Rheumatoid arthritis (RA)
In February 2018, Asahi Kasei Pharma launched 150mg syringe and 200mg syringe subcutaneous injection of sarilumab in Japan  .
As at December 2017, sarilumab is available in the US for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have an inadequate response or intolerance to one or more biologic or non-biologic Disease-Modifying Anti-Rheumatic Drugs (DMARDs)  . In May 2017, Sanofi and Regeneron had received approval for sarilumab from the US FDA. Sarilumab may be used as monotherapy or in combination with methotrexate or other conventional DMARDs. The recommended dosage of Kevzara is 200mg once every two weeks given as a subcutaneous injection. The dosage can be reduced from 200mg to 150mg once every two weeks, as needed, to help manage certain laboratory abnormalities. The approval was based on data from approximately 2 900 adults with moderately to severely active RA who had an inadequate response to previous treatment regimens. In the US, sarilumab will be marketed by Regeneron and Sanofi Genzyme  . In October 2016, the US FDA issued a Complete Response Letter (CRL) regarding the Biologics License Application (BLA) for sarilumab. The CRL did not identify any concerns relating to the safety or efficacy of sarilumab. The letter referred to certain deficiencies identified during a routine good manufacturing practice inspection of the Sanofi Le Trait facility in France where sarilumab is filled and finished. Sanofi submitted a comprehensive corrective action plan to the FDA and is implementing the corrective actions specified in that plan. Sanofi is working closely with the FDA towards a timely resolution that addresses these concerns. In April 2017, the USFDA accepted the resubmission of the sarilumab Biologics License Application (BLA) as a Class I response with a two month review timeline, with the new Prescription Drug User Fee Act (PDUFA) action date set for May 22, 2017. This resubmission will be subjected to successful completion of an inspection by FDA of Sanofi's Le Trait fill and Finish facility, with an anticipated action date in the second quarter     . It was reported in January 2016, that the BLA seeking approval of sarilumab for the treatment of rheumatoid arthritis had been accepted for review by the US FDA. The BLA was submitted by the third quarter of 2015, and included data from the phase III SARIL-RA programme    .
As at December 2017, sarilumab is available in the UK, Germany, Nehterlands and France for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have an inadequate response or intolerance to one or more biologic or non-biologic Disease-Modifying Anti-Rheumatic Drugs (DMARDs)  . In June 2017, the European Commission had granted marketing authorisation for sarilumab. In April 2017, Committee for Medicinal Products for Human Use (CHMP) of the EMA adopted a positive opinion for the marketing authorisation of sarilumab, recommending its approval for use in adult patients with moderately to severely active rheumatoid arthritis. The positive opinion was based on the seven phase III trials of the global SARIL-RA clinical development programme, which include the trials SARIL-RA-MOBILITY, SARIL-RA-TARGET and SARIL-RA-MONARCH [see below], and data covering over 3 300 adults with moderate-to-severe RA, most of whom have responded inadequately to disease-modifying anti-rheumatic drugs (DMARDs) or anti-tumour necrosis factor alpha (anti-TNFα). The application was accepted for review by the EMA in July 2016     .
In September 2017, the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan approved sarilumab for the treatment of adult patients with rheumatoid arthritis who have had an inadequate response to conventional treatments  . In October 2016, Regeneron Pharmaceuticals submitted an application for marketing approval for sarilumab, in Japan  .
In February 2017, Sanofi Genzyme announced that sarilumab (KevzaraTM) is available in Canada for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have an inadequate response or intolerance to one or more biologic or non-biologic Disease-Modifying Anti-Rheumatic Drugs (DMARDs)   . In January 2017, Regeneron and Sanofi received the first approval for sarilumab from Health Canada  . Sarilumab should be used in combination with methotrexate or other traditional DMARDs, or may be given as monotherapy in cases of intolerance or contraindication to methotrexate or DMARDs. The recommended dose of sarilumab is 200mg once every two weeks given as a subcutaneous injection; dosage can be reduced from 200mg to 150mg once every two weeks to help manage certain laboratory abnormalities. The approval was based on the data from seven studies of the SARIL-RA clinical programme, which includes the trials SARIL-RA-MOBILITY, SARIL-RA-TARGET and SARIL-RA-MONARCH [see below], and data covering over 2 900 adults with moderate-to-severe rheumatoid arthritis. The drug is expected to be marketed by Sanofi Genzyme in Canada   .
In June 2018, long-term safety data (5-year follow-up) from six different clinical trials (TARGET, NCT01709578; MOBILITY, NCT01061736; NCT01764997; NCT01768572; NCT02057250; NCT01217814 and also those who continued into extension trials) was presented at the 19th Annual Congress of the European League Against Rheumatism (EULAR-2018)  .
Regeneron and Sanofi have initiated a global phase III programme for sarilumab called the SARIL-RA programme, intended to evaluate the safety and efficacy of sarilumab, as a monotherapy or in combination with conventional DMARDs, including methotrexate (MTX), to reduce the signs and symptoms, improve physical function and inhibit the radiographic progression of RA. The first study in the programme was the phase IIb/III SARIL-RA-MOBILITY trial in 1 675 patients with rheumatoid arthritis which began in March 2010 (NCT01061736; EudraCT2009-016266-90). The trial was conducted in the US, Argentina, Australia, Austria, Belarus, Belgium, Brazil, Canada, Chile, Colombia, Czech Republic, Egypt, Estonia, Finland, Germany, Greece, Hungary, India, South Korea, Lithuania, Malaysia, Mexico, Netherlands, New Zealand, Norway, Philippines, Poland, Portugal, Romania, Russia, South Africa, Spain, Taiwan, Thailand, Turkey and Ukraine. This study was completed in October 2013 and met all three of its co-primary endpoints   . In both parts, the primary endpoint was the proportion of patients achieving 20% improvement by American College of Rheumatology criteria (ACR20). Results were reported in June 2014      . Pharmacodynamics results from the study were presented by the company at the 80th American College of Rheumatology (ARH-2016) and at the 51st Annual Meeting of the Association of Rheumatology and Health Professionals (ARHP-2016) in November 2016  .
In May 2015, Regeneron and Sanofi announced that the second global phase III trial called SARIL-RA-TARGET in 546 patients who did not respond or were intolerant to anti-TNF therapy, met the co-primary efficacy endpoints of a greater improvement in signs and symptoms of rheumatoid arthritis at 24 weeks and physical function at 12 weeks, compared with placebo (NCT01709578; EudraCT2011-003538-16)  . In this double blind trial, patients received single doses of sarilumab (150mg or 200mg) or placebo in combination with non-biologic disease modifying anti-rheumatic drugs (DMARD) therapy. The trial was initiated in the US in October 2012, and has expanded to Argentina, Australia, Austria, Brazil, Canada, Chile, Colombia, the Czech Republic, Ecuador, Germany, Greece, Hungary, Italy, Lithuania, Mexico, New Zealand, Peru, Poland, Portugal, Romania, Russia, Slovakia, Spain, Taiwan, Turkey and Ukraine. Sanofi completed the trial in April 2015. Trial results were presented at the 79th Annual Scientific Meeting of the American College of Rheumatology    .
In May 2015, Regeneron and Sanofi reported that the phase III trial called SARIL-RA-EASY met its primary endpoint of no technical failure with the sarilumab auto-injection device compared with pre-filled syringes  . The trial, which was completed in March 2016, was a usability study of the sarilumab auto-injector device in 217 patients with moderate to severe active rheumatoid arthritis (NCT02057250; EudraCT2012-004339-21). The open-label trial was conducted in the US, Chile, Mexico, Poland, Russia and South Africa  .
As reported by Regeneron and Sanofi, the phase III SARIL-RA-ASCERTAIN trial met its primary endpoint  . The trial, which was completed in October 2014, compared the tolerability of sarilumab versus tocilizumab, both in combination with methotrexate, in patients with moderate to severe rheumatoid arthritis and inadequate response to TNF-α antagonists (SFY13370; EudraCT2012-003536-23; U1111-1133-7839; NCT01768572). The randomised, double-blind trial was initiated in March 2013 and enrolled 202 patients in the US, Belgium, Czech Republic, Estonia, Finland, Hungary, Norway, the Netherlands, the UK, Poland, Spain and Sweden  . In June 2019, results from the study were presented at the 20th Annual Congress of the European League Against Rheumatism (EULAR-2019)  .
In November 2016, Sanofi completed the phase III SARIL-RA-HARUKA trial which evaluated the safety and efficacy of sarilumab added to non-methotrexate disease modifying anti-rheumatic drugs including sulfasalazine, leflunomide, bucillamine, tacrolimus, or mizoribin or as monotherapy in Japanese patients with rheumatoid arthritis (NCT02373202; LTS13618; U1111-1160-6525). The randomised, double-blind trial initiated in February 2015, enrolled 91 patients in Japan  .
In February 2015, Sanofi terminated the phase III RA-COMPARE trial due to difficulty in operational feasibility, delay incurred and failure in obtaining timely results, the decision was not based on any safety related issues (NCT01764997; EudraCT2012-001984-66). The randomised, double-blind trial was initiated in April 2013 and investigated the efficacy and tolerability of sarilumab plus methotrexate, compared with etanercept plus methotrexate in patients with rheumatoid arthritis not responding to adalimumab plus methotrexate. The trial enrolled 452 patients out of 700 patients planned from sites in the US, Europe, the Middle East, South America, Australia, New Zealand, Asia and South Africa   .
In January 2015, Sanofi and Regeneron initiated the phase III SARIL-RA-MONARCH trial which met the primary endpoint of statistically significant difference in DAS28-ESR score from baseline at week 24, in patients with rheumatoid arthritis (EFC14092; U1111-1160-6154; NCT02332590; EudraCT2014-002541-22). The trial evaluated safety and efficacy of sarilumab monotherapy, compared with adalimumab monotherapy. The trial intends to enrol approximately 369 patients in the US, Chile, Czech Republic, Germany, South Korea, Peru, Poland, Romania, Russia, South Africa, Spain, Ukraine, in the UK and Hungary, who are either intolerant to or inappropriate for methotrexate therapy, or those who are deemed inadequate responders following 12 weeks of treatment with methotrexate. The companies released positive top-line results from the phase III trial in March 2016 and November 2016. In November 2017, updated safety and efficacy results were presented at the 81st American College of Rheumatology and the 52nd Association of Rheumatology Health Professionals Annual Scientific Meeting. Updated results from the trial were presented at the 19th Annual Congress of the European League Against Rheumatism (EULAR-2018), in June 2018. In June 2019, Regeneron presented efficacy and safety data from the open-label extension study at the 20th Annual Congress of the European League Against Rheumatism (EULAR-2019)        .
In Sanofi initiated a phase III long-term follow-up trial (ABILITY; RA-EXTEND; SARIL-RA-EXTEND) to investigate the long-term safety and efficacy of sarilumab in patients with rheumatoid arthritis who received disease-modifying antirheumatics in the MOBILITY trial (NCT01146652; EudraCT2010-019262-86). The trial is also open to patients who complete the TARGET and ASCERTAIN studies, and is expected to recruit approximately 2000 patients in the US, Argentina, Australia, Austria, Belarus, Belgium, Brazil, Canada, Chile, Colombia, Czech Republic, Ecuador, Egypt, England, Estonia, Finland, Germany, Greece, Guatemala, Hong Kong, Hungary, India, Israel, Italy, Lithuania, Malaysia, Mexico, Netherlands, New Zealand, Norway, Peru, Philippines, Poland, Portugal, Romania, Russia, Scotland, Slovakia, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey, Ukraine, United Kingdom, USA
 . The primary outcome is the number of patients with adverse events. The estimated study completion date is in August 2015  . In December 2016, results from the trial were presented at 80th American College of Rheumatology and the 51st Annual Meeting of the Association of Rheumatology and Health Professionals (ACR/ARHP - 2016)  .
In October 2016, Sanofi and Regeneron completed the phase III SARIL-RA-KAKEHASI study, which assessed the safety and efficacy of sarilumab as an add-on therapy to methotrexate in patients with moderate to severely active rheumatoid arthritis, who are inadequate responders to methotrexate therapy (NCT02293902; EFC14059; U1111-1155-7401). This randomised, double-blind, placebo-controlled study was initiated in November 2014 and enrolled 243 patients in Japan  .
Sanofi and Regeneron completed the phase III SARIL-RA-ONE study in May 2015 that investigated the immunogenicity and safety of sarilumab when administered as monotherapy to patients with moderate to severe rheumatoid arthritis (EFC13752; U1111-1143-4344; EudraCT2013-002790-22; NCT02121210). The open-label, randomised study was initiated in June 2014 and enrolment 132 patients the US, the Czech Republic, Estonia, Chile, Poland, Russia and Hungary  .
A phase II trial of sarilumab in patients receiving methotrexate enrolled 250 patients in the US, Brazil, Canada, Colombia, the Czech Republic, Germany, Hungary, Italy, Mexico, Norway and Spain (NCT01217814; EudraCT2010-021020-94). However, the trial was terminated in September 2011, as delays would not have allowed the trial to be completed within a reasonable timeframe  .
In March 2016, Regeneron and Sanofi completed a phase I drug-interaction trial that evaluated the effects of sarilumab on the pharmacokinetics of simvastatin, in patients with rheumatoid arthritis (NCT02017639). The study enrolled 19 patients in the US, South Korea and Moldova  .
A phase I trial investigating the safety and tolerability of sarilumab, in combination with methotrexate, in Japanese patients with rheumatoid arthritis was completed in December 2013 (TDU13402; U1111-1134-0048; NCT01850680). The study enrolled 61 patients in Japan, and was initiated in April 2013  .
Initial clinical trials of sarilumab in patients with rheumatoid arthritis began in 2008  . Three phase I trials that began in 2008 were completed in 2009 in the US (NCT01055899, NCT01011959) and Russia (NCT01026519). The trials found sarilumab to be well tolerated by patients with rheumatoid arthritis, with no dose limiting toxicities observed     .
In May 2015, Regeneron completed a phase I trial, in collaboration with Sanofi, which was designed to assess the pharmacodynamic effects, safety and pharmacokinetics of single doses of sarilumab and tocilizumab in patients with rheumatoid arthritis (NCT02097524). Patients will be on background methotrexate therapy. The trial was initiated in March 2014 and enrolled 105 patients in the US and was completed in April 2015  .
A phase I trial to assess the safety and pharmacokinetics of two formulations of sarilumab in patients with rheumatoid arthritis was completed in September 2011 (NCT01328522). The randomised, parallel-assignment, single-blind trial enrolled 32 patients in the US  .
Sanofi, in March 2016, completed a phase I trial that evaluated the safety and tolerability of sarilumab, administered subcutaneously, in patients with rheumatoid arthritis, compared with tocilizumab (NCT02404558). The randomised, open-label trial enrolled 30 patients in Japan  .
In March 2020, Sanofi initiated and dosed the first patient in a phase II/III trial to evaluate efficacy and safety of intravenous injection of sarilumab for hospitalised patients with COVID-2019 infections (EudraCT2020-001162-12; NCT04327388; U1111-1249-6021; EFC16844). The randomised, double-blind, placebo-controlled trial intends to enrol approximately 300 patients in Canada, France, Germany, Italy, Japan, Russia, Spain and may expand to Israel  .
In March 2020, Regeneron and Sanofi alongwith The Feinstein Institutes for Medical Research, initiated phase II/III trial to evaluate the safety and efficacy of intravenous injection of sarilumab in adults hospitalised with serious complications from COVID-2019 (6R88COV2040; NCT04315298). The randomised trial intends to enrol approximately 400 patients in the US     . In April 2020, Sanofi and Regeneron Pharmaceuticals released preliminary results from the phase II portion of the trial. The companies also announced that following a review of all available phase II and phase III data, the Independent Data Monitoring Committee has recommended that the trial will be immediately amended so that only "critical" patients continue to be enrolled to receive sarilumab 400 mg or placebo and the lower dose of the drug 200 mg will be discontinued   .
Giant cell arteritis
In April 2020, Sanofi and Regeneron suspended a phase III trial due to COVID-19 (EFC15068; U1111-1200-2184; EudraCT2017-002988-18; NCT03600805). The trial was initiated in August 2018 to evaluate the efficacy of sarilumab in combination with prednisone, in patients with giant cell arteritis. The randomised, double blind trial intends to enrol approximately 360 patients in the US, Argentina, Australia, Austria, Belgium, Canada, Croatia, Denmark, Estonia, Finland, France, Germany, Hungary, Israel, Italy, Netherlands, Portugal, Russia, Scotland, Slovenia, Spain, Sweden, Switzerland, UK  .
Juvenile rheumatoid arthritis: In February
2020, Sanofi and Regenerone announces intention to submit a regulatory application for systemic juvenile rheumatoid arthritis in 2023 or later  .
In August 2018, Regeneron resumed recruitment in phase II trial. Earlier, in December 2017, Sanofi suspended a phase II trial since they have decided to amend the current protocol, in order to optimise the study design and procedures (DRI13926; U1111-1177-3584; EudraCT2015-004000-35; NCT02991469). The open-label, sequential, ascending, repeated dose-finding study was initiated, in September 2016, to evaluate the pharmacokinetics, pharmacodynamics, efficacy and safety of sarilumab SC in patients with systemic juvenile idiopathic arthritis. The trial intended to enrol 36 patients in Spain, Estonia, France, Russia, Finland, Italy, the Netherlands, the UK, Germany, Czech Republic, Chile, Canada, Argentina, Poland and the US  .
In June 2016, Sanofi initiated an open-label phase II trial of sarilumab administered as a subcutaneous injection in children and adolescents with polyarticular juvenile idiopathic arthritis (DRI13925; U1111-1177-3487; EudraCT2015-003999-79; NCT02776735; P067-2013). The trial will assess the pharmacokinetic profile of sarilumab to identify dose and regimen for further development of the product in this population. The ascending, dose-finding trial intends to enrol 72 subjects in the UK, Russia, Poland, the Netherlands, Mexico, Italy, Finland, Estonia, Czech Republic, Chile, Germany, the US, Argentina, Canada, France and Spain  .Results from the trial were presented at the 20th Annual Congress of the European League Against Rheumatism (ELAR-2019)  .
In April 2020, Sanofi and Regeneron suspended a phase III trial which was designed to evaluate the efficacy and safety of sarilumab, in patients with polymyalgia rheumatica (EFC15160; U1111-1201-0777; EudraCT2017-002989-42; NCT03600818). The trial was suspended due to pandemic COVID-2019 infections. Evaluation of the proportion of patients achieving sustained remission is the defined primary endpoints of the trial. The double-blind, randomised trial was initiated in August 2018 and intends to enrol approximately 280 patients in Argentina, Australia, Belgium, Canada, Estonia, France, Germany, Hungary, Israel, Italy, Japan, Netherlands, Russia, Spain, Switzerland, the UK and the US  .
Sanofi and Regeneron completed the phase II SARILNIUSATURN trial in April 2016, which evaluated the efficacy of sarilumab in patients with non-infectious uveitis (SARIL-NIU-SATURN; ACT13480; U1111-1130-6500; EudraCT 2012-004845-34; NCT01900431). Sarilumab was dosed every 2 weeks, with background therapy continuing. The primary endpoint was percentage of patients with either a ≥2-step reduction in vitreous haze, or the use of prednisone <10mg/day, at 16 weeks. The randomised, double-blinded trial in July 2013, enrolled 58 patients in the US, the Czech Republic, Germany, France, Italy, Spain and Turkey   .
A phase II trial of sarilumab in patients with ankylosing spondylitis was conducted by Regeneron and Sanofi-Aventis in the US, Canada, Australia, Austria, Belgium, the Czech Republic, France, Germany, Hungary, Lithuania, Netherlands, Poland, Spain and Turkey (ALIGN; NCT01061723; EudraCT2009-016068-35). The trial did not meet its primary endpoint. The trial, completed in June 2011, enrolled a total of 300 subjects. In the randomised, double-blind trial, patients received placebo or sarilumab 100mg or 150mg once a week or 100mg, 150mg or 200mg every other week by subcutaneous injection for 12 weeks. The primary endpoint was the proportion of patients achieving the assessment in the Ankylosing Spondylitis International Working Group criteria for 20% improvement (ASAS20)   . A long-term extension study of ALIGN was recruiting subjects by invitation only, however, it was discontinued in January 2012 for lack of benefit on efficacy (NCT01118728; EudraCT2010-019263-11). It appears that the development of sarilumab for ankylosing spondylitis has been discontinued  .
The label for sarilumab carries a boxed warning for increased risk of developing serious infections that may lead to hospitalisation or death  .