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


CONCLUSIONS
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.
Stanford University Medical Center, Palo Alto, California.
Mark C
MC
Genovese
Metroplex Clinical Research Center, Dallas, Texas.
Roy
R
Fleischmann
Altoona Center for Clinical Research, Duncansville, Pennsylvania.
Alan J
AJ
Kivitz
Rheumatology and Osteoporosis Outpatient Clinic, Warsaw, Poland.
Maria
M
Rell-Bakalarska
Sanofi, Prague, Czech Republic.
Renata
R
Martincova
Sanofi, Bridgewater, New Jersey.
Stefano
S
Fiore
Sanofi, Bridgewater, New Jersey.
Patricia
P
Rohane
Sanofi, Bridgewater, New Jersey.
Hubert
H
van Hoogstraten
Sanofi, Bridgewater, New Jersey.
Anju
A
Garg
Sanofi, Bridgewater, New Jersey.
Chunpeng
C
Fan
Regeneron Pharmaceuticals, Tarrytown, New York.
Janet
J
van Adelsberg
Regeneron Pharmaceuticals, Tarrytown, New York.
Steven P
SP
Weinstein
Regeneron Pharmaceuticals, Tarrytown, New York.
Neil M H
NM
Graham
Regeneron Pharmaceuticals, Tarrytown, New York.
Neil
N
Stahl
Regeneron Pharmaceuticals, Tarrytown, New York.
George D
GD
Yancopoulos
Leiden University Medical Centre, Leiden, The Netherlands.
Tom W J
TW
Huizinga
Leiden University Medical Centre, Leiden, The Netherlands.
Désirée
D
van der Heijde
D000293:Adolescent; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000139:chemically induced; D053698:Interleukin-6 Receptor alpha Subunit / Q000037:antagonists & inhibitors*; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D016896:Treatment Outcome; D055815:Young Adult
D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D053698:Interleukin-6 Receptor alpha Subunit; C000592401:sarilumab; D008727:Methotrexate