95)]. The open-label trial enrolled 139 patients [177] [176] .

Interim results from a phase III registrational trial in Japan demonstrated that subcutaneously injected tocilizumab (162 mg Q2W) was non-inferior in efficacy compared with intravenously infused tocilizumab (8 mg/kg Q4W) when administered over a 24-week period. Non-inferiority was determined by American College of Rheumatology (ACR) 20% response criteria, which was the primary endpoint [167] .

Subcutaneously administered tocilizumab administered every week (TCZ-SC qw) was superior to that administered every two weeks (TCZ-SC q2w) in a phase III trial in 43 patients with rheumatoid arthritis, with superiority for adjusted mean change in DAS28-ESR from baseline to week 12 (−2.10 vs −0.89; P = 0.0108). The adjusted mean change in Clinical Disease Activity Index from baseline to week 12 was −16.0 in the TCZ-SC qw group and −8.7 in the TCZ-SC q2w group (P = 0.0979; as per hierarchical testing). For the TCZ-SC qw and TCZ-SC q2w groups, the proportions of patients who achieved DAS28-ESR remission or low disease activity were 42.9% and 25.0%, respectively. A greater proportion of patients achieved improvements in tender joint count, swollen joint count, C-reactive protein and ESR, and ACR20/50 in the TCZ-SC qw group than the TCZ-SC q2w group [170] [171] .

Phase I/II

in an open-label dose study with three treatment arms, at week 9, ACR20/50/70 responses were 12.5%, 0% and 0% for tocilizumab 81mg Q2W; 75.0%, 16.7% and 16.7% for tocilizumab 162mg Q2W, respectively. At week 25, ACR20/50/70 responses were 37.5%, 37.5% and 37.5% for tocilizumab 81mg Q2W; 83.3%, 83.3% and 58.3% for tocilizumab 162mg Q2W, 91.7%, 83.3% and 66.7% for tocilizumab 162mg QW, respectively. CDAI at the end of this study was 11.21 (18.19 at baseline), 3.76 (25.55 at baseline), and 2.03 (27.13 at baseline) for tocilizumab 81mg QW, 162mg Q2W and 162mg QW, respectively [257] .

Rheumatoid arthritis - SC versus IV formulation

Phase III

a study conducted in Japan has demonstrated non-inferiority in terms of efficacy between IV and SC formulations of tocilizumab in patients with RA [303] .

Juvenile rheumatoid arthritis

Post-marketing

Tocilizumab markedly improved disease in 54.2% and was effective in 42.2% at week 28 in a Japanese postmarketing study in 106 patients with polyarticular-course juvenile idiopathic arthritis (pJIA). These interim data were collected from patients enrolled between April 2008 and July 2009 [24] .

Phase III

Clinically meaningful improvement in the signs and symptoms of polyarticular juvenile idiopathic arthritis (PJIA) was reported after treatment with tocilizumab in the phase III CHERISH trial. The trial enrolled patients aged 2-17 years with active disease for at least 6 months who had not responded to treatment with methotrexate. Tocilizumab was administered monthly at doses of 8 mg/kg (body weight ≥30kg) or 10 mg/kg (body weight <30kg). Significantly fewer disease flares were reported in tocilizumab recipients relative to placebo recipients (primary endpoint; 25.6% vs 48.1%, respectively) [28] .

Tocilizumab was effective in patients with systemic-onset juvenile idiopathic arthritis (JIA) in the phase III TENDER trial. At week 12, the ACR30 response rate compared with placebo was 85% vs 24% of patients, and the proportion of patients without fever, who had fever at baseline, was 85% vs 21% (both p<0.0001; primary endpoint). ACR50 (85% vs 11%) and ACR70 (71% vs 8%) and ACR90 (37% vs 5%) response rates were also higher in tocilizumab group (p<0.0001 for all). Tocilizumab normalised haemoglobin (80% vs 7% of patients) in patients who had anaemia at baseline and normalised platelet count (90% vs 4% of patients) in patients who had thrombocytosis at baseline, compared with placebo. Tocilizumab was effective irrespective of baseline characteristics such as number of active joints, fever, high platelet count and previous anakinra or TNF-alpha inhibitor use [131] [130] [129] [259] . In 65 of 112 patients with systemic juvenile idiopathic arthritis who had received tocilizumab for 104 weeks, 88% had achieved the Juvenile Rheumatoid Arthritis 70% (JIA ACR70) response criteria and 71% had achieved the JIA ACR90 response criteria. In addition, 55% of these patients had no active joints and 31% had inactive disease [133] .

Interm data from a phase III trial of tocilizumab monotherapy vs. tocilizumab combination therapy demonstrated that the the primary endpoint was met in the trial, such that tocilizumab reponders who discontinued the methotrexate therapy were non-inferior to those who continued on methotrexate therapy. For the primary efficacy analysis, the mean changes in DAS28 from week 24 to week 40 were 0.46 and 0.14 in the tocilizumab monotherapy and tocilizumab combination therapy groups, respectively (95% CI: 0.045-0.592). In the 296 patients randomised at week 24 (TCZ-MONO, n = 148; TCZ-COMBO, n = 148), early discontinuation in the randomszed cohort occurred in 12.2% of patients in the monotherapy arm and 10.2% in the combination therapy arm. At week 24, DAS28 scores were similar in both groups, but ACR responses were ~8-11% lower in monotherapy group prior to methotrexate withdrawal (randomization). The mean change in DAS28 was similar between the randomized treatment groups. For the primary efficacy analysis, the mean changes in DAS28 from week 24 to week 40 were 0.46 and 0.14 in the tocilizumab monotherapy and tocilizumab combination therapy groups, respectively (95% CI: 0.045-0.592) [254] [182] .

Tocilizumab (TCZ)+ methotrexate (MTX), compared with methotrexate alone, led to significantly greater improvement in EQ-5D scores (p = 0.09) in newly-diagnosed patients with rheumatoid arthritis in the phase III U-ACT-EARLY trial. Significant differences were not observed between the strategies in EQ-VAS scores, over time (p≥0.14); however, when between-group differences at specific time points, were evaluated, significantly greater improvements were observed at week-12 in both tocilizumab treatment strategies, compared with methotrexate, in EQ-5D (TCZ+MTX vs MTX, p = 0.04; TCZ vs MTX, p = 0.01) and EQ-VAS scores (TCZ+MTX vs MTX, p<0.01; TCZ vs MTX, p=0.04). Post-24-week treatment, significance was observed only with respect to EQ-5D score in TCZ+MTX strategy (TCZ+MTX vs MTX, p<0.01). After 52 weeks, significantly lower scores from baseline in Sharp-van der Heijde score (SHS) were reported in the TCZ+MTX arm compared to the MTX arm (p=0.02). After 104 weeks, the difference compared with the MTX arm was significant for both TCZ strategies (TCZ+MTX, p=0.02; TCZ, p=0.04). For erosions, significant between-group differences were noted after 104 weeks in favour of the TCZ strategies (TCZ+MTX vs. MTX, p=0.02; TCZ versus MTX, p=0.02). For joint space narrowing (JSN), no significant differences was reported between the strategies during follow-up (p≥0.20), which was in accordance with the findings of the computerized method (p≥0.09). The randomised, double-blind trial evaluated TCZ+MTX vs TCZ + placebo vs MTX+placebo patients [104] [105] [103] .

Phase II

in an open, early phase II dose-escalation trial, 11 patients with systemic-onset juvenile idiopathic arthritis received an initial intravenous dose of tocilizumab 2 mg/kg; increased doses (≤ 8 mg/kg) were administered subsequently, according to individual levels of C-reactive protein. Disease activity was reduced by 70% in one of three patients receiving three doses of tocilizumab 2 mg/kg, in three of five receiving 4 mg/kg, and in three of three receiving 8 mg/kg [302] [296] .

Results of an open-label phase I NP25737 trial of tocilizumab in patients (n = 11) less than 2 years old with active systemic juvenile idiopathic arthritis (sJIA) observed mean±SD Juvenile Arthritis Disease Activity Score-71 improved from 22.27±10.09 at baseline to 3.66±4.66 at day 71 [134] [135] .

In a long term safety and efficacy phase I study in 52 patients with juvenile rheumatic arthritis, subcutaneous tocilizumab showed acceptable risk-benefit profile. The most frequent adverse event (AE) was infection, reported in 36 patients; two serious infections occurred in one patient. Injection site reactions occurred in 15% patients in the <30kg group and 44% patients in the ≥30kg group. The most common symptoms were erythema, swelling, haematoma, pain and pruritus. No serious hypersensitivity, AE leading to withdrawal, opportunistic infection, serious hepatic AE or death was seen. Four serious AEs were experienced by three patients (7.9/100 pt-y, consistent with that for TCZ IV) [253] [202] .

Data from a phase I trial showed that treatment with tocilizumab subcutaneous improved JIA activity (JADAS-71) in both body weight groups (<30 kg BW and ≥30 kg BW), with trends consistent with those observed for tocilizumab intravenous. The results were reported from 51 systemic Juvenile Idiopathic Arthritis patients aged 1 to 17 years enrolled in a open-label phase I trial [204] [205] .

Polymyalgia Rheumatica

In the phase I TENOR trial, in 20 evaluable patients at week 12, procollagen type I N propeptide (PINP) levels were augmented (p=0.0008), as compared with baseline (week 0), following tocilizumab administration. At week 24, a waning of CTX-I levels was observed following steroid initiation (p=0.001) versus baseline, at week 0. These modifications resulted in an altered correlation between PINP and CTX-I at week 0 (r=0.255 at week 0, versus r=0.641 in healthy controls) and its correction after treatment (r=0.760 at week 12 and r=0.767 at week 24). The PINP levels changed astronomically in patients whose circulating IL-6 levels diminished after tocilizumab therapy. Overall, a control of bone turnover was noted, partially through the inhibition of the IL-6 axis, following tocilizumab and subsequent steroid treatment of polymyalgia rheumatica [208] [209] .

In a clinical study conducted in 107 patients with rheumatoid arthritis, tocilizumab treatment resulted in DAS28 decrease between baseline and months 6 and 12 (p < 0.0001). HAQ, ESR, and CRP levels significantly decreased along the study (p < 0.0001). BMI and abdominal circumference significantly increased at month 6 and 12, as well as lean mass (p=0.0097 at month 6 and 0.021 at month 12). Fat mass% of fat and android fat did not change over the study. Total cholesterol and LDL cholesterol increased while glycaemia and insulin remained stable. Both total and HMW adipokines increased from baseline to month 6 and month 12 (total Adp: baseline vs month 6: p=0.055; HMW Adp: baseline vs month 6: p=0.02, baseline vs month 12: p=0.057). Serum leptin, resistin and ghrelin did not change during the follow-up [107] [108] .

Systemic sclerosis:

In the open-label part of the phase II/III faSScinate study, patients that switched from placebo to tocilizumab showed improvement in observed mean change from baseline in mRSS at week 96 (–9.4) compared with the end of the 48-week double-blinded period (–3.1). In patients initially randomised to tocilizumab, mean change in mRSS was –5.6 at week 48 and –9.1 at week 96. In the open-label period, improvements in patient-reported outcomes were noted at week 96 compared with week 48 in the placebo to tocilizumab converted group (mean [SD] change from baseline at week 96 vs week 48 in HAQ-DI: –0.3 [0.4] vs 0.2 [0.4]; Patient Global VAS: –23.8 [36.0] vs –4.0 [24.0]; FACIT-Fatigue: 11.3 [12.8] vs 1.4 [7.6]). Out of the patients who completed the study, no one experienced a greater thab 10% decline in % predicted FVC during the open-label period on tocilizumab therapy [217] [216] .

The primary modified Rodnan skin score (mRSS) endpoint was not met in a phase III trial. Tocilizumab (TCZ) treatment resulted in clinically relevant differences in forced vital capacity (FVC) with preservation of LFS and improvement in fibrosis, measured by Chest high-resolution computed tomography (HRCT), in systemic sclerosis (SSc) patients. 81% were women and 31% had previous or concurrent interstitial lung disease based on history of 106 placebo (PBO) and 104 TCZ-treated patients. Baseline (BL) mean values were age 48 years, SSc duration 23 months, mRSS 20.4, ppFVC 82.1%, and ppDLCO 75.6%. Mean baseline computer-assisted quantitative lung fibrosis of the most affected lobe (QLF-LM) was 4.7% for the PBO group and 5.5% for the TCZ group. At week 48, the primary endpoint was not significant (BL mRSS: PBO, −4.4; TCZ, −6.1; adjusted least squares mean difference, −1.7 [95% CI: −3.8, 0.3]; p =0.098). All p values for other endpoints were nominal. The cumulative distribution of week 48 BL ppFVC favored TCZ over PBO (median [IQR]: PBO, −3.9 [−7.2, 0.6] vs TCZ, −0.6 [−5.3, 3.9]; van Elteren nominal p =0.0015). The difference in mean BL FVC at week 48 between treatment groups was 167 mL (95% CI: 83, 250), favoring TCZ. At week 48, 5 (5.4%) TCZ-treated patients experienced ≥10% absolute decline in ppFVC compared with 15 (16.5%) for PBO. The HR (95% CI) for time to treatment failure was 0.6 (0.4, 1.1), numerically favoring TCZ (Cox proportional hazards model; p =0.082). ACR CRISS scores favored TCZ over PBO at week 48: median (IQR), 0.89 (0.09-1.00) vs 0.25 (0.00-0.99) ( p =0.023). HRCT showed less progression of lung fibrosis for TCZ than for PBO, which supports the FVC results [214] [215] .

Giant cell arteritis

The phase III GiACTA trial met the primary endpoint with a significant increase in the proportion of patients achieving sustained remission at one year (56% in the weekly treatment group [QW; p < 0.0001] and 53.1% in the bi-weekly treatment group [Q2W; p < 0.0001]) versus 14% in a six-month steroid taper regimen given alone. The secondary endpoint were also met with a significant increase in the proportion of patients achieving sustained remission at one year (56% [QW; p < 0.0001] and 53.1% [Q2W; p = 0.0002]) compared to 17.6% with a 12-month steroid taper regimen given alone. The data was obtained from 251 patients randomised 1:1:2:1 to 4 groups: A, short-course prednisone (26-week prednisone taper + weekly subcutaneous [SC] placebo); B, long-course prednisone (52-week prednisone taper + weekly SC placebo); C, weekly SC TCZ 162 mg + 26-week prednisone taper; D, every other week SC tocilizumab (TCZ) 162 mg + 26-week prednisone taper [256] [235] [238] . Updated results from the trial demonstrated that the SF- 36 MCS scores in all 50 patients who maintained treatment- free clinical remission in part 2 had diverged between the TCZ and palcebo groups as early as 36 weeks after baseline, with greater improve-ments evident in the TCZ group. The difference in least squares mean (LSM) change between TCZ and placebo was statistically significant at week 52 (p = 0.016) and maintained at weeks 100 ( p = 0.023) and 156 ( p = 0.0019). The LSM difference (95% CI) between TCZ and placebo at weeks 52, 100, and 156 was 5.6 (1.1- 10.2), 6.5 (0.9- 12.1), and 7.4 (2.9- 11.9), respectively, exceeding the MCID. Among patients who maintained treatment- free clinical remission during part 2 of GiACTA trial those originally assigned to receive TCZ plus a prednisone taper during part 1 maintained statistically significant and clinically meaningful improvements in 36 item Short- Form Health Survey (SF- 36) Mental Component Summary (MCS) up to week 156 compared with those originally assigned to receive placebo plus a prednisone taper in part 1. New onset GCA at baseline was reported in TCZ QW group (47%), TCZ Q2W group (53%), and in the pooled PBO group (46%), the remaining patients had relapsing GCA. Median time for first flare are over 3 years was reported to be longer for patients with TCZ treatment in part 1 than those with patients in PBO group. Among patients in TCZ groups, the median time for first flare was longer with QW than Q2W dosing for both the new- onset and the relapsing subgroups. Higher proportions of patients in the TCZ QW group (new- onset, 49%; relaps-ing, 47%) than the pooled PBO group (new- onset, 28%; relapsing, 31%) and the TCZ Q2W group (new- onset, 27%; relapsing, 35%) remained flare free during the entire 3- year study. Kaplan- Meier analysis reported a clear separation between the TCZ QW and pooled PBO groups over 3 years for patients with new onset and relapsing GCA. Separation between the TCZ QW and TCZ Q2W groups was also reported over 3 years in patients with new onset and relapsing GCA [239] [241] . Previous results from the part-2 of the study, indicated nearly half the patients treated with tocilizumab QW maintained clinical remission for the entirely of part 2, though flares still occurred in the remaining patients once they discontinued tocilizumab treatment. Among patients who maintained clinical remission in part 2, higher proportions of those originally assigned to tocilizumab were treatment-free compared with those originally assigned to placebo. Among the 81 tocilizumab QW and 36 tocilizumab Q2W patients in clinical remission at week 52, 47% and 36% patients, respectively, maintained clinical remission during part 2. Of these 51 original tocilizumab pateints, 65% were treatment-free (no tocilizumab and no glucocorticoid treatment), which was higher than the treatment-free proportion of original placebo patients who maintained clinical remission in part 2 (45%). Median time to first flare while not receiving tocilizumab was longer for patients in the original tocilizumab groups (tocilizumab QW, 575 days; tocilizumab Q2W, 428 days) than for patients in the original placebo groups (placebo + 26, 162 days; placebo + 52, 295 days); tocilizumab QW patients remained flare-free the longest. Retreatment with tocilizumab (with or without GC) for flare was effective for restoring clinical remission in part 2. Cumulative glucocorticoid dose over the three-year study was lowest in the tocilizumab QW group (median dose [mg/day]: tocilizumab QW, 2647; tocilizumab Q2W, 3782; placebo + 26, 5248; placebo + 52, 5323). Results were reported from 215 of 250 patients enrolled in the study [237] . Results from univariate analysis indicated 45% of patients were responders of which 27% were treated in the placebo + prednisone group and 58% in the tocilizumab+prednisone group. In contrast, 44% of patients experienced treatment failure: 66% in the placebo +prednisone group and 30% in the tocilizumab+prednisone group. The other 10% of patients were non-responders. Female sex and lower baseline SF-36 Physical Component Summary (PCS), Mental Component Summary, and FACIT-Fatigue scores were associated with treatment failure among placebo + prednisone treated patients, whereas higher patient global assessment of disease activity scores and lower SF-36 PCS, FACIT-Fatigue, and EQ-5D scores were associated with treatment failure among the tocilizumab+prednisone treated patients. Among tocilizumab+prednisone treated patients, no treatment response difference according to sex was observed. Age, previous relapse, starting prednisone dose, and GCA clinical features (cranial or polymyalgia rheumatica symptoms) were not associated with treatment failure in either group based on univariate analysis. Multivariate logistic regression demonstrated that placebo +prednisone treatment, female sex, worsen FACIT-Fatigue scores at baseline, and historical C-reactive protein > 2.5 mg/dL all independently increased the risk for treatment failure [305] [236] .

Future Events

Expected Date Event Type Description Updated
08 May 2020 Trial Update Genentech plans a phase III trial for Pneumonia (in patients with COVID-19) in May 2020 (IV) (NCT04372186) (700321387) 07 May 2020
04 May 2020 Trial Update Roche plans the phase II MARIPOSA trial for Pneumonia (in patients with COVID-19) in May 2020 (IV) (NCT04363736) (700321282) 07 May 2020
30 Apr 2020 Trial Update Roche in collaboration with the BARDA plans the phase III COVACTA trial for COVID-2019 pneumonia in USA in April 2020 (700319907) [251] 27 Mar 2020
31 Dec 2019 Regulatory Status Roche announces intention to launch to the single-dose prefilled autoinjector of tocilizumab 162 mg/0.9 mL (ACTPen™) for Giant cell arteritis, Juvenile rheumatoid arthritis and Rheumatoid arthritis in USA in 2019 [155] 29 Nov 2018
01 May 2019 Trial Update Hoffmann-La Roche plans a phase I trial for Giant cell arteritis in May 2019 (700306681) (EudraCT2018-004718-17) (NCT03923738) 19 Sep 2019
30 Apr 2019 Trial Update Hoffmann-La Roche plans the phase-Ib/II MORPHEUS mUC trial for Urogenital cancer (Combination therapy, Second-line therapy or greater, Late-stage disease, Metastatic disease) in USA, France, Greece, South Korea, Spain, United Kingdom (IV,Infusion) (NCT03869190) 17 May 2019
30 Sep 2017 Trial Update Roche plans a phase III extension trial for Giant cell arteritis in France (NCT03202368) 08 May 2018

Development History

Event Date Update Type Comment
28 May 2020 Phase Change - III Phase-III clinical trials in COVID-2019 infections (Combination therapy) in Europe, Canada, USA (IV) [9] Updated 03 Jun 2020
14 May 2020 Trial Update Genentech initiates enrolment in the phase III EMPACTA trial for COVID-2019 infections (IV) in USA (NCT04372186) [7] Updated 03 Jun 2020
01 May 2020 Trial Update Genentech plans a phase III trial for Pneumonia (in patients with COVID-19) in May 2020 (IV) (NCT04372186) Updated 07 May 2020
27 Apr 2020 Trial Update Roche plans the phase II MARIPOSA trial for Pneumonia (in patients with COVID-19) in May 2020 (IV) (NCT04363736) Updated 07 May 2020
26 Apr 2020 Phase Change - II Phase-II clinical trials in COVID-2019 infections in Switzerland (IV) (NCT04335071) Updated 07 May 2020
08 Apr 2020 Phase Change - III Phase-III clinical trials in COVID-2019 infections in United Kingdom (IV), Germany (IV), Denmark (IV), Spain (IV), Netherlands (IV), Italy (IV), France (IV) (EudraCT2020-001154-22) [10] Updated 13 Apr 2020
08 Apr 2020 Trial Update Chugai Pharmaceutical plans a phase III trial for COVID-19 infections in Japan [10] Updated 13 Apr 2020
08 Apr 2020 Trial Update MedSIR plans a phase II COPERNICO trial for the COVID-19 infections (Treatment-experienced) in March 2020 (NCT04335305) Updated 08 Apr 2020
02 Apr 2020 Financial Update Credit Suisse financial data update Updated 11 Apr 2020
24 Mar 2020 Regulatory Status The US FDA approves a Phase III trial in COVID-2019 infections [1] Updated 26 Mar 2020
19 Mar 2020 Phase Change - III Phase-III clinical trials in COVID-2019 infections in USA (IV) [12] Updated 27 Mar 2020
19 Mar 2020 Trial Update Roche in collaboration with the BARDA plans the phase III COVACTA trial for COVID-2019 pneumonia in USA in April 2020 [251] Updated 27 Mar 2020
08 Nov 2019 Scientific Update E fficacy data from the phase III GiACTA trial in Giant cell arteritis presented at the 83rd American College of Rheumatology and the 54th Association of Rheumatology Health Professionals Annual Scientific (ACR/ARHP-2019) [239] Updated 10 Feb 2020
08 Nov 2019 Scientific Update Three year Pharmacokinetics, Pharmacodynamics and efficacy data from the phase III GiACTA trial in Giant cell arteritis presented at the 83rd American College of Rheumatology and the 54th Association of Rheumatology Health Professionals Annual Scientific (ACR/ARHP-2019) [240] [241] Updated 10 Feb 2020
09 Sep 2019 Trial Update Chugai Pharmaceutical completes the phase II T-Rex trial in Rheumatoid arthritis in Japan (SC) (UMIN000021247) Updated 18 Sep 2019
21 Aug 2019 Trial Update Hoffmann-La Roche completes a phase III extension trial for Giant cell arteritis in France (SC) (NCT03202368) Updated 17 Oct 2019
05 Aug 2019 Phase Change - I Phase I clinical trials in Giant cell arteritis in Switzerland (IV) (NCT03923738) Updated 19 Sep 2019
31 Jul 2019 Trial Update Roche completes the phase II TOCISCH trial in Schnitzler's syndrome (Treatment-experienced) in Germany (SC) (NCT03046381) Updated 01 Oct 2019
31 Jul 2019 Trial Update Genentech completes a phase II trial in Dermatomyositis and Polymyositis (Treatment-experienced) in USA (IV) (NCT02043548) Updated 20 Sep 2019
25 Jul 2019 Phase Change - Discontinued(III) Discontinued - Phase-III for Systemic scleroderma in Croatia, Ireland, Switzerland, South Africa, Romania, Puerto Rico, Poland, Netherlands, Mexico, Lithuania, Japan, Italy, Greece, Bulgaria, Belgium, Argentina, Canada, France, Germany, United Kingdom, Spain, Portugal, Hungary, Denmark, USA (SC) (Chugai Pharmaceutical pipeline, July 2019) Updated 01 Oct 2019
28 Jun 2019 Phase Change - No development reported No recent reports of development identified for phase-I development in Polymyalgia-rheumatica(First-line therapy, In the elderly, In adults) in France (IV, Infusion) Updated 28 Jun 2019
20 Jun 2019 Scientific Update Adverse events data from long-term extension study in Juvenile rheumatoid arthritis presented at 20th Annual Congress of the European League Against Rheumatism (EULAR- 2019) [121] Updated 20 Jun 2019
12 Jun 2019 Scientific Update Efficacy and adverse events data from a phase III trial in Systemic scleroderma presented at the 20th Annual Congress of the European League Against Rheumatism (EULAR-2019) [214] Updated 02 Jul 2019
12 Jun 2019 Scientific Update Efficacy data from a clinical trial in Rheumatoid arthritis presented at the 20th Annual Congress of the European League Against Rheumatism (EULAR-2019) [107] Updated 21 Jun 2019
12 Jun 2019 Scientific Update Updated efficacy and adverse events data from the Giacta phase III trial in Giant cell arteritis presented at the 20th Annual Congress of the European League Against Rheumatism (EULAR-2019) [237] Updated 21 Jun 2019
12 Jun 2019 Scientific Update Updated efficacy data from Giacta phase III trial in Giant cell arteritis presented at the 20th Annual Congress of the European League Against Rheumatism (EULAR-2019) [236] Updated 21 Jun 2019
12 Jun 2019 Scientific Update Efficacy data from a phase I trial in Polymyalgia rheumatica presented at the 20th Annual Congress of the European League Against Rheumatism (EULAR-2019) [208] Updated 19 Jun 2019
24 May 2019 Active Status Review 9267645 - updated KDM , Progressed developmnet lines, profile already reviewed Updated 24 May 2019
23 May 2019 Phase Change - Registered Registered for Adult-onset Still's disease (Treatment-experienced) in Japan (IV) [146] Updated 24 May 2019
30 Apr 2019 Phase Change - I/II Phase-I/II clinical trials in Urogenital cancer (Combination therapy, Late-stage disease, Metastatic disease, Second-line therapy or greater) in Spain, South Korea (IV) (NCT03869190) Updated 17 May 2019
23 Apr 2019 Trial Update Hoffmann-La Roche plans a phase I trial for Giant cell arteritis in May 2019 (EudraCT2018-004718-17) (NCT03923738) Updated 19 Sep 2019
26 Mar 2019 Phase Change - Marketed Launched for Drug hypersensitivity in Japan (IV) [139] Updated 10 Apr 2019
26 Mar 2019 Phase Change - Registered Registered for Drug hypersensitivity in Japan (IV) [139] Updated 29 Mar 2019
11 Mar 2019 Trial Update Hoffmann-La Roche plans the phase-Ib/II MORPHEUS mUC trial for Urogenital cancer (Combination therapy, Second-line therapy or greater, Late-stage disease, Metastatic disease) in USA, France, Greece, South Korea, Spain, United Kingdom (IV,Infusion) (NCT03869190) Updated 17 May 2019
04 Feb 2019 Trial Update Roche completes the phase III focuSSced trial in Systemic scleroderma in United Kingdom, France, Canada, Germany, Argentina, Belgium, Bulgaria, Greece, Italy, Japan, Lithuania, Mexico, Netherlands, Poland, Puerto Rico, Romania, South Africa, Irealnd and Switzerland (SC) (NCT02453256) (EudraCT2015-000424-28) Updated 10 Apr 2019
01 Feb 2019 Trial Update Roche completes phase-III clinical trials in Osteoarthritis (Treatment-experienced) in France (IV-infusion) (NCT02477059) Updated 09 Aug 2019
01 Feb 2019 Trial Update Chugai Pharmaceutical completes the phase III TOCITAKA trial in Vasculitis (Takayasu arteritis) in France (IV) (NCT02101333) Updated 29 Mar 2019
28 Dec 2018 Phase Change - No development reported No recent reports of development identified for phase-I development in Juvenile-rheumatoid-arthritis in Argentina (SC, Injection) Updated 28 Dec 2018
28 Dec 2018 Phase Change - No development reported No recent reports of development identified for phase-I development in Juvenile-rheumatoid-arthritis in Australia (SC, Injection) Updated 28 Dec 2018
28 Dec 2018 Phase Change - No development reported No recent reports of development identified for phase-I development in Juvenile-rheumatoid-arthritis in Brazil (SC, Injection) Updated 28 Dec 2018
28 Dec 2018 Phase Change - No development reported No recent reports of development identified for phase-I development in Juvenile-rheumatoid-arthritis in Canada (SC, Injection) Updated 28 Dec 2018
28 Dec 2018 Phase Change - No development reported No recent reports of development identified for phase-I development in Juvenile-rheumatoid-arthritis in Mexico (SC, Injection) Updated 28 Dec 2018
28 Dec 2018 Phase Change - No development reported No recent reports of development identified for phase-I development in Juvenile-rheumatoid-arthritis in Russia (SC, Injection) Updated 28 Dec 2018
01 Dec 2018 Scientific Update Safety and pharmacokinetic data from the phase Ib GALACTA trial in Chronic lymphocytic leukaemia presented at the 60th Annual Meeting and Exposition of the American Society of Hematology (ASH-Hem-2018) [137] Updated 05 Jan 2019
26 Nov 2018 Regulatory Status Roche announces intention to launch to the single-dose prefilled autoinjector of tocilizumab 162 mg/0.9 mL (ACTPen™) for Giant cell arteritis, Juvenile rheumatoid arthritis and Rheumatoid arthritis in USA in 2019 [155] Updated 29 Nov 2018
26 Nov 2018 Regulatory Status The US FDA approves single-dose tocilizumab (ACTPen™) prefilled autoinjector for the treatment of Giant cell arteritis, Juvenile rheumatoid arthritis and Rheumatoid arthritis in USA [155] Updated 29 Nov 2018
28 Oct 2018 Phase Change - No development reported No recent reports of development identified for phase-I development in Chronic-lymphocytic-leukaemia(Combination therapy, First-line therapy) in Israel (IV, Infusion) Updated 28 Oct 2018
28 Oct 2018 Phase Change - No development reported No recent reports of development identified for phase-I development in Chronic-lymphocytic-leukaemia(Combination therapy, First-line therapy) in Italy (IV, Infusion) Updated 28 Oct 2018
28 Oct 2018 Phase Change - No development reported No recent reports of development identified for phase-I development in Chronic-lymphocytic-leukaemia(Combination therapy, First-line therapy) in Latvia (IV, Infusion) Updated 28 Oct 2018
28 Oct 2018 Phase Change - No development reported No recent reports of development identified for phase-I development in Chronic-lymphocytic-leukaemia(Combination therapy, First-line therapy) in Spain (IV, Infusion) Updated 28 Oct 2018
28 Oct 2018 Phase Change - No development reported No recent reports of development identified for phase-I development in Chronic-lymphocytic-leukaemia(Combination therapy, First-line therapy) in United Kingdom (IV, Infusion) Updated 28 Oct 2018
25 Oct 2018 Trial Update Roche discontinues a phase I trial in Chronic lymphocytic leukaemia (Combination therapy, First-line therapy) in Latvia, Israel, United Kingdom and Spain (IV)(NCT02336048) Updated 25 Oct 2018
19 Oct 2018 Scientific Update Interim adverse events data from a long-term extension study in Juvenile rheumatoid arthritis presented at the 82nd American College of Rheumatology and the 52nd Association of Rheumatology Health Professionals Annual Scientific Meeting (ACR/ARHP - 2018) [122] Updated 19 Nov 2018
19 Oct 2018 Scientific Update Updated adverse events data from a phase I trial in Juvenile idiopathic arthritis presented at the 82nd American College of Rheumatology and the 52nd Association of Rheumatology Health Professionals Annual Scientific Meeting (ACR/ARHP-2018) [136] Updated 19 Nov 2018
21 Sep 2018 Regulatory Status Committee for Medicinal Products for Human Use (CHMP) recommends approval of Tocilizumab for Juvenile rheumatoid arthritis (active systemic juvenile idiopathic arthritis (sJIA) in European Union [200] Updated 28 Sep 2018
13 Sep 2018 Regulatory Status Registered for Juvenile rheumatoid arthritis (active systemic juvenile idiopathic arthritis (sJIA), (Combination therapy) in USA (SC) [198] Updated 17 Sep 2018
13 Aug 2018 Trial Update University of Nebraska and Genentech withdraws a phase II trial in Diabetic macular oedema in USA prior to enrolment (NCT02511067) Updated 30 Aug 2018
11 Jul 2018 Trial Update Barrow Neurological Institute and Genentech completes a phase II trial in Amyotrophic lateral sclerosis in USA (IV) (NCT02469896) Updated 16 Aug 2018
29 Jun 2018 Phase Change - Preregistration Preregistration for Drug hypersensitivity (CART cell-induced cytokine release syndrome) (In adolescents, In adults, In children) in European Union (IV) before June 2018 [142] Updated 11 Jul 2018
29 Jun 2018 Regulatory Status CHMP recommended an extension to include the treatment of CAR-T-cell-induced cytokine release syndrome [142] Updated 11 Jul 2018
28 Jun 2018 Phase Change - No development reported No recent reports of development identified for phase-I development in Chronic-lymphocytic-leukaemia(Combination therapy, First-line therapy) in Italy (IV, Infusion) Updated 28 Jun 2018
24 Jun 2018 Biomarker Update Biomarkers information updated Updated 31 Aug 2018
13 Jun 2018 Scientific Update Updated efficacy data from the phase III COMP-ACT trial in Rheumatoid arthritis presented at the 19th Annual Congress of the European League Against Rheumatism (EULAR-2018) (EULAR-2018) [183] Updated 10 Jul 2018
13 Jun 2018 Scientific Update Pharmacodynamics data from a phase III trial presented at the 19th Annual Congress of the European League Against Rheumatism (EULAR-2018) [252] Updated 06 Jul 2018
13 Jun 2018 Scientific Update Updated safety, pharmacokinetics and pharmacodynamics data from a phase-I trial in Juvenile idiopathic arthritis presented at the 19th Annual Congress of the European League Against Rheumatism (EULAR-2018) [206] Updated 05 Jul 2018
04 Jun 2018 Trial Update Roche completes the phase III GiACTA trial for Giant cell arteritis in USA, Canada, United Kingdom, Austria, Belgium, Denmark, France, Germany, Italy, Netherlands, Poland, Portugal, Spain, Sweden and Norway (NCT01791153) (EudraCT2011-006022-25) Updated 01 Mar 2019
01 Jun 2018 Phase Change - Preregistration Preregistration for Adult-onset Still's disease in Japan (IV) [147] Updated 01 Jun 2018
29 May 2018 Phase Change - Preregistration Preregistration for Drug hypersensitivity in Japan (IV) [140] Updated 31 May 2018
18 May 2018 Scientific Update Adverse events data from the phase II TRANSFORM-UK trial in Pulmonary arterial hypertension presented at the 114th International Conference of the American Thoracic Society (ATS-2018) [223] Updated 05 Jul 2018
14 May 2018 Phase Change - Registered Registered for Juvenile rheumatoid arthritis (Active Polyarticular Juvenile Idiopathic Arthritis (PJIA), (Combination therapy) in USA (SC) [199] Updated 18 May 2018
14 May 2018 Scientific Update Adverse events data from a phase Ib trial in Juvenile rheumatoid arthritis released by Genentech [199] Updated 18 May 2018
23 Apr 2018 Phase Change - II Phase-II clinical trials in Familial Mediterranean fever in Germany (IV) (NCT03446209) Updated 30 May 2018
13 Apr 2018 Phase Change - Marketed Launched for Juvenile rheumatoid arthritis (juvenile idiopathic polyarthritis) in Finland, France, Spain, Poland, Austria, Austria, Hungary, Greece, Netherlands, Denmark, Belgium, Germany, Czech Republic, Portugal, United Kingdom, Sweden, Ireland and Norway (SC) Updated 01 Oct 2018
12 Apr 2018 Phase Change - Registered Registered for Juvenile rheumatoid arthritis (juvenile idiopathic polyarthritis (pJIA)) in European Union, Norway, Iceland, Liechtenstein (SC) (EMA website, September 2018) Updated 01 Oct 2018
01 Apr 2018 Phase Change - Marketed Launched for Giant cell arteritis (Combination therapy) in United Kingdom (SC) before April 2018 [226] Updated 04 Jun 2018
01 Apr 2018 Regulatory Status The UK's NICE recommends tocilizumab for Giant cell arteritis Updated 04 Jun 2018
22 Feb 2018 Phase Change - Preregistration Preregistration for Juvenile rheumatoid arthritis in European Union before February 2018 (SC) [201] Updated 28 Sep 2018
22 Feb 2018 Regulatory Status Committee for Medicinal Products for Human Use (CHMP) recommends approval of Tocilizumab for Juvenile rheumatoid arthritis (polyarticular juvenile idiopathic arthritis (pJIA) in European Union [201] Updated 28 Sep 2018
18 Feb 2018 Trial Update Roche completes the phase II TRANSFORM-UK trial in Pulmonary arterial hypertension in United Kingdom (NCT02676947) Updated 05 Jul 2018
16 Feb 2018 Trial Update Roche terminates a phase III extension trial in Rheumatoid arthritis in Poland due due to market authorisation of tocilizumab for the study population (NCT01665430) Updated 16 Feb 2018
01 Jan 2018 Trial Update Chugai Pharmaceutical completes the phase III TAKT trial in Vasculitis (Takayasu arteritis, In adolescents, In adults, In children, In the elderly) in Japan (SC) (JapicCTI-142616) Updated 23 Feb 2018
04 Nov 2017 Phase Change - No development reported No recent reports of development identified for phase-I development in Juvenile-rheumatoid-arthritis in Germany (SC, Injection) Updated 04 Nov 2017
04 Nov 2017 Phase Change - No development reported No recent reports of development identified for phase-I development in Juvenile-rheumatoid-arthritis in Italy (SC, Injection) Updated 04 Nov 2017
04 Nov 2017 Phase Change - No development reported No recent reports of development identified for phase-I development in Juvenile-rheumatoid-arthritis in Spain (SC, Injection) Updated 04 Nov 2017
04 Nov 2017 Phase Change - No development reported No recent reports of development identified for phase-I development in Juvenile-rheumatoid-arthritis in United Kingdom (SC, Injection) Updated 04 Nov 2017
04 Nov 2017 Phase Change - No development reported No recent reports of development identified for phase-I development in Juvenile-rheumatoid-arthritis in USA (SC, Injection) Updated 04 Nov 2017
04 Nov 2017 Phase Change - No development reported No recent reports of development identified for phase-I development in Rheumatoid-arthritis(Combination therapy, In the elderly, Treatment-experienced, In adults) in New Zealand (IV, Infusion) Updated 04 Nov 2017
04 Nov 2017 Phase Change - No development reported No recent reports of development identified for phase-I development in Rheumatoid-arthritis(Combination therapy, In the elderly, Treatment-experienced, In adults) in USA (IV, Infusion) Updated 04 Nov 2017
03 Nov 2017 Scientific Update Interim efficacy data from the phase III COMP-ACT trial in Rheumatoid arthritis presented at the 81st American College of Rheumatology and the 52nd Association of Rheumatology Health Professionals Annual Scientific Meeting (ACR/ARHP-2017) [184] Updated 29 Dec 2017
03 Nov 2017 Scientific Update Adverse events, pharmacodynamic, pharmacokinetic and efficacy data from a phase I trial in Juvenile idiopathic arthritis presented at the 81st American College of Rheumatology and the 52nd Association of Rheumatology Health Professionals Annual Scientific Meeting (ACR/ARHP-2017) [204] Updated 21 Dec 2017
03 Nov 2017 Scientific Update Efficacy data from the phase III U-Act-Early trial in Rheumatoid arthritis presented at the 81st American College of Rheumatology and the 52nd Association of Rheumatology Health Professionals Annual Scientific Meeting (ACR/ARHP-2017) [105] [104] Updated 18 Dec 2017
02 Nov 2017 Phase Change - Registered Registered for Giant cell arteritis (Combination therapy) in Canada (SC) [229] Updated 06 Nov 2017
25 Oct 2017 Trial Update Hoffmann-La Roche initiates enrolment in a long-term extension trial for Giant cell arteritis in France (NCT03202368) Updated 08 May 2018
22 Sep 2017 Phase Change - Registered Registered for Giant cell arteritis (Combination therapy) in European Union, Norway, Iceland and Liechtenstein (SC) [224] Updated 28 Sep 2017
04 Sep 2017 Regulatory Status The US FDA granted Priority Review to tocilizumab for Drug hypersensitivity in USA [141] Updated 04 Sep 2017
30 Aug 2017 Phase Change - Registered Registered for Drug hypersensitivity in USA (IV) [141] Updated 01 Sep 2017
30 Aug 2017 Regulatory Status Tocilizumab receives Orphan Drug status for Drug hypersensitivity in USA [141] Updated 01 Sep 2017
30 Aug 2017 Scientific Update Pooled analysis efficacy data from trials in Drug hypersensitivity released by Genentech [141] Updated 01 Sep 2017
25 Aug 2017 Phase Change - Registered Registered for Giant cell arteritis (Combination therapy) in Japan (SC) [218] Updated 28 Aug 2017
25 Aug 2017 Phase Change - Registered Registered for Vasculitis (In adults, In adolescents) in Japan (SC) [218] Updated 28 Aug 2017
01 Aug 2017 Trial Update Chugai initiates enrolment in a phase III trial for Systemic scleroderma in Japan (JapicCTI-173760) Updated 15 Nov 2017
26 Jul 2017 Scientific Update Updated adverse events data from the phase III GiACTA trial in Giant cell arteritis released by Genentech [233] Updated 28 Jul 2017
21 Jul 2017 Phase Change - Preregistration Preregistration for Giant cell arteritis (Combination therapy) in European Union (SC) [225] Updated 27 Jul 2017
21 Jul 2017 Regulatory Status CHMP recommends approval of tocilizumab for Giant cell arteritis in European Union [225] Updated 27 Jul 2017
19 Jul 2017 Phase Change - II Phase-II clinical trials in Schnitzler syndrome (Treatment-experienced) in Germany (SC) (NCT03046381) Updated 03 Aug 2017
13 Jul 2017 Trial Update Roche completes a phase I trial for Juvenile rheumatoid arthritis (In infants) in USA, Argentina, Belgium, Canada, Germany, Hungary, Poland, Spain, France, United Kingdom (NCT01455701) Updated 01 Sep 2017
30 Jun 2017 Trial Update Roche plans a phase III extension trial for Giant cell arteritis in France (NCT03202368) Updated 08 May 2018
26 Jun 2017 Regulatory Status Ministry of Health, Labour and Welfare (MHLW) approves additional dosage and administration for tocilizumab in Rheumatoid arthritis [158] Updated 04 Jul 2017
14 Jun 2017 Scientific Update Adverse events and pharmacokinetic from a phase I trial in Juvenile rheumatoid arthritis presented at the 18th Annual Congress of the European League Against Rheumatism (EULAR-2017) [253] Updated 25 Jul 2017
14 Jun 2017 Scientific Update Efficacy and adverse events data from a phase III trial oin Rheumatoid arthritis presented at the 18th Annual Congress of the European League Against Rheumatism (EULAR-2017) [254] Updated 24 Jul 2017
14 Jun 2017 Scientific Update Efficacy and adverse events data from the phase I trial in Juvenile idiopathic arthritis presented at the 18th Annual Congress of the European League Against Rheumatism (EULAR-2017) [134] Updated 22 Jul 2017
14 Jun 2017 Scientific Update Efficacy and adverse events data from the phase III TOSCA trial in Rheumatoid arthritis presented at the 18th Annual Congress of the European League Against Rheumatism (EULAR-2017) [177] Updated 22 Jul 2017
13 Jun 2017 Trial Update Roche completes a phase Ib trial in Juvenile rheumatoid arthritis in USA, Argentina, Australia, Brazil, Canada, France, Germany, Italy, Mexico, Russia, Poland, Spain and the UK (NCT01904279) Updated 17 Oct 2017
23 May 2017 Phase Change - Registered Registered for Giant cell arteritis (Combination therapy) in New Zealand (SC) [224] Updated 28 Sep 2017
22 May 2017 Phase Change - Registered Registered for Giant cell arteritis (Combination therapy) in USA (SC) [227] Updated 25 May 2017
18 May 2017 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis (Treatment-experienced, Combination therapy) in China (SC) before May 2017 (NCT03155347) Updated 18 May 2017
18 May 2017 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis (Treatment-experienced, Monotherapy) in China (SC) before May 2017 (NCT03155347) Updated 18 May 2017
16 May 2017 Trial Update Chugai Pharmaceuticals completes a phase III trial for Rheumatoid arthritis in Japan (SC) (JapicCTI142505) Updated 05 Jun 2017
24 Jan 2017 Phase Change - Preregistration Preregistration for Giant cell arteritis (Combination therapy) in USA (SC) [228] Updated 25 Jan 2017
24 Jan 2017 Regulatory Status Tocilizumab receives priority review status for Giant cell arteritis in USA [228] Updated 25 Jan 2017
30 Nov 2016 Phase Change - Preregistration Preregistration for Giant cell arteritis (Combination therapy) in Japan (SC) [219] Updated 28 Aug 2017
30 Nov 2016 Phase Change - Preregistration Preregistration for Vasculitis (In adolescents, In adults) in Japan (SC) [219] Updated 06 Dec 2016
27 Nov 2016 Phase Change - III Phase-III clinical trials in Osteoarthritis (Treatment-experienced) in France (IV-infusion) (NCT02477059) Updated 06 Dec 2016
12 Nov 2016 Scientific Update Efficacy data from the phase III GiACTA trial in Giant cell arteritis presented at the American College of Rheumatology and Association for Rheumatology Health Professionals Annual Meeting (ACR-ARHP 2016) [235] Updated 15 Nov 2016
12 Nov 2016 Trial Update Genentech initiates enrolment in an open label extension trial from the phase III GiACTA trial for Giant cell arteritis [235] before November 2016 Updated 15 Nov 2016
11 Nov 2016 Scientific Update Adverse events and efficacy data from phase III faSScinate trial in Systemic scleroderma presented at the 80th American College of Rheumatology and the 51st Annual Meeting of the Association of Rheumatology and Health Professionals (ACR/ARHP-2016) [217] Updated 24 Feb 2017
11 Nov 2016 Scientific Update Efficacy and adverse events data from a phase III trial in Rheumatotid arthritis presented at the 80th American College of Rheumatology and the 51st Annual Meeting of the Association of Rheumatology and Health Professionals (ACR-ARHP-2016) [170] Updated 24 Feb 2017
11 Nov 2016 Scientific Update Adverse events and efficacy data from a phase III trial in Vasculitis presented at the 80th American College of Rheumatology and the 51st Annual Meeting of the Association of Rheumatology and Health Professionals (ACR/ARHP-2016) [255] Updated 23 Feb 2017
11 Nov 2016 Scientific Update Adverse events and efficacy data from phase III GiACTA trial in Giant cell arteritis presented at the 80th American College of Rheumatology and the 51st Annual Meeting of the Association of Rheumatology and Health Professionals (ACR/ARHP-2016) [256] Updated 20 Feb 2017
05 Oct 2016 Regulatory Status Tocilizumab receives Breakthrough Therapy status for Giant cell arteritis in USA Updated 05 Oct 2016
01 Oct 2016 Trial Update Roche completes a phase III trial in Rheumatoid arthritis (Combination therapy, Monotherapy, Treatment-resistant) in Venezuela, Mexico, Dominican Republic, Colombia, Brazil, Argentina (SC) (NCT02011334) Updated 14 Dec 2016
01 Oct 2016 Trial Update Roche completes a phase III trial in Rheumatoid arthritis (Combination therapy) in USA (SC) (NCT01855789) Updated 16 Nov 2016
01 Sep 2016 Trial Update Roche completes a phase-III trial in Rheumatoid arthritis in Sweden, Norway, Finland, Denmark (SC) (NCT02046616) Updated 14 Oct 2016
25 Aug 2016 Regulatory Status Chugai Pharmaceuticals files an application with the Ministry of Health, Labour and Welfare for an additional weekly dosage of 162mg treatment of patients with Rheumatoid arthritis (Treatment-resistant) in Japan [159] Updated 01 Sep 2016
25 Aug 2016 Trial Update Chugai Pharmaceuticals initiates enrolment in a clinical trial for Rheumatoid arthritis (Treatment-experienced) in Japan before September 2016 [159] Updated 01 Sep 2016
01 Aug 2016 Trial Update Roche completes a phase III trial in Rheumatoid arthritis (Monotherapy, Combination therapy) in United Kingdom (NCT02046603) Updated 20 Sep 2016
22 Jul 2016 Phase Change - II Phase-II clinical trials in Rheumatoid arthritis in Japan (SC) (UMIN000021247) Updated 03 Jan 2017
01 Jul 2016 Trial Update Roche completes a phase III trial in Rheumatoid arthritis (Combination therapy, Monotherapy) in Italy (SC) (NCT01941940) Updated 26 Dec 2016
01 Jul 2016 Trial Update Roche completes a phase III trial in Rheumatoid arthritis in Greece (SC) (NCT01941095) Updated 16 Nov 2016
06 Jun 2016 Regulatory Status Genentech announces intention to submit NDA to FDA [231] Updated 08 Jun 2016
01 Jun 2016 Trial Update Chugai Pharmaceutical and Roche complete a phase I bioequivalence trial in Healthy volunteers in Japan (SC) (JapicCTI-163150) Updated 02 Jun 2017
01 Jun 2016 Trial Update Roche completes a phase I bioequivalence trial in Healthy volunteers in USA (SC) (NCT02678988) Updated 10 Aug 2016
01 May 2016 Trial Update Roche completes a phase III extension trial in Rheumatoid arthritis (early stage disease) in Brazil (NCT01668966) Updated 10 Aug 2016
01 May 2016 Trial Update Roche completes a phase III trial in Rheumatoid arthritis in the Netherlands (NCT01987479) Updated 12 Jul 2016
30 Mar 2016 Trial Update Trials shelf - NCT02721004/ML22551: observational trial of the well-launched drug not added Updated 30 Mar 2016
17 Mar 2016 Regulatory Status Tocilizumab receives Orphan Drug status for Systemic scleroderma in Japan [210] Updated 22 Mar 2016
09 Mar 2016 Trial Update Roche completes a phase III trial in Rheumatoid arthritis (as combination therapy or monotherapy) in Ireland, Portugal and Spain (SC) (NCT01995201) Updated 12 May 2016
01 Feb 2016 Trial Update Chugai Pharmaceutical and Roche initiate a phase I bioequivalence trial in Healthy volunteers in Japan (SC) (JapicCTI-163150) Updated 14 Jun 2016
01 Feb 2016 Trial Update Hoffmann-La Roche initiates a phase I bioequivalence trial in Healthy volunteers in USA (SC) (NCT02678988) Updated 16 Feb 2016
26 Jan 2016 Regulatory Status The UK's NICE issues final draft guidance recommending tocilizumab for Severe rheumatoid arthritis [30] Updated 28 Jan 2016
01 Jan 2016 Phase Change - II Phase-II clinical trials in Pulmonary arterial hypertension in United Kingdom (IV) [223] Updated 05 Jul 2018
31 Dec 2015 Trial Update Genentech completes a phase IIa trial in Polymyalgia rheumatics in USA (NCT01396317) Updated 23 May 2016
01 Dec 2015 Trial Update Roche completes the phase III TOSCA trial in Rheumatoid arthritis in France (SC) (NCT02001987) Updated 16 Nov 2016
25 Nov 2015 Phase Change - III Phase-III clinical trials in Systemic scleroderma in Ireland (SC) (EudraCT2015-000424-28) Updated 10 Apr 2019
20 Nov 2015 Phase Change - III Phase-III clinical trials in Systemic scleroderma in Croatia (SC) (NCT02453256) Updated 18 Apr 2019
20 Nov 2015 Phase Change - III Phase-III clinical trials in Systemic scleroderma in United Kingdom, France, Canada, Germany, Argentina, Belgium, Bulgaria, Greece, Italy, Japan, Lithuania, Mexico, Netherlands, Poland, Puerto Rico, Romania, South Africa and Switzerland (SC) (NCT02453256) Updated 15 Nov 2017
09 Nov 2015 Phase Change - I Phase-I clinical trials in Juvenile rheumatoid arthritis in Argentina, Australia, Brazil, Canada, France, Mexico, Russia and Poland (SC) Updated 09 Nov 2015
02 Nov 2015 Trial Update Roche completes enrolment in its phase III trial for Giant cell arteritis in USA, Canada, United Kingdom, Austria, Belgium, Denmark, France, Germany, Italy, Netherlands, Poland, Portugal, Spain, Sweden and Norway (NCT01791153) Updated 04 Nov 2015
01 Nov 2015 Trial Update Roche completes a phase III trial in Juvenile rheumatoid arthritis in Brazil (NCT01727986) Updated 11 Jan 2016
01 Nov 2015 Phase Change - II Phase-II clinical trials in Amyotrophic lateral sclerosis in USA (IV) Updated 17 Dec 2015
21 Oct 2015 Regulatory Status The UK's NICE issues the final draft guidance provisionally recommending tocilizumab for Juvenile rheumatoid arthritis [117] Updated 28 Oct 2015
23 Sep 2015 Trial Update University Hospital Inselspital completes a phase II trial in Giant cell arteritis (Combination therapy) in Switzerland (NCT01450137) Updated 04 Nov 2015
18 Sep 2015 Regulatory Status The National Institute for Health and Clinical Excellence in the UK recommends use of tocilizumab monotherapy for severe rheumatoid arthritis where methotrexate treatment is intolerable or inappropriate [27] Updated 21 Sep 2015
02 Sep 2015 Regulatory Status The UK's NICE issues a draft guidance recommending tocilizumab for Rheumatoid arthritis in United Kingdom [31] Updated 09 Sep 2015
01 Sep 2015 Trial Update Roche completes a phase III extension trial in Rheumatoid arthritis in France (NCT01734993) Updated 16 Nov 2015
01 Sep 2015 Trial Update Roche completes the phase III TOSCARA trial in Rheumatoid arthritis (Mid-stage disease, Late-stage disease) in Belgium and Luxembourg (NCT02031471) Updated 04 Nov 2015
01 Aug 2015 Trial Update Roche completes the Ac-Acute phase III trial for Rheumatoid arthritis (SC) in Australia (NCT01951170) Updated 24 Sep 2015
01 Aug 2015 Phase Change - III Phase-III clinical trials in Systemic scleroderma in USA, Denmark, Hungary, Portugal and Spain (SC) (NCT02453256) Updated 12 Jun 2015
30 Jul 2015 Trial Update Roche completes a phase III trial for Rheumatoid Arthritis in United Kingdom (UKCRN 14117) Updated 24 Jun 2016
23 Jul 2015 Trial Update Roche initiates enrolment in a phase I trial for Juvenile rheumatoid arthritis (Systemic onset and Juvenile Idiopathic Arthritis) in Italy after July 2014 (NCT02165345) Updated 23 Jul 2015
01 Jul 2015 Trial Update Roche completes a phase III trial for Rheumatoid arthritis in Israel (NCT01988012) Updated 06 Oct 2015
26 Jun 2015 Phase Change - I Phase-I clinical trials in Chronic lymphocytic leukaemia (Combination therapy, First-line therapy) in Latvia, Israel, United Kingdom, Spain (IV)(NCT02336048) Updated 25 Oct 2018
15 Jun 2015 Scientific Update Efficacy and adverse events data from a post-marketing study in Rheumatoid arthritis presented at the 16th Annual Congress of the European League Against Rheumatism (EULAR-2015) [23] Updated 10 Jul 2015
10 Jun 2015 Regulatory Status Tocilizumab receives Breakthrough Therapy status for Systemic scleroderma in USA [212] Updated 12 Jun 2015
01 Jun 2015 Trial Update Roche completes an extension phase III trial for Rheumatoid arthritis in Russia (NCT01664598) Updated 15 Mar 2016
01 Jun 2015 Trial Update Roche completes a phase III, open-label extension trial in Rheumatoid arthritis in France (NCT01655381) Updated 06 Oct 2015
01 Jun 2015 Trial Update Roche completes a phase III trial in Systemic scleroderma in USA, Canada, France, Germany and United Kingdom (NCT01532869) Updated 23 Jul 2015
30 May 2015 Trial Update Roche initiates enrolment in a phase I trial for Juvenile rheumatoid arthritis (Systemic onset and Juvenile Idiopathic Arthritis) in Canada after July 2014 (NCT02165345) Updated 30 May 2015
30 May 2015 Trial Update Roche plans a phase III trial in Systemic scleroderma in the US, Argentina, Belgium, Brazil, Canada, Denmark, Greece, Italy, Mexico, Netherlands, Portugal, South Africa, Spain, Switzerland and the UK (NCT02453256) Updated 30 May 2015
01 May 2015 Phase Change - I Phase-I clinical trials in Chronic lymphocytic leukaemia (Combination therapy, First-line therapy) in Italy (IV) (NCT02336048) Updated 30 Jun 2015
09 Apr 2015 Active Status Review Tocilizumab is still in active development for Juvenile rheumatoid arthritis in Brazil, Russia, Norway and Peru (IV) Updated 09 Apr 2015
09 Apr 2015 Phase Change - Marketed Launched for Juvenile rheumatoid arthritis in Philippines, Myanmar, Thailand, Malaysia, Israel and Hong Kong (IV) prior to April 2015 Updated 09 Apr 2015
09 Apr 2015 Phase Change - Marketed Launched for Rheumatoid arthritis (Mid-stage disease, Late-stage disease) in Switzerland, Philippines, South Korea, Myanmar, Vietnam, Thailand, Singapore, Malaysia, Hong Kong, Indonesia, Israel, Ukraine, Chile and Russia (IV) prior to April 2015 Updated 09 Apr 2015
09 Apr 2015 Phase Change - No development reported(III) No recent reports on development identified - Phase-III for Rheumatoid arthritis (Late-stage disease, Mid-stage disease) in Egypt, Morocco and Saudi Arabia (IV) Updated 09 Apr 2015
08 Apr 2015 Active Status Review Phase-III development for Systemic scleroderma is ongoing in USA, Canada, France, Germany and United Kingdom (SC) Updated 08 Apr 2015
08 Apr 2015 Active Status Review Tocilizumab is still in active development for Rheumatoid arthritis (Early-stage disease) in New Zealand, South Africa, USA, Turkey, Australia, Brazil, Philippines, Hong Kong, Singapore, Thailand, Argentina, Mexico, Colombia, Guatemala, Israel, Panama, Peru, Russia and China (IV) Updated 08 Apr 2015
08 Apr 2015 Active Status Review Tocilizumab is still in active development for Rheumatoid arthritis (Mid-stage disease, Late-stage disease) in New Zealand, Russia, Switzerland, South Africa, Australia, Argentina, Bosnia-Herzegovina, Hong Kong, Philippines, Malaysia, Singapore, Mexico, Thailand, Brazil, Colombia, Guatemala, Panama, Peru, Puerto Rico and Israel (SC) Updated 08 Apr 2015
01 Apr 2015 Trial Update Roche completes a phase III extension trial in Rheumatoid arthritis (Treatment-experienced) in Spain (NCT01772316) Updated 29 Jun 2015
10 Feb 2015 Trial Update Roche plans a phase I trial for Chronic lymphocytic leukaemia (Combination therapy, First-line therapy) in Italy (NCT02336048) Updated 10 Feb 2015
01 Feb 2015 Trial Update Roche completes a phase III extension trial in Rheumatoid arthritis (Early-stage disease) in Poland (NCT01665430) Updated 18 Mar 2015
08 Jan 2015 Phase Change - Registered Registered for Rheumatoid arthritis (Early-stage disease) in Canada (IV) Updated 10 Jan 2015
08 Jan 2015 Phase Change - Registered Registered for Rheumatoid arthritis (Early-stage disease) in Canada (SC) Updated 10 Jan 2015
31 Dec 2014 Phase Change - Marketed Launched for Juvenile rheumatoid arthritis in Argentina (IV) prior to December 2014 Updated 09 Apr 2015
31 Dec 2014 Phase Change - Marketed Launched for Rheumatoid arthritis (Late-stage disease, Mid-stage disease) in Argentina, Turkey and China (IV) prior to December 2014 Updated 09 Apr 2015
01 Dec 2014 Trial Update Roche completes a phase III long-term extension trial in Rheumatoid arthritis in Hungary (NCT01649804) Updated 10 Mar 2015
07 Oct 2014 Phase Change - Marketed Launched for Juvenile rheumatoid arthritis in India, Switzerland, Australia and New Zealand (IV) prior to October 2014 Updated 08 Apr 2015
01 Oct 2014 Trial Update Chugai Pharmaceutical and University Hospital, Brest complete the phase I TENOR trial in Polymyalgia rheumatica (First-line therapy, In adults, In the elderly) in France (IV) (NCT01713842) Updated 19 Jun 2019
01 Oct 2014 Phase Change - II Phase-II clinical trials in Dermatomyositis (Treatment-experienced) and Polymyositis (Treatment-experienced) in USA (IV) (NCT02043548) Updated 24 Nov 2014
08 Sep 2014 Phase Change - Registered Registered for Rheumatoid arthritis (Early-stage disease) in European Union (IV) Updated 10 Sep 2014
01 Sep 2014 Trial Update Roche completes a phase III trial for Rheumatoid arthritis in the Netherlands (NCT01034137) Updated 14 Nov 2014
01 Sep 2014 Trial Update Roche completes the phase III long-term extension trial in Rheumatoid arthritis in North America, South America, Europe, Russia, South Africa, Israel and Thailand(NCT00720798) Updated 07 Nov 2014
01 Aug 2014 Trial Update Pfizer completes a phase III trial in Rheumatoid arthritis in Turkey (NCT01245439) Updated 14 Nov 2014
28 Jul 2014 Regulatory Status EMA's Committee for Medicinal Products for Human Use issued a positive opinion for use of tocilizumab for Rheumatoid arthritis (early-stage disease) in the European Union [94] Updated 30 Jul 2014
16 Jul 2014 Trial Update Roche initiates enrolment in the phase I extension trial for Juvenile Idiopathic Arthritis in USA (NCT02165345) Updated 18 May 2018
01 Jul 2014 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis (Combination therapy, Monotherapy, Treatment-resistant) in Venezuela, Mexico, Dominican Republic, Colombia, Brazil, Argentina (SC) (NCT02011334) Updated 14 Dec 2016
01 Jul 2014 Phase Change - I Phase-I clinical trials in Juvenile rheumatoid arthritis in Germany (SC) (NCT02165345) Updated 14 Nov 2014
01 Jul 2014 Phase Change - I Phase-I clinical trials in Juvenile rheumatoid arthritis in Spain and USA after July 2014 (SC) Updated 10 Sep 2014
10 Jun 2014 Phase Change - III Phase-III clinical trials in Vasculitis in France (SC) (NCT02101333) Updated 29 Mar 2019
01 Jun 2014 Regulatory Status Tocilizumab receives Orphan Drug status for Vasculitis in Japan [218] Updated 28 Aug 2017
01 Jun 2014 Phase Change - III Phase-III clinical trials in Vasculitis (Takayasu arteritis, In adolescents, In adults, In children, In the elderly) in Japan (SC) (JapicCTI-142616) Updated 10 Jun 2016
01 Jun 2014 Trial Update Genentech completes a phase III long-term extension trial in Rheumatoid arthritis (mid- to late-stage disease) in the US and Puerto Rico (NCT01662063) Updated 10 Sep 2014
01 Jun 2014 Trial Update Roche initiates enrolment in a phase I trial for Juvenile rheumatoid arthritis in United Kingdom (NCT02165345) Updated 31 Jul 2014
15 May 2014 Phase Change - Marketed Launched for Rheumatoid arthritis (Late-stage disease, Mid-stage disease) and Juvenile rheumatoid arthritis in Mexico (IV) prior to May 2014 Updated 08 Apr 2015
08 May 2014 Phase Change - Registered Registered for Rheumatoid arthritis (mid- to late-stage disease, monotherapy/combination therapy, treatment-resistant) in Canada (SC) Updated 12 May 2014
01 May 2014 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis (Treatment-experienced) in Sweden, Norway, Finland, Denmark (SC) (NCT02046616) Updated 18 Mar 2016
28 Apr 2014 Phase Change - Marketed Launched for Rheumatoid arthritis (mid- to late-stage disease; monotherapy/combination therapy; treatment-experienced patients) in European Union, including Ireland and United Kingdom (SC) Updated 30 Apr 2014
28 Apr 2014 Phase Change - Registered Registered for Rheumatoid arthritis (mid- to late-stage disease; monotherapy/combination therapy; treatment-experienced patients) in European Union (SC) Updated 30 Apr 2014
03 Mar 2014 Trial Update Roche completes a phase III trial in Rheumatoid arthritis in Austria (NCT01587989) Updated 16 May 2014
01 Mar 2014 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis (as combination therapy or monotherapy, treatment-resistant) in United Kingdom (SC) Updated 24 Feb 2014
28 Feb 2014 Trial Update Roche initiates the phase III TOSCA trial for Rheumatoid arthritis (SC) in France (NCT02001987) Updated 16 Jun 2014
28 Feb 2014 Trial Update Roche completes a phase III trial in Rheumatoid arthritis in Germany (NCT01332994) Updated 27 May 2014
17 Feb 2014 Trial Update Roche plans a phase III trial for Rheumatoid arthritis (as combination therapy or monotherapy, treatment-resistant) in Denmark, Finland and Sweden (NCT02046616) Updated 25 Feb 2014
04 Feb 2014 Phase Change - Marketed Launched for Rheumatoid arthritis in USA (as combination therapy and monotherapy) (SC) before February 2014 Updated 05 Feb 2014
01 Feb 2014 Trial Update Chugai Pharmaceuticals initiates enrolment in a phase III trial for Rheumatoid arthritis in Japan (JapicCTI142505) Updated 24 Feb 2017
01 Feb 2014 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis (Mid-stage disease, Late-stage disease) in Belgium and Luxembourg (SC) Updated 04 Nov 2015
01 Jan 2014 Trial Update Roche initiates a phase III trial for Rheumatoid arthritis in Israel (NCT01988012) Updated 09 Jul 2014
01 Jan 2014 Trial Update Roche completes phase III trial in Rheumatoid arthritis (Early-stage disease) (NCT01007435) Updated 12 Jun 2014
01 Jan 2014 Trial Update Roche completes a phase III trial in Juvenile idiopathic arthritis in France (NCT01673919) Updated 16 Apr 2014
20 Dec 2013 Regulatory Status Committee for Medicinal Products for Human Use (CHMP)recommends approval of subcutaneous tocilizumab for Rheumatoid arthritis in European Union [157] Updated 23 Dec 2013
13 Dec 2013 Trial Update Roche plans a phase III trial for Rheumatoid arthritis (SC) in France (NCT02001987) Updated 13 Dec 2013
01 Dec 2013 Phase Change - Clinical Clinical trials in Adult-onset Still's disease in Japan (IV) [147] Updated 01 Jun 2018
01 Dec 2013 Trial Update Roche terminates a phase III trial in Juvenile rheumatoid arthritis in Russia and Poland (NCT01575769) Updated 20 Jan 2016
30 Nov 2013 Phase Change - Preregistration Preregistration for Rheumatoid arthritis in Taiwan (SC) Updated 03 Feb 2014
19 Nov 2013 Trial Update Roche plans a phase III trial for Rheumatoid arthritis in Israel (NCT01988012) Updated 05 Dec 2013
01 Nov 2013 Trial Update Roche completes a Phase-III trial in Rheumatoid arthritis (Mid-stage disease, Late-stage disease, combination therapy) in USA, Argentina, Australia, Brazil, Bulgaria, Canada, Colombia, Greece, Guatemala, Hungary, Israel, Malaysia, Mexico, New Zealand, Phillipines, Russia, South Africa, Spain, Swizerland, Thailand and Poland (NCT01232569) Updated 05 Mar 2015
01 Nov 2013 Trial Update Roche initiates enrolment in the Ac-Acute phase III trial for Rheumatoid arthritis (SC) in Australia (NCT01951170) Updated 31 Oct 2013
24 Oct 2013 Trial Update Roche initiates enrolment in a phase III OSCAR trial in Rheumatoid arthritis (treatment-resistant) in the Netherlands (EudraCT2013-000342-19) Updated 12 Dec 2013
21 Oct 2013 Phase Change - Registered Registered for Rheumatoid arthritis (monotherapy and combination therapy) in USA (SC) Updated 24 Oct 2013
21 Oct 2013 Phase Change - Marketed Launched for Juvenile rheumatoid arthritis (systemic onset and polyarticular juvenile idiopathic arthritis) in Canada (IV) Updated 23 Oct 2013
17 Oct 2013 Phase Change - Preregistration Preregistration for Rheumatoid arthritis (early-stage disease) in European Union (IV) Updated 25 Oct 2013
01 Oct 2013 Trial Update Roche initiates enrolment in a phase III extension trial in Rheumatoid arthritis (early stage disease) in Brazil (NCT01668966) Updated 11 Nov 2013
30 Sep 2013 Trial Update Roche initiates a phase III trial in Rheumatoid arthritis (as combination therapy or monotherapy) in Ireland, Portugal and Spain (SC) (NCT01995201) Updated 11 Dec 2013
30 Sep 2013 Trial Update Roche initiates a phase III trial in Rheumatoid arthritis (as combination therapy or monotherapy) in Italy (SC) (NCT01941940) Updated 11 Dec 2013
12 Sep 2013 Trial Update Roche initiates enrolment in a phase III trial for Rheumatoid arthritis (SC) in Greece (EudraCT 2013-000359-42) Updated 31 Oct 2013
12 Sep 2013 Trial Update Roche plans a phase III trial for Rheumatoid arthritis (SC formulation) in Greece (NCT01941095) Updated 18 Sep 2013
01 Sep 2013 Trial Update Roche completes the phase II ACT-FAST trial in Rheumatoid arthritis in Denmark and Iceland (NCT01468077) Updated 25 Nov 2013
20 Aug 2013 Trial Update Roche terminates two phase III trials in Ankylosing spondylitis in countries worldwide (NCT01209689 and NCT01209702) Updated 20 Aug 2013
12 Aug 2013 Trial Update Roche initiates enrolment in a phase III trial for Rheumatoid Arthritis in United Kingdom (UKCRN 14117) Updated 24 Jun 2016
01 Aug 2013 Trial Update Roche initiates enrolment in the phase III U-Act-After extension trial for Rheumatoid arthritis (early disease) in Netherlands (NCT01918267) Updated 20 Aug 2013
31 Jul 2013 Trial Update Roche initiates enrolment in a phase III trial for Rheumatoid arthritis (combination therapy, SC) in the USA (NCT01855789) Updated 31 Oct 2013
01 Jul 2013 Trial Update Roche completes enrolment in a phase III, open-label extension trial in Rheumatoid arthritis in France (NCT01655381) Updated 12 Jul 2013
24 Jun 2013 Trial Update Roche plans a phase III trial for Rheumatoid arthritis (SC formulation) in USA (NCT01855789) Updated 24 Jun 2013
20 Jun 2013 Trial Update Roche initiates a phase Ib trial for Juvenile rheumatoid arthritis (polyarticular) in Italy and the UK (EudraCT2012-003486-18) Updated 22 Jul 2013
13 Jun 2013 Scientific Update Efficacy data from the phase III AMBITION and FUNCTION trials in Rheumatoid arthritis presented at the 14th Annual Congress of the European League Against Rheumatism (EULAR-2013) [65] Updated 26 Jun 2013
11 Jun 2013 Phase Change - I Phase-I clinical trials in Juvenile rheumatoid arthritis (systemic) in Italy (SC) Updated 18 Jul 2013
11 Jun 2013 Phase Change - I Phase-I clinical trials in Juvenile rheumatoid arthritis (systemic) in United Kingdom (SC) Updated 18 Jul 2013
10 Jun 2013 Phase Change - Registered Registered for Rheumatoid arthritis in China prior to June 2013 (IV) Updated 11 Jun 2013
10 Jun 2013 Regulatory Status EMA approves tocilizumab for treatment of polyarticular juvenile rheumatoid arthritis in European Union [28] Updated 11 Jun 2013
10 Jun 2013 Scientific Update Efficacy and adverse events data from a Phase-III trial (CHERISH) in polyarticular juvenile idiopathic arthritis released by Roche [28] Updated 11 Jun 2013
24 May 2013 Phase Change - Marketed Launched for Rheumatoid arthritis (that does not respond adequately to one or more existing therapies) given at two-weeks interval in Japan (SC) Updated 27 May 2013
30 Apr 2013 Phase Change - III Phase-III clinical trials in Giant cell arteritis (Combination therapy) in Belgium, Canada, Denmark, France, Germany, Italy, the Netherlands, Norway, Poland and Spain after April 2013 (SC) Updated 09 Jul 2014
30 Apr 2013 Phase Change - III Phase-III clinical trials in Vasculitis (Giant cell arteritis; combination therapy) in USA, United Kingdom, Austria, Portugal and Sweden (SC) (NCT01791153; Eudra2011-006022-25) Updated 29 Jul 2013
30 Apr 2013 Regulatory Status The US FDA approves tocilizumab for treatment of Juvenile rheumatoid arthritis (polyarticular juvenile idiopathic arthritis) in the USA [109] Updated 02 May 2013
29 Apr 2013 Regulatory Status The European Union Committee for Medicinal Products for Human Use (CHMP) issues a positive opinion for tocilizumab for the treatment of Juvenile rheumatoid arthritis (polyarticular-course) [114] Updated 29 Apr 2013
03 Apr 2013 Trial Update Chugai Pharma completes a phase III trial in Rheumatoid arthritis in Taiwan (NCT01347983) Updated 07 May 2013
27 Mar 2013 Phase Change - Marketed Launched for Rheumatoid arthritis in Switzerland (IV) before 2013 Updated 27 Mar 2013
25 Mar 2013 Phase Change - Registered Registered for Rheumatoid arthritis (in patients who do not respond adequately to one or more existing therapies) in Japan (SC) Updated 27 Mar 2013
01 Mar 2013 Trial Update Roche completes a phase III trial in Rheumatoid arthritis in Saudi Arabia (NCT01326962) Updated 15 Oct 2013
27 Feb 2013 Regulatory Status PDUFA action date of 31/10/2013 assigned by FDA for subcutaneous tocilizumab for Rheumatoid arthritis Updated 01 Mar 2013
19 Feb 2013 Trial Update Roche completes a phase III trial in Rheumatoid arthritis in Tunisia (NCT01254331) Updated 20 Mar 2013
01 Jan 2013 Trial Update Roche completes the phase III ACT-RAY trial in Rheumatoid arthritis (mid- to late-stage disease) in the US, Brazil, Croatia, Denmark, Estonia, France, Germany, Greece, Israel, Italy, Latvia, Netherlands, Norway, Romania, Russia, Serbia, Spain, Sweden, Thailand and the UK (NCT00810199) Updated 10 Sep 2014
01 Jan 2013 Trial Update Roche completes its CHERISH phase III trial for Juvenile rheumatoid arthritis in USA, the EU, Argentina, Australia, Brazil, Canada, Mexico, Peru and Russia (NCT00988221) Updated 19 Sep 2013
31 Dec 2012 Phase Change - Preregistration Preregistration for Rheumatoid arthritis in European Union (SC) Updated 04 Feb 2013
31 Dec 2012 Phase Change - Preregistration Preregistration for Rheumatoid arthritis in USA (SC) Updated 04 Feb 2013
31 Dec 2012 Regulatory Status Roche obtains approval for a line extension for use of tocilizumab as monotherapy in patients with Rheumatoid arthritis who are resistant to or intolerant of methotrexate, in the EU Updated 04 Feb 2013
12 Dec 2012 Trial Update Chugai Pharma completes a phase III trial in Rheumatoid arthritis in Taiwan (NCT01258712) Updated 07 May 2013
01 Dec 2012 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis (Treatment-experienced) in Spain (SC) (NCT01772316) Updated 29 Jun 2015
12 Oct 2012 Regulatory Status The US FDA approves tocilizumab for the treatment of patients with moderate to severe Rheumatoid arthritis who have had inadequate response to one or more DMARDs [21] Updated 15 Oct 2012
01 Oct 2012 Regulatory Status Roche files an application for a line extension for use of tocilizumab as monotherapy in patients with Rheumatoid arthritis who are resistant to or intolerant of methotrexate, in the EU Updated 19 Oct 2012
01 Oct 2012 Trial Update Roche initiates enrolment in a phase I trial for Juvenile rheumatoid arthritis (in patients under 2 years of age) in USA, Argentina, Belgium, Canada, Germany, Hungary, Poland, Spain, France, United Kingdom (NCT01455701) Updated 23 Jul 2012
01 Aug 2012 Trial Update Genentech initiates enrolment in a phase III trial for Rheumatoid arthritis in the USA (NCT01662063) Updated 28 Aug 2012
31 Jul 2012 Regulatory Status Tocilizumab receives orphan drug status for Polyarticular course juvenile Idiopathic arthritis in USA [120] Updated 23 Oct 2012
30 Jul 2012 Scientific Update Efficacy data from the phase III SUMMACTA trial in Rheumatoid arthritis released by Roche [166] Updated 30 Jul 2012
27 Jul 2012 Scientific Update Efficacy data from the phase III BREVACTA trial in Rheumatoid arthritis released by Roche [173] Updated 30 Jul 2012
26 Jul 2012 Phase Change - Discontinued(I/II) Discontinued - Phase-I/II for Pancreatic cancer in Japan (IV) Updated 01 Aug 2012
06 Jul 2012 Trial Update Roche completes enrolment in its phase III trial in Rheumatoid arthritis (combination therapy; mid- or late-stage disease) in Bosnia-Herzegovina (NCT01235507) Updated 25 Jul 2012
01 Jul 2012 Phase Change - I Phase-I clinical trials in Polymyalgia rheumatica (First-line therapy, In adults, In the elderly) in France (IV) (NCT01713842) Updated 19 Jun 2019
01 Jul 2012 Trial Update Roche completes a phase IIIb trial for Rheumatoid arthritis (Combination therapy, Treatment-experienced) in Indonesia (IV) (NCT01353859) Updated 03 Oct 2016
30 Jun 2012 Trial Update Roche completes the phase III REMISSION trial in Rheumatoid arthritis in Morocco (NCT01610791) Updated 15 Oct 2012
06 Jun 2012 Scientific Update Efficacy data from a phase IV ADACTA study in Rheumatoid arthritis released by Roche [48] Updated 08 Jun 2012
30 Apr 2012 Trial Update Roche completes the phase III TORPEDO trial in Rheumatoid arthritis in France (NCT00977106) Updated 24 Aug 2012
24 Apr 2012 Phase Change - Preregistration Preregistration for Rheumatoid arthritis in Japan (SC) Updated 02 May 2012
24 Apr 2012 Phase Change - Registered Registered for Rheumatoid arthritis in South Korea (IV) Updated 02 May 2012
18 Apr 2012 Phase Change - II/III Phase-II/III clinical trials in Systemic scleroderma in Canada, France, Germany and United Kingdom (SC) after April 2012 (NCT01532869) Updated 29 Jul 2013
18 Apr 2012 Phase Change - III Phase-III clinical trials in Systemic scleroderma in USA (SC) Updated 02 May 2012
01 Apr 2012 Trial Update Roche completes a phase III extension trial for Rheumatoid arthritis in Australia, Canada, European Union and Saudi Arabia (IV) (NCT00883753) Updated 10 Jul 2017
31 Mar 2012 Trial Update Roche initiates enrolment in a observational study for Rheumatoid Arthritis in Finland (NCT01565122) Updated 24 Jul 2012
02 Mar 2012 Scientific Update Efficacy and adverse events data from a phase IV trial in Rheumatoid arthritis released by Genentech (Roche) and Chugai Pharmaceuticals [49] , [50] Updated 06 Mar 2012
23 Feb 2012 Regulatory Status NICE recommends earlier use of tocilizumab for treatment of rheumatoid arthritis in UK [29] Updated 23 Feb 2012
22 Feb 2012 Regulatory Status US FDA accepts sBLA for review and assigns a PDUFA date of October 2012 for earlier use of tocilizumb for treatment of rheumatoid arthritis [22] Updated 23 Feb 2012
15 Feb 2012 Trial Update Roche plans a phase III trial for Systemic scleroderma in USA, Canada, France, Germany & United Kingdom (NCT01532869) Updated 05 Mar 2012
15 Feb 2012 Trial Update Roche completes a phase I trial in Healthy volunteers in France (NCT01418989) Updated 02 Mar 2012
31 Jan 2012 Phase Change - Registered Registered for Juvenile rheumatoid arthritis (systemic onset) in Canada (IV) Updated 23 Oct 2013
31 Jan 2012 Trial Update Roche completes a phase I trial in Rheumatoid arthritis in Italy (NCT00951275) Updated 24 Aug 2012
20 Dec 2011 Regulatory Status Genentech submits sBLA to the US FDA seeking to remove the condition that patients with moderately to severely active RA can only receive tocilizumab after they have had an inadequate response to one or more TNF antagonist therapies [20] Updated 21 Dec 2011
13 Dec 2011 Regulatory Status The UK's National Institute for Health and Clinical Excellence (NICE) publishes final guidance recommending tocilizumab for the treatment of systemic juvenile idiopathic arthritis [118] Updated 18 Dec 2011
05 Dec 2011 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis in Israel (SC) Updated 30 Jul 2012
05 Dec 2011 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis in Russia (SC) Updated 30 Jul 2012
05 Dec 2011 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis in Switzerland (SC) Updated 30 Jul 2012
05 Dec 2011 Trial Update Roche completes enrolment in its phase III trial for Rheumatoid arthritis in Italy (NCT00951275) Updated 09 Dec 2011
09 Nov 2011 Scientific Update Two-year efficacy and tolerability data from the phase III TENDER trial in Rheumatoid arthritis presented at the 75th Annual Scientific Meeting of the American College of Rheumatology and the 46th Annual Meeting of the Association of Rheumatology Health Professionals (ACR/ARHP-2011) [133] Updated 09 Dec 2011
05 Nov 2011 Scientific Update Efficacy and adverse events data from the phase III ACT-RAY and ACT-STAR trials and adverse events data from the phase III OPTION, TOWARD, RADIATE, AMBITION, LITHE, GROWTH95 and GROWTH96 trials in Rheumatoid arthritis presented at the 75th Annual Scientific Meeting of the American College of Rheumatology and the 46th Annual Meeting of the Association of Rheumatology Health Professionals (ACR/ARHP-2011) [82] Updated 07 Nov 2011
31 Oct 2011 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis in Saudi Arabia (IV) Updated 17 Jan 2012
17 Oct 2011 Trial Update Roche completes a phase III trial in Rheumatoid arthritis in North America, Europe, Australia, India, and Saudi Arabia (NCT00750880) Updated 31 Oct 2011
17 Oct 2011 Trial Update Roche completes a phase III mechanism of action trial in Rheumatoid arthritis (mid to late stage disease, in combination with methotrexate) in US, Canada, Puerto Rico and UK (NCT00535782) Updated 25 Oct 2011
14 Oct 2011 Trial Update Roche initiates enrolment for a phase I trial in Healthy volunteers in France (NCT01418989) Updated 27 Oct 2011
14 Oct 2011 Trial Update Roche initiates enrolment in a phase III trial for Rheumatoid arthritis in Spain (NCT01399697) Updated 26 Oct 2011
14 Oct 2011 Trial Update Roche completes enrolment in a phase III trial in Juvenile rheumatoid arthritis in USA, Argentina, Australia, Brazil, Canada, EU, Mexico, Peru, and Russia (NCT00988221) Updated 25 Oct 2011
13 Oct 2011 Phase Change - Discontinued(III) Discontinued - Phase-III for Ankylosing spondylitis in United Kingdom (IV) Updated 19 Oct 2011
13 Oct 2011 Phase Change - Discontinued(III) Discontinued - Phase-III for Ankylosing spondylitis in USA (IV) Updated 19 Oct 2011
30 Sep 2011 Phase Change - II Phase-II clinical trials in Giant cell arteritis (Combination therapy) in Switzerland (SC) Updated 04 Nov 2015
30 Sep 2011 Trial Update Roche completes a Phase-III trial in Rheumatoid arthritis (early-stage disease, in combination with disease-modifying antirheumatic drugs) in South Africa (NCT01214733) Updated 31 Jul 2012
30 Sep 2011 Trial Update Roche initiates enrolment in a phase III trial for Rheumatoid arthritis in Turkey (NCT01245439) Updated 30 Nov 2011
26 Sep 2011 Trial Update Roche completes the ROSE Phase-III trial in Rheumatoid arthritis in the US and Puerto Rico (NCT00531817) Updated 04 Nov 2011
19 Sep 2011 Trial Update Roche completes a phase I trial in Rheumatoid arthritis in Canada, Spain, and New Zealand (NCT00965653) Updated 04 Oct 2011
19 Sep 2011 Trial Update Roche completes enrolment in its phase III extension trial for Rheumatoid arthritis in Australia, Canada, European Union and Saudi Arabia (NCT00883753) Updated 04 Oct 2011
11 Aug 2011 Regulatory Status NICE requests information on use ot tocilizumab in systemic juvenile idiopathic arthritis [119] Updated 11 Aug 2011
03 Aug 2011 Phase Change - Marketed Launched for Juvenile rheumatoid arthritis in Austria, Czech Republic, Netherlands, United Kingdom, Greece, Spain and Hungary (IV) after August 2011 Updated 09 Apr 2015
03 Aug 2011 Phase Change - Marketed Launched for systemic Juvenile rheumatoid arthritis in European Union (IV) Updated 04 Aug 2011
03 Aug 2011 Phase Change - Registered Registered for systemic Juvenile rheumatoid arthritis in European Union (IV) Updated 04 Aug 2011
31 Jul 2011 Trial Update Roche completes the ACT-STAR phase III trial in Rheumatoid arthritis in USA (NCT00891020) Updated 08 Dec 2011
28 Jul 2011 Trial Update Roche initiates enrolment in a phase III trial for Rheumatoid arthritis in Austria (EudraCT2011-001863-39) Updated 31 Oct 2011
19 Jul 2011 Trial Update Roche completes enrolment in its phase III trial for Rheumatoid arthritis (SC) in Australia, Canada, Europe, Latin America, New Zealand, South Africa and South-East Asia (NCT01194414) Updated 01 Aug 2011
19 Jul 2011 Scientific Update Interim efficacy and adverse event data from a phase III trial of subcutaneouly injected tocilizumab in Rheumatoid arthritis released by Chugai Pharmaceutical [167] Updated 20 Jul 2011
01 Jul 2011 Phase Change - II Phase-II clinical trials in Polymyalgia rheumatica in USA (IV) (NCT01396317) Updated 23 May 2016
31 May 2011 Trial Update Chugai initiates enrolment in a phase III extension trial for Rheumatoid arthritis in Taiwan (NCT01347983) Updated 24 Apr 2012
28 May 2011 Scientific Update Efficacy and adverse events data from the phase III LITHE trial in Rheumatoid arthritis presented at the 12th Annual Congress of the European League Against Rheumatism (EULAR-2011) [66] Updated 18 Jul 2011
26 May 2011 Phase Change - Registered Registered for Juvenile rheumatoid arthritis in Mexico (IV) Updated 30 May 2011
26 May 2011 Scientific Update Efficacy and adverse events data from the phase IIIB ACT-RAY trial in Rheumatoid arthritis released by Roche [112] Updated 30 May 2011
20 May 2011 Regulatory Status CHMP recommends approval of tocilizumab for systemic Juvenile rheumatoid arthritis (in patients from 2 years and above) in European Union [116] Updated 24 May 2011
18 Apr 2011 Trial Update Roche completes the phase III PICTURE trial in Rheumatoid arthritis in Egypt (NCT01063062) Updated 06 May 2011
16 Apr 2011 Phase Change - Marketed Launched for systemic Juvenile rheumatoid arthritis in USA (IV) Updated 19 Apr 2011
31 Mar 2011 Trial Update Roche initiates enrolment in a phase III trial for Rheumatoid arthritis in Germany (NCT01332994) Updated 27 May 2014
29 Mar 2011 Trial Update Roche initiates enrolment in a Phase-III trial for Rheumatoid arthritis (Mid-stage disease, Late-stage disease, combination therapy) in USA, Argentina, Australia, Brazil, Bulgaria, Canada, Colombia, Greece, Guatemala, Hungary, Israel, Malaysia, Mexico, New Zealand, Phillipines, Russia, South Africa, Spain, Swizerland, Thailand and Poland (NCT01232569) Updated 15 Apr 2011
01 Mar 2011 Trial Update Roche initiates a phase IIIb trial for Rheumatoid arthritis (Combination therapy, Treatment-experienced) in Indonesia (IV) (NCT01353859) Updated 03 Oct 2016
01 Mar 2011 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis (Combination therapy, Late-stage disease, Mid-stage disease) in Panama (SC) Updated 04 Mar 2015
01 Mar 2011 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis (Mid-stage disease, Late-stage disease, Combination therapy) in Malaysia (SC) Updated 04 Mar 2015
28 Feb 2011 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis (combination therapy) in Bosnia-Herzegovina (SC) Updated 20 Jun 2011
28 Feb 2011 Trial Update Roche initiates enrolment in the ALABASTER trial for Rheumatoid arthritis (combination therapy) in Bosnia-Herzagovina (NCT01235507) Updated 20 Jun 2011
18 Jan 2011 Trial Update Roche initiates enrolment in a phase III trial for Rheumatoid arthritis in South Africa (NCT01214733) Updated 11 Feb 2011
06 Jan 2011 Regulatory Status US FDA extends label to include inhibition and slowing of structural joint damage, improvement of physical function, and achievement of major clinical response in adults with moderate to severe Rheumatoid arthritis [35] Updated 06 Jan 2011
31 Dec 2010 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis (combination therapy, moderate to severe disease) in Taiwan (SC) Updated 26 May 2011
14 Dec 2010 Phase Change - III Phase-III clinical trials in Ankylosing spondylitis in United Kingdom (IV) Updated 05 Jan 2011
14 Dec 2010 Trial Update Roche initiates enrolment in Phase-III trials for Ankylosing spondylitis in USA (IV) Updated 05 Jan 2011
13 Dec 2010 Trial Update Roche completes enrolment in its phase III trial in Rhematoid arthritis in EU, Turkey, Switzerland, the US, Canada and Australia (IV) Updated 13 Dec 2010
18 Nov 2010 Phase Change - III Phase-III clinical trials in Ankylosing spondylitis in USA (IV) Updated 08 Dec 2010
11 Nov 2010 Scientific Update Efficacy and adverse events data from the phase III TENDER trial in Juvenile rheumatoid arthritis presented at the 74th Annual Scientific Meeting of the American College of Rheumatology and the 45th Annual Meeting of the Association of Rheumatology Health Professionals (ACR/ARHP-2010) [131] Updated 10 Dec 2010
11 Nov 2010 Scientific Update Efficacy, adverse events, pharmacodynamics and pharamcokinetics data from a clinical trial in Rheumatoid arthritis presented at the 74th Annual Scientific Meeting of the American College of Rheumatology and the 45th Annual Meeting of the Association of Rheumatology Health Professionals (ACR/ARHP-2010) [257] Updated 09 Dec 2010
11 Nov 2010 Scientific Update Efficacy data from phase III GROWTH95, GROWTH96 and LITHE extension trials in Rheumatoid arthritis presented at the 74th Annual Scientific Meeting of the American College of Rheumatology and the 45th Annual Meeting of the Association of Rheumatology Health Professionals (ACR/ARHP-2010) [258] Updated 06 Dec 2010
02 Nov 2010 Trial Update ChoongWae completes a phase III trial (NCT01211834) for Rheumatoid arthritis in South Korea Updated 30 Nov 2010
18 Oct 2010 Phase Change - Preregistration Preregistration for systemic Juvenile rheumatoid arthritis in USA (IV) Updated 14 Jan 2011
18 Oct 2010 Phase Change - Preregistration Preregistration for systemic Juvenile rheumatoid arthritis in European Union (IV) Updated 14 Jan 2011
01 Sep 2010 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis (late-stage disease & mid-stage disease) in Brazil, Colombia, Guatemela, Mexico, Peru, Puerto Rico, Philippines, Singapore and Thailand after September 2010 (SC) Updated 11 Feb 2014
01 Sep 2010 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis (combination therapy) in USA (SC) Updated 28 Sep 2010
01 Sep 2010 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis in Australia (SC) Updated 28 Sep 2010
01 Sep 2010 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis in Canada (SC) Updated 28 Sep 2010
01 Sep 2010 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis in European Union (SC) Updated 28 Sep 2010
01 Sep 2010 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis in Latin America (SC) Updated 28 Sep 2010
01 Sep 2010 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis in New Zealand (SC) Updated 28 Sep 2010
01 Sep 2010 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis in South Africa (SC) Updated 28 Sep 2010
01 Sep 2010 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis in South-East Asia (SC) Updated 28 Sep 2010
01 Sep 2010 Trial Update Roche initiates enrolment in a multinational phase III trial of subcutaneous versus intravenous tocilizumab in combination with DMARDs in patients with Rheumatoid arthritis Updated 28 Sep 2010
16 Aug 2010 Trial Update Roche completes a phase III trial in Rheumatoid arthritis in China Updated 08 Sep 2010
16 Aug 2010 Trial Update Roche completes a phase III trial (NCT00848120) in mid-stage to late-stage Rheumatoid arthritis in Philippines Updated 27 Aug 2010
10 Aug 2010 Phase Change - Marketed Launched for Rheumatoid arthritis (Late-stage disease, Mid-stage disease) in Austria, Belgium, Finland, Norway, Denmark, Ireland, Poland, Portugal, Sweden, Netherlands, Czech Republic, Greece, Spain and Hungary (IV) after August 2010 Updated 09 Apr 2015
05 Aug 2010 Trial Update Roche completes enrolment in its phase III mechanism of action study for Rheumatoid arthritis (NCT00535782) Updated 09 Sep 2010
04 Aug 2010 Scientific Update Interim adverse events and efficacy data from a post-marketing study in Juvenile rheumatoid arthritis released by Chugai [24] Updated 11 Aug 2010
04 Aug 2010 Scientific Update Interim adverse events and efficacy data from a post-marketing study in Rheumatoid arthritis released by Chugai [24] Updated 11 Aug 2010
04 Aug 2010 Regulatory Status Japaneses Ministry of Health, Labour and Welfare removes surveillance conditions for tocilizumab treatment of Rheumatoid arthritis and Polyarticular-course juvenile idiopathic arthritis in Japan [24] Updated 10 Aug 2010
18 Jun 2010 Scientific Update Interim efficacy data from the phase III TENDER trial in Juvenile rheumatoid arthritis released by Roche [259] , [129] Updated 21 Jun 2010
08 Jun 2010 Regulatory Status European Commission extends tocilizumab's indications to include reduction in the rate of joint damage progression and improvement in physical function in patients with rheumatoid arthritis (when administered in combination with methotrexate) in Europe [32] Updated 11 Jun 2010
31 May 2010 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis in Japan (SC) Updated 14 Jan 2011
31 May 2010 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis in Japan (SC) Updated 29 Jul 2010
26 May 2010 Trial Update Roche completes a phase III trial in Rheumatoid arthritis (Monotherapy, Combination therapy) in Finland (IV)(NCT00810277) Updated 09 Aug 2017
26 May 2010 Phase Change - Marketed Launched for Rheumatoid arthritis in Canada (IV) Updated 10 Aug 2010
25 May 2010 Trial Update Hoffmann-La Roche completes enrolment in a phase III trial of tocilizumab in patients with Rheumatoid arthritis who have had an inadequate response to non-Biologic DMARDs in Finland (NCT00910277) Updated 04 Jun 2010
05 May 2010 Phase Change - Registered Registered for Rheumatoid arthritis in Canada (IV) Updated 06 May 2010
30 Apr 2010 Trial Update Roche initiates enrolment in a phase III ADACTA trial in Rheumatoid arthritis Updated 28 Jul 2011
23 Apr 2010 Regulatory Status EMA recommends approval of tocilizumab for reduction in joint damage and improved physical function in patients with Rheumatoid arthritis in European Union [33] Updated 27 Apr 2010
31 Mar 2010 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis (treatment-experienced patients) in Morocco (IV) Updated 25 Jun 2012
17 Mar 2010 Regulatory Status Roche files sBLA for the prevention of structural joint damage and to improve physical function in Rheumatoid arthritis in USA [36] , [68] Updated 19 Mar 2010
27 Feb 2010 Trial Update Roche completes enrolment in a phase III trial of tocilizumab in combination with DMARDs Rheumatoid arthritis in China Updated 04 Mar 2010
26 Feb 2010 Trial Update Roche completes enrolment in a phase III trial (in combination with DMARD therapy) for Rheumatoid arthritis in China Updated 04 Mar 2010
23 Feb 2010 Trial Update Roche completes enrolment in a phase III study of the effect of tocilizumab on markers of atherogenic risk in Rheumatoid arthritis in USA, Canada, Puerto Rico and the United Kingdom Updated 04 Mar 2010
23 Feb 2010 Trial Update Roche initiates enrolment in a phase II study comparing infusion rates of tocilizumab in Rheumatoid arthritis in Spain Updated 04 Mar 2010
03 Feb 2010 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis in Egypt (IV) Updated 17 Feb 2010
25 Jan 2010 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis in Puerto Rico (IV) Updated 17 Feb 2010
25 Jan 2010 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis in Thailand (IV) Updated 17 Feb 2010
18 Jan 2010 Phase Change - Marketed Launched for Rheumatoid arthritis in USA (IV) Updated 20 Jan 2010
09 Jan 2010 Phase Change - Registered Registered for Rheumatoid arthritis in USA (IV) Updated 12 Jan 2010
01 Jan 2010 Trial Update Roche initiates a phase III trial for Rheumatoid arthritis in the Netherlands (NCT01034137) Updated 14 Nov 2014
31 Dec 2009 Phase Change - Marketed Launched for Rheumatoid arthritis in European Union (IV) Updated 10 Aug 2010
31 Dec 2009 Phase Change - Registered Registered for Rheumatoid arthritis in Mexico (IV) Updated 12 Jan 2010
20 Nov 2009 Trial Update Roche initiates enrolment in the phase III WA19926 trial for Rheumatoid arthritis in Canada Updated 20 Jan 2010
20 Nov 2009 Scientific Update Top-line efficacy & adverse events data from the phase III TENDER trial in Juvenile rheumatoid arthritis released by Roche [130] Updated 24 Nov 2009
19 Nov 2009 Phase Change - III Phase-III clinical trials in Juvenile rheumatoid arthritis in Peru (IV) Updated 25 Oct 2011
19 Nov 2009 Phase Change - III Phase-III clinical trials in Juvenile rheumatoid arthritis in Russia (IV) Updated 25 Oct 2011
16 Nov 2009 Phase Change - Marketed Launched for Rheumatoid arthritis in New Zealand (IV) Updated 10 Aug 2010
31 Oct 2009 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis (early-stage disease) in Macedonia (IV) Updated 12 Jun 2014
31 Oct 2009 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis (early stage disease) in Argentina, Colombia, Guatemala, Hong Kong, Israel, Mexico, Panama, Peru, Philippines, Puerto Rico, Russia, Singapore and Thailand after October 2009 (IV) Updated 11 Feb 2014
31 Oct 2009 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis in South Korea (IV) Updated 15 Oct 2010
31 Oct 2009 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis (early-stage disease) in the EU (IV) Updated 01 Jun 2010
31 Oct 2009 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis (early-stage disease) in Asia (IV) Updated 01 Jun 2010
31 Oct 2009 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis (early-stage disease) in Australia (IV) Updated 01 Jun 2010
31 Oct 2009 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis (early-stage disease) in Canada (IV) Updated 01 Jun 2010
31 Oct 2009 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis (early-stage disease) in Eastern Europe (IV) Updated 01 Jun 2010
31 Oct 2009 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis (early-stage disease) in New Zealand (IV) Updated 01 Jun 2010
31 Oct 2009 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis (early-stage disease) in South Africa (IV) Updated 01 Jun 2010
31 Oct 2009 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis (early-stage disease) in USA (IV) Updated 01 Jun 2010
31 Oct 2009 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis (early-stage disease) in Latin America (IV) Updated 01 Jun 2010
27 Oct 2009 Phase Change - Discontinued(I) Discontinued - Phase-I for Giant lymph node hyperplasia in USA (IV) Updated 22 Jan 2010
27 Oct 2009 Phase Change - Discontinued(I) Discontinued - Phase-I for Systemic lupus erythematosus in Japan (IV) Updated 22 Jan 2010
27 Oct 2009 Phase Change - Discontinued(II) Discontinued - Phase-II for Crohn's disease in Japan (IV) Updated 22 Jan 2010
27 Oct 2009 Phase Change - Discontinued(II) Discontinued - Phase-II for Multiple myeloma in France (IV) Updated 22 Jan 2010
27 Oct 2009 Phase Change - I/II Phase-I/II clinical trials in Pancreatic cancer in Japan (IV) Updated 22 Jan 2010
21 Oct 2009 Scientific Update Efficacy and adverse events data from clinical trials presented at the 73rd Annual Scientific Meeting of the American College of Rheumatology and the 44th Annual Meeting of the Association of Rheumatology Health Professionals (ACR/ARHP-2009) [260] , [261] , [262] , [263] , [264] , [265] , [266] Updated 10 Nov 2009
21 Oct 2009 Scientific Update Efficacy data from two long-term extension studies presented at the 73rd Annual Scientific Meeting of the American College of Rheumatology and the 44th Annual Meeting of the Association of Rheumatology Health Professionals (ACR/ARHP-2009) [267] Updated 21 Oct 2009
18 Oct 2009 Scientific Update Long-term efficacy and adverse events data from a pooled analysis of five phase III trials and two extension studies in Rheumatoid arthritis presented at the 73rd Annual Scientific Meeting of the American College of Rheumatology and the 44th Annual Meeting of the Association of Rheumatology Health Professionals (ACR/ARHP-2009) [268] Updated 22 Oct 2009
18 Oct 2009 Scientific Update Two-year efficacy data from the phase III LITHE trial in Rheumatoid arthritis presented at the 73rd Annual Scientific Meeting of the American College of Rheumatology and the 44th Annual Meeting of the Association of Rheumatology Health Professionals (ACR/ARHP-2009) [268] Updated 22 Oct 2009
30 Sep 2009 Regulatory Status Roche submits filing to extend the indication of tocilizumab to inhibit the progression of joint damage and to improve physical function in patients with rheumatoid arthritis in European Union [34] Updated 02 Oct 2009
22 Sep 2009 Phase Change - Registered Registered for Rheumatoid arthritis in New Zealand (IV) Updated 12 Jan 2010
31 Jul 2009 Phase Change - Marketed Launched for Rheumatoid arthritis in Australia (IV) Updated 12 Jan 2010
23 Jul 2009 Phase Change - I/II Phase-I/II clinical trials in Rheumatoid arthritis in New Zealand (IV) Updated 29 Sep 2009
30 Jun 2009 Phase Change - Marketed Launched for Rheumatoid arthritis in Brazil (IV) Updated 12 Jan 2010
30 Jun 2009 Phase Change - Marketed Launched for Rheumatoid arthritis in France (IV) Updated 12 Jan 2010
30 Jun 2009 Phase Change - Marketed Launched for Rheumatoid arthritis in Germany (IV) Updated 12 Jan 2010
30 Jun 2009 Phase Change - Marketed Launched for Rheumatoid arthritis in India (IV) Updated 12 Jan 2010
30 Jun 2009 Phase Change - Marketed Launched for Rheumatoid arthritis in United Kingdom (IV) Updated 12 Jan 2010
10 Jun 2009 Phase Change - Registered Registered for Rheumatoid arthritis in Australia (IV) Updated 11 Jun 2009
10 Jun 2009 Phase Change - Registered Registered for Rheumatoid arthritis in Brazil (IV) Updated 11 Jun 2009
25 May 2009 Scientific Update Two-year efficacy data from the LITHE trial in Rheumatoid arthritis released by Roche Updated 27 May 2009
01 Mar 2009 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis (Late-stage disease, Mid-stage disease) in Croatia, Israel, Norway, Russia, Serbia and Thailand (IV) Updated 10 Sep 2014
19 Feb 2009 Phase Change - III Phase-III clinical trials in mid-stage to late-stage Rheumatoid arthritis in Philippines (IV) Updated 27 Aug 2010
21 Jan 2009 Phase Change - Registered Registered for Rheumatoid arthritis in European Union (IV) Updated 23 Jan 2009
31 Dec 2008 Phase Change - Registered Registered for Rheumatoid arthritis in India (IV) Updated 23 Jan 2009
16 Dec 2008 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis in patients who have had an inadequate response to non-biologic DMARDs in Finland (IV) Updated 04 Jun 2010
03 Dec 2008 Phase Change - Registered Registered for Rheumatoid arthritis in Switzerland (IV) Updated 08 Dec 2008
25 Nov 2008 Regulatory Status The Committee for Medicinal Products for Human Use (CHMP) recommends that approval be granted for tocilizumab in the EU for moderate to severe rheumatoid arthritis Updated 25 Nov 2008
31 Oct 2008 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis in China (IV) Updated 16 Dec 2008
29 Oct 2008 Scientific Update Efficacy and adverse events data from the LITHE, RADIATE, and AMBITION trials presented at the 72nd Annual Scientific Meeting of the American College of Rheumatology and the 43rd Annual Meeting of the Association of Rheumatology Health Professionals (ACR/ARHP-2008) [269] , [270] , [271] , [272] , [273] , [274] Updated 05 Nov 2008
20 Oct 2008 Scientific Update Serious adverse events data from clinical trials in Rheumatoid arthritis released by Roche [275] Updated 23 Oct 2008
30 Sep 2008 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis in Australia (IV) Updated 16 Dec 2008
30 Sep 2008 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis in Canada (IV) Updated 16 Dec 2008
30 Sep 2008 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis in Turkey (IV) Updated 16 Dec 2008
22 Sep 2008 Regulatory Status Roche receives complete response letter from the FDA for tocilizumab in Rheumatoid arthritis Updated 22 Sep 2008
07 Aug 2008 Phase Change - III Phase-III clinical trials in Juvenile rheumatoid arthritis in South America (IV) Updated 16 Dec 2008
07 Aug 2008 Phase Change - III Phase-III clinical trials in Juvenile rheumatoid arthritis in Europe (IV) Updated 07 Aug 2008
07 Aug 2008 Phase Change - III Phase-III clinical trials in Juvenile rheumatoid arthritis in North America (IV) Updated 07 Aug 2008
31 Jul 2008 Licensing Status Chugai Pharmaceutical enters into a toll manufacturing and supply agreement with Genentech Updated 07 Aug 2008
30 Jul 2008 Regulatory Status US FDA Advisory Committee recommends approval for rheumatoid arthritis in USA Updated 31 Jul 2008
29 Jul 2008 Regulatory Status US FDA action date for NDA review in rheumatoid arthritis is targeted for September 2008 Updated 29 Jul 2008
03 Jul 2008 Phase Change - Discontinued(I) Discontinued - Phase-I for Multiple myeloma in USA (IV) Updated 03 Jul 2008
03 Jul 2008 Phase Change - Discontinued(II) Discontinued - Phase-II for Giant lymph node hyperplasia in European Union (IV) Updated 03 Jul 2008
14 Jun 2008 Scientific Update Pooled efficacy data from the OPTION and TOWARD phase III trials in Rheumatoid arthritis presented at the 2008 Annual European Congress of Rheumatology (EULAR-2008) [276] , [277] , [278] Updated 21 Aug 2008
14 Jun 2008 Scientific Update Efficacy data from phase III trials in Rheumatoid arthritis presented at the Annual European Congress of Rheumatology (EULAR-2008) [279] , [280] Updated 07 Jul 2008
14 Jun 2008 Scientific Update Final adverse events data from the phase III AMBITION trial in rheumatoid arthritis presented at the Annual European Congress of Rheumatology (EULAR-2008) [72] Updated 07 Jul 2008
14 Jun 2008 Scientific Update Final efficacy data from the phase III AMBITION, RADIATE, and TOWARD trials in Rheumatoid arthritis presented at the Annual European Congress of Rheumatology (EULAR-2008) [73] , [281] , [282] Updated 20 Jun 2008
31 May 2008 Phase Change - III Phase-III clinical trials in Juvenile rheumatoid arthritis in Greece (IV) Updated 09 Aug 2010
31 May 2008 Phase Change - III Phase-III clinical trials in Juvenile rheumatoid arthritis in Netherlands (IV) Updated 09 Aug 2010
31 May 2008 Phase Change - III Phase-III clinical trials in Juvenile rheumatoid arthritis in Belgium (IV) Updated 01 Jun 2010
31 May 2008 Phase Change - III Phase-III clinical trials in Juvenile rheumatoid arthritis in Canada (IV) Updated 01 Jun 2010
31 May 2008 Phase Change - III Phase-III clinical trials in Juvenile rheumatoid arthritis in Czech Republic (IV) Updated 01 Jun 2010
31 May 2008 Phase Change - III Phase-III clinical trials in Juvenile rheumatoid arthritis in Denmark (IV) Updated 01 Jun 2010
31 May 2008 Phase Change - III Phase-III clinical trials in Juvenile rheumatoid arthritis in Germany (IV) Updated 01 Jun 2010
31 May 2008 Phase Change - III Phase-III clinical trials in Juvenile rheumatoid arthritis in Italy (IV) Updated 01 Jun 2010
31 May 2008 Phase Change - III Phase-III clinical trials in Juvenile rheumatoid arthritis in Mexico (IV) Updated 01 Jun 2010
31 May 2008 Phase Change - III Phase-III clinical trials in Juvenile rheumatoid arthritis in Poland (IV) Updated 01 Jun 2010
31 May 2008 Phase Change - III Phase-III clinical trials in Juvenile rheumatoid arthritis in Slovakia (IV) Updated 01 Jun 2010
31 May 2008 Phase Change - III Phase-III clinical trials in Juvenile rheumatoid arthritis in Spain (IV) Updated 01 Jun 2010
31 May 2008 Phase Change - III Phase-III clinical trials in Juvenile rheumatoid arthritis in Sweden (IV) Updated 01 Jun 2010
31 May 2008 Phase Change - III Phase-III clinical trials in Juvenile rheumatoid arthritis in United Kingdom (IV) Updated 01 Jun 2010
31 May 2008 Phase Change - III Phase-III clinical trials in Juvenile rheumatoid arthritis in Australia (IV) Updated 03 Jul 2008
09 May 2008 Scientific Update One-year efficacy and safety data from the LITHE study in Rheumatoid arthritis released by Roche [283] , [284] Updated 15 May 2008
16 Apr 2008 Phase Change - Marketed Launched for Juvenile rheumatoid arthritis in Japan (Injection) Updated 18 Apr 2008
16 Apr 2008 Phase Change - Marketed Launched for Rheumatoid arthritis in Japan (IV) Updated 18 Apr 2008
16 Apr 2008 Phase Change - Registered Registered for Juvenile rheumatoid arthritis in Japan (Injection) Updated 18 Apr 2008
16 Apr 2008 Phase Change - Registered Registered for Rheumatoid arthritis in Japan (IV) Updated 18 Apr 2008
01 Apr 2008 Trial Update Roche completes a phase I trial in Rheumatoid arthritis (Combination therapy, In adults, In the elderly, Treatment-experienced) in New Zealand, USA (IV) (NCT00365001) Updated 10 Jul 2017
29 Nov 2007 Phase Change - Preregistration Preregistration for Rheumatoid arthritis in European Union (IV) Updated 05 Dec 2007
21 Nov 2007 Phase Change - Preregistration Preregistration for Rheumatoid arthritis in USA (IV) Updated 23 Nov 2007
15 Nov 2007 Scientific Update Data presented at the 71st Annual Scientific Meeting of the American College of Rheumatology and the 42nd Annual Meeting of the Association of Rheumatology Health Professionals (ACR/AHRP-2007) added to the adverse events and Rheumatic Disease therapeutic trials sections [285] , [286] Updated 15 Nov 2007
30 Jul 2007 Scientific Update Interim results from a phase III clinical trial (AMBITION) in rheumatoid arthritis added to the adverse events and Rheumatic Disease therapeutic trials sections [74] Updated 30 Jul 2007
11 Jul 2007 Scientific Update Results from a phase III clinical trial (RADIATE) in patients with rheumatoid arthritis added to the adverse events and Rheumatic Disease therapeutic trials sections [78] Updated 11 Jul 2007
25 Jun 2007 Scientific Update Data presented at the Annual European Congress of Rheumatology (EULAR-2007) added to the adverse events and Rheumatic Disease therapeutic trials sections [287] , [288] , [289] Updated 25 Jun 2007
08 Jun 2007 Scientific Update Results from a phase III clinical trial (TOWARD) in rheumatoid arthritis added to the Rheumatic Disease therapeutic trials section [76] Updated 08 Jun 2007
26 Jan 2007 Scientific Update Interim results from a phase III clinical trial (OPTION) in rheumatoid arthritis have been added to the Rheumatic Disease therapeutic trials section Updated 26 Jan 2007
01 Dec 2006 Scientific Update Data presented at the 70th Annual Scientific Meeting of the American College of Rheumatology (ACR-2006) added to the adverse events and Rheumatic Disease therapeutic trials sections [290] Updated 01 Dec 2006
06 Nov 2006 Phase Change - No development reported(II) No development reported - Phase-II for Giant lymph node hyperplasia in European Union (Injection) Updated 06 Nov 2006
29 Sep 2006 Phase Change - III Phase-III clinical trials in Juvenile rheumatoid arthritis in United Kingdom (Injection) Updated 06 Nov 2006
28 Apr 2006 Phase Change - Preregistration Preregistration for Juvenile rheumatoid arthritis in Japan (Injection) Updated 02 May 2006
28 Apr 2006 Phase Change - Preregistration Preregistration for Rheumatoid arthritis in Japan (IV-infusion) Updated 02 May 2006
28 Apr 2006 Scientific Update Results from a phase III clinical trial in patients with rheumatoid arthritis have been added to the adverse events and Rheumatic Disease therapeutic trials sections [291] Updated 28 Apr 2006
01 Apr 2006 Trial Update Chugai Pharmaceutical completes a phase III trial in Rheumatoid arthritis (In adults, In the elderly) in Japan (IV) (NCT00144521) Updated 11 Jun 2018
01 Feb 2006 Trial Update Chugai Pharmaceutical completes the phase III SAMURAI trial in Rheumatoid arthritis in Japan (IV) (NCT00144508) Updated 11 Jun 2018
01 Nov 2005 Phase Change - I Phase-I clinical trials in Rheumatoid arthritis (Combination therapy, In adults, In the elderly, Treatment-experienced) in New Zealand, USA (IV) (NCT00365001) Updated 10 Jul 2017
20 Oct 2005 Scientific Update Data from a media release have been added to the adverse events and Rheumatic Disease therapeutic trials sections [292] Updated 20 Oct 2005
04 Aug 2005 Trial Update Chugai Pharmaceutical has completed Phase-III trials in Rheumatoid arthritis in Japan Updated 06 Sep 2005
13 Jun 2005 Phase Change First global launch for Giant lymph node hyperplasia in Japan (Injection) Updated 21 Jun 2005
14 Apr 2005 Phase Change - Registered Registered for Giant lymph node hyperplasia in Japan (Injection) Updated 21 Apr 2005
10 Feb 2005 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis in Europe (IV-infusion) Updated 21 Apr 2005
10 Feb 2005 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis in USA (IV-infusion) Updated 21 Apr 2005
01 Nov 2004 Scientific Update Data presented at the 68th Annual Scientific Meeting of the American College of Rheumatology and the 39th Annual Meeting of the Association of Rheumatology Health Professionals (ACR/ARHP-2004) have been added to the Rheumatic Disease pharmacodynamics and Therapeutic trials sections [293] , [294] Updated 01 Nov 2004
21 Oct 2004 Phase Change - III Phase-III clinical trials in Juvenile rheumatoid arthritis in Japan (IV-infusion) Updated 22 Nov 2004
15 Jun 2004 Scientific Update A study has been added to the adverse events and inflammatory bowel disorders therapeutic trials sections [295] Updated 15 Jun 2004
01 Feb 2004 Trial Update Chugai Pharmaceutical initiates a phase III trial in Rheumatoid arthritis (In adults, In the elderly) in Japan (IV) (NCT00144521) Updated 11 Jun 2018
13 Nov 2003 Scientific Update Data from a media release have been added to the Rheumatic Disease therapeutic trials section [296] Updated 13 Nov 2003
14 Aug 2003 Scientific Update A study has been added to the adverse events and Rheumatic Disease therapeutic trials sections [297] Updated 14 Aug 2003
31 Jul 2003 Scientific Update A study has been added to the Cancer therapeutic trials section [298] Updated 31 Jul 2003
30 Jul 2003 Phase Change - I Phase-I clinical trials in Giant lymph node hyperplasia in USA (Injection) Updated 30 Jul 2003
30 Jul 2003 Phase Change - I Phase-I clinical trials in Systemic lupus erythematosus in USA (Injection) Updated 30 Jul 2003
30 Jul 2003 Trial Update Chugai has completed a phase II trial in Rheumatoid arthritis in European Union Updated 30 Jul 2003
08 Jul 2003 Scientific Update Data presented at the Annual European Congress of Rheumatology (EULAR-2003) have been added to the adverse events and Rheumatic Disease therapeutic trials sections [299] Updated 08 Jul 2003
31 May 2003 Phase Change - Preclinical Preclinical trials in Systemic lupus erythematosus in USA (Injection) Updated 10 Jun 2003
30 May 2003 Phase Change - Preregistration Preregistration for Giant lymph node hyperplasia in Japan (Injection) Updated 24 Jun 2003
28 May 2003 Scientific Update A study has been added to the adverse events and Rheumatic Disease therapeutic trials sections [300] Updated 28 May 2003
28 Apr 2003 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis in Japan (Injection) Updated 09 Jun 2003
11 Apr 2003 Licensing Status MRA has been licensed to Roche worldwide, except for Japan, South Korea and Taiwan Updated 11 Apr 2003
01 Mar 2003 Trial Update Chugai Pharmaceutical initiates the phase III SAMURAI trial in Rheumatoid arthritis in Japan (IV) (NCT00144508) Updated 11 Jun 2018
11 Dec 2002 Phase Change - I Phase-I clinical trials in Multiple myeloma in USA (Injection) Updated 11 Dec 2002
28 Nov 2002 Licensing Status MRA is available for licensing worldwide, except for Japan and Korea (http://www.chugai-pharm.co.jp) Updated 28 Nov 2002
28 Nov 2002 Regulatory Status MRA has received orphan drug status for Giant lymph node hyperplasia in Japan Updated 28 Nov 2002
30 Oct 2002 Company Involvement Chugai Pharmaceutical has been acquired by Roche Updated 30 Oct 2002
30 Oct 2002 Phase Change - II Phase-II clinical trials in Juvenile rheumatoid arthritis in United Kingdom (Injection) Updated 30 Oct 2002
13 Aug 2002 Phase Change - I Phase-I clinical trials in Multiple myeloma in USA (Injection) Updated 15 May 2006
13 Aug 2002 Phase Change - II Phase-II clinical trials in Multiple myeloma in France (Injection) Updated 15 May 2006
01 Jul 2002 Scientific Update A phase II trial in Japan in rheumatoid arthritis has been completed Updated 01 Jul 2002
20 May 2002 Phase Change - I Phase-I clinical trials in Juvenile rheumatoid arthritis in United Kingdom (Injection) Updated 14 Oct 2002
20 May 2002 Phase Change - II Phase-II clinical trials in Juvenile rheumatoid arthritis in Japan (Injection) Updated 14 Oct 2002
12 Nov 2001 Phase Change - II Phase-II clinical trials for Crohn's disease in Japan (Injection) Updated 12 Nov 2001
12 Nov 2001 Phase Change - II Phase-II clinical trials for Giant lymph node hyperplasia in European Union (Injection) Updated 12 Nov 2001
12 Nov 2001 Phase Change - II Phase-II clinical trials for Giant lymph node hyperplasia in Japan (Injection) Updated 12 Nov 2001
12 Nov 2001 Phase Change - II Phase-II clinical trials for Giant lymph node hyperplasia in USA (Injection) Updated 12 Nov 2001
12 Nov 2001 Phase Change - II Phase-II clinical trials for Multiple myeloma in European Union (Injection) Updated 12 Nov 2001
12 Nov 2001 Phase Change - II Phase-II clinical trials for Multiple myeloma in USA (Injection) Updated 12 Nov 2001
12 Nov 2001 Phase Change - II Phase-II clinical trials for Rheumatoid arthritis in USA (Injection) Updated 12 Nov 2001
31 Mar 2001 Phase Change - II Phase-II clinical trials for Rheumatoid arthritis in United Kingdom (Injection) Updated 31 Mar 2001
29 Jun 2000 Scientific Update A preclinical study has been added to the Inflammatory Bowel Disorders pharmacodynamics section [301] Updated 29 Jun 2000
26 Jun 2000 Licensing Status Patent licence agreement reached between Chugai and Protein Design Labs Updated 26 Jun 2000
12 May 2000 Phase Change - II Phase-II clinical trials for Rheumatoid arthritis in Japan (Injection) Updated 12 May 2000
01 Nov 1999 Phase Change - I Phase-I clinical trials for Multiple myeloma in Japan (Injection) Updated 01 Nov 1999
25 Nov 1998 Phase Change - I Phase-I clinical trials for Rheumatoid arthritis in Japan (Injection) Updated 25 Nov 1998
25 Nov 1998 Phase Change - I Phase-I clinical trials for Rheumatoid arthritis in United Kingdom (Injection) Updated 25 Nov 1998
28 Jul 1998 Phase Change - I Phase-I clinical trials for Rheumatic disorders in Japan (Unknown route) Updated 28 Jul 1998
28 Jul 1998 Phase Change - I Phase-I clinical trials for Rheumatic disorders in United Kingdom (Unknown route) Updated 28 Jul 1998
11 Jun 1998 Phase Change - Preclinical Preclinical development for Rheumatic disorders in Japan (Unknown route) Updated 11 Jun 1998

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