法国制药巨头赛诺菲（Sanofi）与合作伙伴再生元（Regeneron）近日宣布，双方合作开发的抗炎新药Kevzara（sarilumab）获得加拿大卫生部批准，用于既往接受一种或多种生物类或非生物类疾病修饰抗风湿药物（DMARDs）治疗缓解不足或不耐受的中度至重度活动性类风湿性关节炎（RA）成人患者。Kevzara需要联合甲氨蝶呤（MTX）或其他传统的DMARDs药物联合用药；若患者对甲氨蝶呤或DMARDs不耐受或有禁忌时，Kevzara也可单独用药。
  Kevzara的推荐剂量为每2周一次皮下注射200mg，在某些情况下，该剂量可由200mg降至150mg，以便管理特定的实验室异常。
  值得一提的是，此次批准，使Kevzara在全球范围内收获的首个监管批准。目前，sarilumab也正在接受美国和欧盟的审查，预计将会在今年获得审查结果。业界对sarilumab的商业前景非常看好。之前，全球知名医药市场研究机构evaluatePharma发布报告，预计sarilumab在2020年的销售峰值将达到18亿美元。
  Kevzara的获批，是基于全球性SARIL-RA III期临床项目的数据，该项目包括7个III期临床研究，涉及超过3300例活动性中度至重度RA成人患者，其中大部分患者对之前的治疗方案反应不足。SARIL-RA III期临床项目专注于对疾病修饰抗风湿药物（DMARDs，包括甲氨蝶呤）或肿瘤坏死因子-α（TNF-α）抑制剂应答不足的活动性中度至重度类风湿性关节炎（RA）成人患者群体，旨在广泛的患者中评估皮下注射sarilumab作为单药疗法或联合传统的疾病修饰抗风湿药物（DMARDs，包括氨甲喋呤）在改善疾病症状和体征、抑制RA放射学进展方面的疗效和安全性。
  去年底公布的III期临床研究SARIL-RA-MONARCH的数据显示，对甲氨蝶呤治疗缓解不足或不耐受或不适用的活动性类风湿性关节炎（RA）成人患者群体中，与艾伯维重磅抗炎药修美乐（Humira，通用名：adalimumab，阿达木单抗）相比，sarilumab在改善临床症状和体征方面具有优越性，数据具有统计学显著差异。
  sarilumab（REGN88/SAR15319）是首个直接靶向IL-6受体复合物α亚基（IL-6R α）的全人源化单克隆抗体，能够特异性结合可溶性的和膜结合型的IL-6受体，抑制通过这些受体介导的细胞信号传导。IL-6在类风湿性关节炎（RA）患者血清和滑液（synovial fluid）中是含量最丰富的一种细胞因子，其水平与疾病活动度和关节破坏密切相关。sarilumab由Regeneron公司利用其专有的Veloclmmune抗体技术开发，该抗体能够阻断IL-6与其受体的结合，中断细胞因子介导的炎症信号级联。

Kevzara (sarilumab) for the Treatment of Rheumatoid Arthritis
Kevzara® (sarilumab) is a human monoclonal antibody indicated for the treatment of adult patients with moderate-to-severely active rheumatoid arthritis (RA).
Jointly developed by Sanofi and Regeneron Pharmaceuticals, the drug’s biologics license application (BLA) was accepted for review by the US Food and Drug Administration (FDA) in January 2016. The FDA issued a complete response letter (CRL) for the approval of Kevzara in October 2016 and the BLA resubmission was accepted for review by the FDA in April 2017.
Kevzara® was approved by the FDA in May 2017 and by Health Canada in February 2017. The drug also received positive opinion for marketing authorisation (MA) from the Committee for Medicinal Products for Human Use (CHMP) of European Medicine Agency (EMA) in April 2017.
The European Commission (EC) granted MA for Kevzara® in combination with methotrexate (MTX) in June 2017.
Rheumatoid arthritis disease details
RA is an inflammatory autoimmune disease that affects multiple joints in the body. It causes pain and swelling in the wrist and small joints of the hands and feet. Other symptoms include swollen joints, morning stiffness and fatigue. The disease is more common in women and people aged between 30 and 60 years.
RA is estimated to affect approximately 1.3 million in the US, 300,000 in Canada and 70 million people worldwide.
Kevzara’s mechanism of action
Kevzara® binds to IL-6 receptors and restrains IL-6-mediated signalling. The drug is available in 200mg and 150mg doses, which can be administered thorough subcutaneous injection.
Clinical trials on Kevzara
The FDA’s approval for Kevzara® was based on results obtained from the global SARIL-RA clinical trial programme, which includes pivotal Phase III clinical trials MOBILITY and TARGET. The studies enrolled more than 2,900 adults with moderately-to-severely active RA who had inadequate response to previous treatment regimens.
In the MOBILITY study, patients were administered with Kevzara® plus MTX compared to placebo plus MTX. The study was conducted for 16, 24 and 52 weeks.
Results of the study after 16 weeks demonstrated that patients treated with Kevzara® plus MTX showed greater improvement from baseline in physical function, which was measured using the Health Assessment Questionnaire Disability Index (HAQ-DI).
Patients treated with Kevzara plus MTX showed improvement in the primary endpoint of signs and symptoms, which were measured based on the proportion of patients achieving a 20% improvement in the American College of Rheumatology Criteria after 24 weeks.
Patients treated with Kevzara® plus MTX showed less radiographic progression of structural damage, which was measured based on changes in modified Total Sharp Score after 52 weeks.
In the Phase III TARGET study, patients were treated with Kevzara® plus disease-modifying anti-rheumatic drugs (DMARD). The study was conducted for 12 and 24 weeks.
Study results after 12 weeks showed that Kevzara® plus DMARD attained a greater improvement in the primary endpoint of signs and symptoms, which were measured by the proportion of patients achieving an ACR20 response.
The results also demonstrated that patients treated with Kevzara® plus DMARD attained greater improvement in the primary endpoint of signs and symptoms, which were also measured based on the proportion of patients achieving an ACR20 response at week 24.
The most common adverse reactions found in patients treated with Kevzara® in combination with DMARD were neutropenia, increased alanine aminotransferase, injection site erythema, upper respiratory infections, and urinary tract infections.
The EC granted approval of Kevzara® based on results from the Phase III MONARCH study, which evaluated with the safety and efficacy of Kevzara 200mg monotherapy compared to adalimumab 40mg monotherapy for 24 weeks.
Results of the study indicated that the patients administered with Kevzara 200mg showed greater reduction in disease activity as measured by change from baseline in the Disease Activity Score.
Marketing commentary
Regeneron and Sanofi Genzyme will launch Kevzara in the US market. Other medications available for the treatment of RA include Abatacept (Orencia) produced by Bristol-Myers Squibb, Xeljanz XR (tofacitinib citrate) developed by Pfizer, and Enbrel produced by Pfizer and Amgen.