Positive results from a phase 3 trial of investigational drug Sarilumab in rheumatoid arthritis ( RA ) patients who were inadequate responders to Methotrexate ( MTX ) therapy were presented at the European League Against Rheumatism Annual Congress ( EULAR 2014 ) Congress.
New data have shown that Sarilumab increased major clinical response rates defined as achieving an ACR70 for at least 24 consecutive weeks and showed sustained improvement in signs and symptoms of rheumatoid arthritis after 52 weeks, which were secondary endpoints of the trial.
Sarilumab is the first fully-human monoclonal antibody directed against the IL-6 receptor ( IL-6R ). Sarilumab is a subcutaneously delivered inhibitor of IL-6 signaling, which binds with high affinity to the IL-6 receptor. It blocks the binding of IL-6 to its receptor and interrupts the resultant cytokine-mediated inflammatory signaling.
In the study, called SARIL-RA-MOBILITY, Sarilumab met all three coprimary endpoints, demonstrating improvement in disease signs and symptoms at 24 weeks, physical function at 16 weeks and inhibition of joint damage progression at 52 weeks.
The SARIL-RA-MOBILITY phase 3 trial enrolled 1,197 adult patients with active, moderate-to-severe rheumatoid arthritis, who were inadequate responders to MTX therapy.
Patients were randomized to one of three treatment groups dosed subcutaneously every other week, Sarilumab 150 mg, Sarilumab 200 mg, or placebo, all in combination with Methotrexate.
Both Sarilumab groups showed statistically significant improvements compared to the placebo group in all three co-primary endpoints ( p less than 0.0001 ).
1. Improvement in signs and symptoms of RA at 24 weeks, as measured by the American College of Rheumatology score of 20 percent improvement ( ACR20 ). These results were 58%, 66%, and 33% in the Sarilumab 150 mg, Sarilumab 200 mg, and placebo groups respectively, all in combination with Methotrexate.
2. Improvement in physical function at week 16 as measured by Health Assessment Questionnaire - Disability Index ( HAQ-DI ). Newly presented HAQ-DI results were -0.53, -0.55, and -0.29 in the Sarilumab 150 mg, Sarilumab 200 mg, and placebo groups respectively, all in combination with Methotrexate.
3. Inhibition of progression of structural damage at week 52, as measured by change in the van der Heijde modified total Sharp score ( mTSS ). These results were 0.90, 0.25, and 2.78 in the Sarilumab 150 mg, Sarilumab 200 mg, and placebo groups respectively, all in combination with Methotrexate. The group receiving the 200 mg dose of Sarilumab plus Methotrexate had a reduction of approximately 90% in the radiographic progression assessed by the mTSS compared to the radiographic progression with placebo plus Methotrexate at week 52.
Both Sarilumab groups also showed improvement on the major clinical response secondary endpoint:
Sarilumab combined with Methotrexate demonstrated statistically significantly greater effect than Methotrexate alone in achieving a major clinical response, defined as reducing signs and symptoms of rheumatoid arthritis by 70% or more, as measured by improvement of the American College of Rheumatology score ( ACR70 response ), for at least 24 consecutive weeks. These results were 13%, 15% and 3% in the Sarilumab 150 mg, Sarilumab 200 mg, and placebo groups, respectively ( p less than 0.0001 ).
Both doses also demonstrated a sustained response in improvement of signs and symptoms of rheumatoid arthritis compared to placebo at 52 weeks as measured by the ACR20 response. These results were 54%, 59%, and 32% in the Sarilumab 150 mg, Sarilumab 200 mg, and placebo groups, respectively.
In the SARIL-RA-MOBILITY trial, there was a higher incidence of treatment-emergent adverse events leading to withdrawal in the Sarilumab treatment groups compared to placebo ( 12.5% in 150 mg, 13.9% in 200 mg and 4.7% in placebo ).
Infections were the most frequently reported adverse events and were reported with a higher incidence in the Sarilumab groups compared to placebo, all in combination with Methotrexate ( 40.1% for 150 mg, 39.6% for the 200 mg group and 31.1% for placebo ).
The incidence of serious infections was 2.6% in the 150 mg plus Methotrexate group, 4.0% in the 200 mg plus Methotrexate group, and 2.3% in the placebo plus Methotrexate group.
Among patients treated with Sarilumab, a dose-dependent decrease in mean neutrophil counts was observed. Serious infections were not associated with grades 3 and 4 neutropenia in this study. Increases in mean LDL cholesterol, and transaminases were observed. These safety findings were consistent with those observed in prior investigational studies with Sarilumab. ( Xagena )
Source: Sanofi & Regeneron, 2014