Clinical Trials

Date: 2017-06-14

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the Annual European Congress of Rheumatology (EULAR) 2017

Company: Janssen Research & Development, a J&J company (USA - NJ)

Product: sirukumab

Action mechanism:

• monoclonal antibody. Sirukumab is a fully human anti-interleukin-6 (IL-6) immunoglobulin G1-kappa with a high affinity and specificity for binding to the human IL-6 molecule. Sirukumab inhibits IL-6-mediated signal transducer and activator of transcription 3 (STAT3) phosphorylation, resulting in the inhibition of the biological effect of IL-6.
• In December 2011, Janssen and GSK entered into a licensing and co-development agreement with respect to sirukumab. Janssen has exclusive rights to commercialise sirukumab in Asia Pacific, Europe, the Middle East and Africa, while GSK retains commercialisation rights in North, Central and South America, with global profit shared equally between the two companies. Prior to the agreement, Janssen had been developing sirukumab for rheumatoid arthritis. As part of the collaboration, a Phase 3 program began in August 2012 to investigate sirukumab for the treatment of moderately to severely active rheumatoid arthritis. Janssen is responsible for the MHLW regulatory file in Japan. The agreement gives both companies the option to investigate sirukumab for other indications beyond rheumatoid arthritis.

Disease: rheumatoid arthritis

Therapeutic area: Autoimmune diseases – Inflammatory diseases - Rheumatic diseases

Country:

Trial details:

• The Phase 3 SIRROUND clinical program in patients with active RA includes five studies investigating subcutaneously administered sirukumab 50 mg every four weeks and sirukumab 100 mg every two weeks in combination with conventional disease-modifying antirheumatic drugs  or as monotherapy. The program involves more than 3,000 patients encompassing the following five studies: - SIRROUND-D study: patients who had an inadequate response to disease-modifying antirheumatic drugs. This study is estimated to complete in 2017. (NCT01604343) - SIRROUND-H study: patients with an inadequate response or who were intolerant to methotrexate or for whom methotrexate was inappropriate. This study has completed. (NCT02019472) - SIRROUND-T study: patients who had an inadequate response or were intolerant to anti-TNF-alpha agents. This study has completed. (NCT01606761) - SIRROUND-M study: Japanese patients who had an inadequate response to MTX or sulfasalazine. This study has completed. - SIRROUND-LTE study: a long-term extension study for patients completing SIRROUND-D and SIRROUND-T. This study is estimated to complete in 2020 (NCT01856309).

Latest news:

• • On June 14, 2017, Janssen-Cilag International announced the presentation of long-term results from SIRROUND-T at the Annual European Congress of Rheumatology (EULAR) 2017 in Madrid, Spain. This pivotal Phase 3 study showed sirukumab improved the signs and symptoms of moderately to severely active rheumatoid arthritis through 52 weeks of treatment in adult patients with an inadequate response and/or intolerance to anti-tumour necrosis factor (TNF)-alpha treatments.  Data from the SIRROUND-T study showed that more than half of patients receiving either sirukumab 50 mg or 100 mg achieved at least a 20% improvement in the signs and symptoms of disease (ACR20) at week 52 (54.3% sirukumab 50 mg; 59.3% sirukumab 100 mg). Patients receiving sirukumab also demonstrated clinically meaningful improvements from baseline through week 52 in quality of life measures, as demonstrated by the health assessment questionnaire disability index (HAQ-DI) and the short form-36 (SF-36) health survey, for patient-reported outcomes in both physical and emotional well-being.
•  The incidences of adverse events and serious adverse events were comparable between sirukumab 50 mg (79.6% and 14.2%, respectively) and sirukumab 100 mg (81.3% and 13.2%, respectively).
• In a post-hoc analysis from four sirukumab Phase 3 studies presented at the congress, investigators reported that treatment with sirukumab consistently increased levels of haemoglobin in adult patients with moderately to severely active rheumatoid arthritis, thus reducing by week 16 the proportion of patients with anaemia, which is common in rheumatoid arthritis.
• An oral presentation of a post-hoc analysis (SIRROUND-D) highlighted the effect of sirukumab plus methotrexate on circulating biomarkers and demonstrated that in addition to inhibiting radiographic progression (bone destruction measured on x-ray images), treatment with sirukumab strongly inhibited biomarkers of bone and tissue destruction, and enhanced markers of bone formation.
• • On November 16, 2016,  Janssen Research & Development announced results from two pivotal Phase 3 studies evaluating subcutaneous sirukumab for the treatment of adults with moderately to severely active rheumatoid arthritis. Data from the Janssen-sponsored head-to-head study, SIRROUND-H, showed patients receiving sirukumab monotherapy demonstrated significantly greater improvement in Disease Activity Score (DAS28), the first of two co-primary endpoints, when compared with Humira® (adalimumab) monotherapy.
• The Phase 3 SIRROUND-H trial  is  a comparator study of sirukumab monotherapy versus adalimumab monotherapy. It included 559 biologic-naive patients with moderately to severely active rheumatoid arthritis who were intolerant to methotrexate, considered inappropriate for methotrexate treatment for safety reasons or were inadequate responders to methotrexate. Patients were randomised evenly to receive sirukumab 50 mg q4w or sirukumab 100 mg q2w or adalimumab 40 mg q2w as monotherapy. In addition to the co-primary endpoints evaluated, a clinically relevant proportion of patients in all three treatment groups attained the major secondary endpoints of DAS28 remission at week 24 (sirukumab 50 mg q4w, 13 percent; sirukumab 100 mg q2w, 20 percent; adalimumab 40mg q2w, 8 percent [P = 0.086 and P < 0.001, respectively]) and ACR20 response at week 24 (sirukumab 50 mg q4w, 54 percent; sirukumab 100 mg q2w, 59 percent; adalimumab 40mg q2w, 57 percent [P > 0.05]).
• The incidence of patients reporting adverse events was 57 percent, 64 percent and 55 percent in the sirukumab 50 mg q4w, sirukumab 100 mg q2w and adalimumab q2w groups, respectively. The incidence of patients reporting serious adverse events was 7 percent, 3 percent and 4 percent in the sirukumab 50 mg q4w, sirukumab 100 mg q2w and adalimumab q2w groups, respectively. The rate of reported infections was 20 percent, 24 percent and 19 percent in the sirukumab 50 mg q4w, sirukumab 100 mg q2w and adalimumab 40mg q2w groups, respectively, and there were few serious infections reported (sirukumab 50 mg q4w, 3 percent; sirukumab 100 mg q2w, 0 percent; adalimumab, 1 percent). The reported incidence of injection-site reactions was dose-related and greater with sirukumab 100 mg q2w (21 percent) compared with sirukumab 50 mg q4w (11 percent) and adalimumab (8 percent). No injection-site reactions were considered serious, and there were no deaths reported through week 24.
• In SIRROUND-H, patients receiving sirukumab 50 mg every four weeks (q4w) and patients receiving sirukumab 100 mg every two weeks (q2w) experienced significant mean changes from baseline in DAS28 at week 24 of -2.58 and -2.96, respectively, compared with a mean change of -2.19 in patients receiving adalimumab 40 mg q2w (P = 0.013 and P < 0.001, respectively). All treatment groups showed clinically relevant improvements in achieving the other co-primary endpoint versus baseline, at least 50 percent improvement in ACR response criteria at week 24. However, the proportions of patients reaching ACR50 response were not significantly different between adalimumab 40 mg q2w (32%), sirukumab 50 mg q4w (27%), or sirukumab 100 mg q2w (35%), with P < 0.05 in both cases.
• Investigators also reported results from the SIRROUND-T study, which showed that patients refractory to or intolerant to one or more anti-tumor necrosis factor (TNF) treatments receiving sirukumab demonstrated significant improvement in ACR 20 response compared with placebo.
• In SIRROUND-T, among patients refractory/intolerant to anti-TNF treatments, 40 percent of patients receiving sirukumab 50 mg q4w and 45 percent of patients receiving sirukumab 100 mg q2w achieved the study's primary endpoint, at least a 20 percent improvement in ACR response criteria at week 16, compared with 24 percent of patients receiving placebo (P ? 0.001). Approximately 40 percent of patients in the study had prior exposure to non-TNF biologic therapies.
• The trial included 878 patients refractory to anti-TNF therapy, approximately 40 percent of whom had prior exposure to non-TNF biologic therapies. Patients were randomised evenly to receive sirukumab 50 mg q4w or sirukumab 100 mg q2w or placebo. Patients receiving placebo with less than 20 percent improvement from baseline in both swollen and tender joint counts at weeks 18, as well as those still on placebo at week 24, were re-randomised to receive SC injections of sirukumab 50 mg q4w or 100 mg q2w through week 52. In addition to meeting the primary endpoint (ACR20 at week 16), patients receiving sirukumab also demonstrated statistically significant improvements across secondary endpoints compared with placebo. These included a change from baseline in the Health Assessment Questionnaire Disability Index (HAQ-DI), percentage of patients achieving ACR50 and percentage of patients achieving DAS28 remission at week 24 (P ? 0.001 for all measures). These improvements were seen as early as week four and were maintained with sirukumab therapy through week 52. Additionally, the efficacy of sirukumab was similar in patients who had previously received both anti-TNF therapy as well as other biologic therapy and in patients who had taken only TNF inhibitors.
• The incidence of patients reporting adverse events at week 24 was 62 percent, 69 percent and 62 percent in the sirukumab 50 mg q4w, sirukumab 100 mg q2w and placebo groups, respectively. Incidence of patients reporting serious adverse events was 8 percent, 8 percent and 5 percent in the sirukumab 50 mg q4w, sirukumab100 mg q2w and placebo groups, respectively. Through week 52, the incidences of adverse events and serious adverse events were comparable between sirukumab 50 mg q4w (80 percent and 14 percent, respectively) and sirukumab 100 mg q2w (81 percent and 13 percent, respectively). No deaths were reported through week 24; there were five deaths reported through week 52 (two in the sirukumab 50 mg q4w group and three in the sirukumab 100 mg q2w group).

Is general: Yes