A pivotal global phase 3 study investigating subcutaneous sirukumab (GlaxoSmithKline/Janssen Biologics), a human anti-interleukin (IL)-6 monoclonal antibody, in adult patients with moderately to severely active rheumatoid arthritis (RA) has met both coprimary endpoints. The SIRROUND-D trial enrolled RA patients who had an inadequate response to treatment with disease-modifying antirheumatic drugs (DMARDs).
The results showed that inhibition of radiographic progression, or joint destruction, was significantly greater among sirukumab-treated patients, with a mean change from baseline to week 52 in the van der Heijde–Sharp score of 0.50 among patients receiving sirukumab 50 mg every four weeks (n = 557) and 0.46 for patients receiving sirukumab 100 mg every two weeks (n = 557) compared with 3.69 in the placebo group (n = 556) (both P < 0.001). Significant inhibition of radiographic progression was demonstrated in both patients naïve to biologic therapy and those treated with biologics in the past, and was seen as early as week 24.
The van der Heijde–Sharp scoring method is an x-ray measure of changes in joint destruction and damage, including joint erosion and joint-space narrowing. With this method, higher scores indicate greater structural damage, while lower scores indicate less structural damage.
At least a 20% improvement in RA signs and symptoms as measured by the American College of Rheumatology response criteria (ACR20) at week 16 was achieved by 54.8% and 53.5% of patients receiving sirukumab 50 mg and sirukumab 100 mg, respectively, compared with 26.4% of the placebo group (both P < 0.001).
All major secondary endpoints were also met with statistical significance for both doses of sirukumab compared with placebo (P < 0.001 for all measures across both doses). These endpoints included the change from baseline in the health assessment questionnaire disability index (HAQ-DI); the percentage of patients achieving a 50% improvement in RA symptoms (ACR50); the percentage of patients with an improved disease activity score in 28 joints (DAS28) at week 24; and the percentage of patients achieving at least a 70% improvement in RA signs and symptoms (ACR70) for six consecutive months (a major clinical response) by week 52.
During the 18-week control period, the proportion of patients experiencing adverse events (AEs) and serious AEs, respectively, was higher with sirukumab 50 mg (79.6% and 11.0%) and sirukumab 100 mg (80.2% and 9.8%) compared with the placebo group (65.5% and 6.8%). The most common AEs included elevated liver enzymes, upper respiratory tract infection, injection-site erythema, and nasopharyngitis. Through week 52, the types of AEs and SAEs were similar to those associated with placebo. Before week 18 (the formal placebo-controlled period), three patients died, one in each treatment group (placebo, sirukumab 50 mg, and sirukumab 100 mg). From week 18 to week 52, eight deaths occurred: three in patients who originally received placebo and then switched to sirukumab 50 mg; three in the group receiving sirukumab 50 mg; and two in the group receiving sirukumab 100 mg.
Sirukumab is an investigational human monoclonal immunoglobulin G1 kappa (IgG1 kappa) antibody that selectively binds with high affinity to the IL-6 cytokine, a naturally occurring protein that plays a role in autoimmune conditions. Global regulatory applications for sirukumab for patients with RA are anticipated in the third quarter of 2016. Sirukumab has not been approved as a treatment for any indication anywhere in the world.
Source: GlaxoSmithKline; June 8, 2016.