Sarilumab Plus Methotrexate in Patients With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate: Results of a Phase III Study.

Abstract

OBJECTIVE:

To evaluate the efficacy and safety of sarilumab in combination with methotrexate (MTX) for the treatment of rheumatoid arthritis (RA).

METHODS:

Adults with moderate-to-severe RA and an inadequate response to MTX were randomized (1:1:1) to receive sarilumab (doses of 150 mg or 200 mg) or placebo every 2 weeks in conjunction with weekly MTX for 52 weeks. Co-primary end points were the proportion of patients achieving American College of Rheumatology 20% (ACR20) improvement responses at week 24, change from baseline in the Health Assessment Questionnaire (HAQ) disability index (DI) at week 16, and change from baseline in the modified Sharp/van der Heijde score (SHS) of radiographic damage at week 52.

RESULTS:

Baseline characteristics were similar among the groups. For all 3 co-primary end points, the sarilumab 150 mg and 200 mg groups demonstrated statistically significant improvements as compared with the placebo group (ACR20 response rate at week 24, 58.0%, 66.4%, and 33.4%, respectively [P < 0.0001]; least squares mean change in HAQ DI at week 16, -0.53, -0.55, and -0.29, respectively [P < 0.0001]; and mean change in SHS at week 52, 0.90, 0.25, and 2.78, respectively [P < 0.0001]). The most common treatment-emergent adverse event was infection. In the sarilumab 150 mg, sarilumab 200 mg, and placebo groups, the incidence of serious infections was 2.6%, 4.0%, and 2.3%, respectively. Elevations in alanine aminotransferase levels >3-fold the upper limit of normal occurred in 9.5%, 8.0%, and 2.1% of patients, respectively; in 24 patients, this led to discontinuation of treatment. Elevated total cholesterol levels were observed in 36.8%, 43.0%, and 18.3% of patients, respectively. In patients receiving 150 mg and 200 mg sarilumab, neutrophil counts of 0.5 to <1.0 × 10(9) /liter were observed in 5.1% and 7.8% of patients, respectively, while neutrophil counts of <0.5 × 10(9) /liter were observed in 0.9% and 0.7% of patients, respectively; none of the patients receiving placebo experienced changes in neutrophil counts.

CONCLUSION:

In RA patients treated with sarilumab (150 mg or 200 mg every 2 weeks) in combination with MTX, both doses provided sustained clinical efficacy, as shown by significant improvements in symptomatic, functional, and radiographic outcomes. Sarilumab was generally well tolerated. The adverse events observed in this study were consistent with the effects of interleukin-6 signaling blockade.

• Authors: Mark C Genovese, Roy Fleischmann, Alan J Kivitz, Maria Rell-Bakalarska, Renata Martincova, Stefano Fiore, Patricia Rohane, Hubert van Hoogstraten, Anju Garg, Chunpeng Fan, Janet van Adelsberg, Steven P Weinstein, Neil M H Graham, Neil Stahl, George D Yancopoulos, Tom W J Huizinga, Désirée van der Heijde
• Journal: Arthritis & rheumatology (Hoboken, N.J.) (Arthritis Rheumatol) Vol. 67 Issue 6 Pg. 1424-37 (Jun 2015) ISSN: 2326-5205 [Electronic] United States
• PMID: 25733246 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 sanofi-aventis U.S. LLC. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.

Chemical References

• Antibodies, Monoclonal, Humanized
• Antirheumatic Agents
• Interleukin-6 Receptor alpha Subunit
• sarilumab
• Methotrexate

Topics

• Adolescent
• Adult
• Aged
• Antibodies, Monoclonal, Humanized (therapeutic use)
• Antirheumatic Agents (therapeutic use)
• Arthritis, Rheumatoid (drug therapy)
• Double-Blind Method
• Drug Therapy, Combination
• Female
• Humans
• Hypercholesterolemia (chemically induced)
• Interleukin-6 Receptor alpha Subunit (antagonists & inhibitors)
• Male
• Methotrexate (therapeutic use)
• Middle Aged
• Neutropenia (chemically induced)
• Treatment Outcome
• Young Adult