GlaxoSmithKline (GSK) Announces Results from Two Sirukumab Phase 3 in RA; SIRROUND-T Study Met Primary Endpoint
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GlaxoSmithKline (NYSE: GSK) announced results from two pivotal phase III studies evaluating subcutaneous sirukumab, a human anti-interleukin (IL)-6 monoclonal antibody in development for the treatment of adults with moderately to severely active rheumatoid arthritis (RA).
The first study (SIRROUND-T), in patients who were refractory to or intolerant to one or more anti-tumor necrosis factor (TNF) agents, demonstrated that sirukumab met the primary endpoint showing significant improvement in the signs and symptoms of moderately to severely active RA compared to placebo. The second study (SIRROUND-H), a head-to-head study in patients who were refractory to or intolerant to methotrexate (MTX), demonstrated that sirukumab monotherapy met the first of two co-primary endpoints showing significant improvement in disease activity compared to adalimumab monotherapy.
The full results are being presented for the first time during oral sessions at the Annual Meeting of the American College of Rheumatology/Association for Rheumatology Health Professionals Meeting (ACR/ARHP 2016).
Sirukumab is being co-developed as part of a collaboration with Janssen Biologics (Ireland) [Janssen].
The SIRROUND-T study investigated sirukumab in adult patients with moderately to severely active RA who were refractory to or intolerant to one or more anti-TNF agents, which are often the first biological agents prescribed when a patient has failed treatment with a disease-modifying anti-rheumatic drug (DMARD). Approximately 40 percent of patients had prior exposure to both anti-TNF therapy and biologic therapy other than anti-TNFs, and 19 percent of patients were receiving sirukumab as monotherapy. Key results reported (Abstract 3223):
- A significantly higher proportion of sirukumab treated patients (40 percent with 50mg every four weeks and 45 percent with 100mg every two weeks) achieved at least a 20 percent improvement in signs and symptoms (ACR20) at week 16, the study’s primary endpoint, compared with placebo (24 percent);P ≤ 0.001.
- Statistically significant improvements for all major secondary endpoints for sirukumab treated patients compared with placebo. These were the change from baseline in the health assessment questionnaire disability index (HAQ-DI), percentage of patients achieving at least a 50 percent improvement in signs and symptoms (ACR50) and percentage of patients with improved disease activity score in 28 joints (DAS28 remission) at week 24; P ≤ 0.001 for all measures. These improvements were seen as early as week 4 and maintained with sirukumab therapy through week 52.
- Statistically significant improvements were also observed for sirukumab treated patients compared to placebo for other patient reported outcomes including the physical and mental components of the SF-36, a patient reported survey of health status from baseline at week 24; P < 0.01.
The SIRROUND–H study compared sirukumab monotherapy with adalimumab monotherapy, an approved anti-TNF agent, in adult patients with moderately to severely active RA who were refractory to, or were intolerant to or inappropriate for MTX, a type of DMARD. Key results reported (Abstract 3222):
- Significantly greater improvements in disease activity, as assessed by DAS28, in sirukumab treated patients (mean change from baseline of -2.58 with 50mg, -2.96 with 100mg) at week 24, the first of two co-primary endpoints of the study, compared to adalimumab treated patients (-2.19 with 40mg every 2 weeks); P = 0.013 and P < 0.001, respectively.
- Clinically relevant improvements in signs and symptoms of disease, as assessed by ACR50, the second of two co-primary endpoints, at week 24 for all treatment groups, although differences were not statistically significant between sirukumab 50mg, sirukumab 100mg and adalimumab 40mg (27 percent, 35 percent and 32 percent, respectively; P > 0.05).
- A clinically relevant proportion of patients in all three treatment groups attained both major secondary endpoints of DAS28 remission (13 percent with sirukumab 50mg, 20 percent with sirukumab 100mg, 8 percent with adalimumab 40mg) and ACR20 response at week 24 (54 percent with sirukumab 50mg, 59 percent with sirukumab 100mg, 57 percent with adalimumab; P > 0.05).
Paul-Peter Tak, GSK’s Chief Immunology Officer & Senior Vice President, R&D Pipeline, said: “Patients suffering with rheumatoid arthritis need access to a range of treatment options during different stages of their long-term disease. The results presented today show that both doses of sirukumab tested, including a 50mg subcutaneous dose taken every four weeks, reduced the signs and symptoms and disease activity in difficult-to-treat patients who had failed both conventional and biologic therapy.”
In the SIRROUND-T study, through week 24 of the study (the placebo controlled phase), the incidence of patients reporting adverse events (AEs) was 66 percent, 71 percent and 62 percent for sirukumab 50mg, sirukumab 100mg and placebo, respectively. The incidence of patients reporting serious AEs was 10 percent, 8 percent and 5 percent for sirukumab 50mg, sirukumab 100mg and placebo, respectively. Most common AEs (incidence >5% in any treatment group) were injection-site erythema, ALT increased, nasopharyngitis, injection-sire pruritus, upper respiratory infection, rheumatoid arthritis, and injection-site reaction. No deaths were reported through week 24. Through week 52 (not placebo-controlled), the incidences of AEs was 80 percent and 81 percent for sirukumab 50mg and sirukumab 100mg, respectively. The incidence of patients reporting serious AEs were 14 percent and 13 percent, for sirukumab 50mg and sirukumab 100mg, respectively. There were five deaths reported through week 52 (two in the sirukumab 50mg group and three in the sirukumab 100mg group).
In the SIRROUND-H study, through week 24 of the study, the incidence of patients reporting AEs was 57 percent, 64 percent and 55 percent for sirukumab 50mg, sirukumab 100mg and adalimumab, respectively. The incidence of patients reporting serious AEs was 7 percent, 3 percent and 4 percent with sirukumab 50mg, sirukumab 100mg and adalimumab, respectively. There were no deaths reported through week 24. The rate of reported infections was 20 percent, 24 percent and 19 percent for sirukumab 50mg, sirukumab 100mg and adalimumab, respectively. The rate of serious infections was 3 percent, 0 percent and 1 percent for sirukumab 50mg, sirukumab 100mg and adalimumab, respectively. The reported incidence of injection-site reactions was dose-related for sirukumab with 21 percent and 11 percent for sirukumab 100mg and sirukumab 50mg, respectively and 8 percent for adalimumab. No injection-site reactions were considered serious. Most common AEs for sirukumab (incidence >5% in any treatment group) were injection site erythema, ALT increased, AST increased, injection site pruritus, and neutropenia; the only AE that occurred at an incidence >5% for adalimumab was injection site erythema.
Additional abstracts reporting patient-reported outcomes (PRO) and other clinical efficacy and safety data from the SIRROUND-D and SIRROUND-T studies will be presented at the meeting and/or published in the ACR program book.
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