FDA Rejects Application for Arthritis Treatment Sarilumab

Agency cites manufacturing issues

The FDA has issued a complete response letter (CRL) regarding the biologics license application (BLA) for sarilumab (Sanofi/Regeneron Pharmaceuticals), an investigational interleukin-6 receptor antibody, for the treatment of adults with moderate-to-severe rheumatoid arthritis (RA).

The CRL referred to certain deficiencies identified during a routine inspection of the facility where sarilumab is filled and finished––one of the last steps in the manufacturing process. Satisfactory resolution of these deficiencies is required before the BLA can be approved. Sanofi submitted a comprehensive corrective action plan to the FDA and is implementing the corrective actions specified in that plan. The CRL did not express any concerns related to the safety or efficacy of sarilumab.

The FDA had accepted for review the BLA for sarilumab in January 2016, with a target action date of October 30. If approved, sarilumab will be commercialized by Regeneron and Sanofi Genzyme, a specialty-care business unit of Sanofi.

In March, Sanofi and Regeneron announced that sarilumab had bested adalimumab (Humira, AbbVie) in a phase 3, head-to-head trial. The study met its primary endpoint, demonstrating that sarilumab was superior to adalimumab in improving the signs and symptoms of RA in patients with active disease at week 24.

The SARIL-RA-MONARCH trial enrolled 369 adults with active RA who were inadequate responders to, intolerant of, or inappropriate candidates for methotrexate. The patients were randomly assigned to receive either subcutaneous sarilumab monotherapy (200 mg every two weeks) or adalimumab monotherapy (40 mg every two weeks); patients who did not respond adequately to adalimumab could increase their dosing to weekly intervals.

The trial’s primary endpoint was the change from baseline in the Disease Activity Score (28 Joints)–Erythrocyte Sedimentation Rate (DAS28-ESR) at 24 weeks. This endpoint demonstrated a statistically significant difference in favor of sarilumab compared with adalimumab (–3.25 vs. –2.22, respectively; P < 0.0001).

The study also met clinically important secondary endpoints, including improvements in the signs and symptoms of RA, as measured by patients achieving a 20% improvement in the American College of Rheumatology criteria (ACR20) (72% for sarilumab vs. 58% for adalimumab; P < 0.01). Additional positive secondary endpoints included ACR50 and ACR70 responses, and improvement in physical function, as measured by the Health Assessment Questionnaire–Disability Index (HAQ-DI), for sarilumab compared with adalimumab (P < 0.01 for sarilumab for all of these measures).

The rates of adverse events (64% for both groups), serious adverse events (5% for sarilumab vs. 7% for adalimumab), infections (29% vs. 28%), and serious infections (1% for both groups) were generally similar between the two treatments. Neutropenia was more common with sarilumab than with adalimumab (14% vs. 1%, respectively). Injection-site erythema was also more common with sarilumab (8% vs. 3%).

Sources: Sanofi; October 28, 2016; and Regeneron; March 11, 2016.