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] .
