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Sirukumab in rheumatoid arthritis refractory to sulfasalazine or methotrexate: a randomized phase 3 safety and efficacy study in Japanese patients.

ABSTRACT: BACKGROUND:Sirukumab, a high-affinity human monoclonal antibody that selectively binds to interleukin-6, has demonstrated efficacy in the treatment of rheumatoid arthritis (RA) in global phase 1 and phase 2 studies. The present study evaluated the safety and efficacy of sirukumab, as monotherapy in Japanese patients with RA refractory to methotrexate or sulfasalazine. METHODS:In this phase 3, double-blind study, 122 patients (age ? 20 years) were randomized (1:1, 61 patients in each arm) to sirukumab administered subcutaneously: 50 mg once every 4 weeks (q4w) or 100 mg once every 2 weeks (q2w) through 52 weeks. Disease-modifying anti-rheumatic drugs were allowed after 24 weeks. Safety was assessed and efficacy was evaluated using American College of Rheumatology (ACR) responses, Disease Activity Score C-reactive protein (DAS28-CRP) and Health Assessment Questionnaire-Disability Index (HAQ-DI). RESULTS:Amongst the 122 randomized patients, 99 (81.1%) patients completed the study. Adverse events (AEs) were reported in 114/122 (93.4%) patients and serious AEs were reported in 9/122 (7.4%) patients. No deaths, major cardiovascular AEs, serious gastrointestinal perforations or tuberculosis cases were reported during this study period. Grade 3 hematologic abnormalities (neutropenia and leukopenia) were reported in seven patients and no grade 4 abnormalities were observed. ACR20 responses were observed within 2 weeks, achieved in 47/61 (77.0%, 50 mg q4w) patients and 44/61 (72.1%, 100 mg q2w) patients at week 16 and maintained through week 52. ACR50/70, DAS28-CRP and HAQ-DI responses were also maintained through week 52 in both groups. CONCLUSIONS:Safety findings were comparable between the two treatment groups. The 52-week administration of sirukumab at 50 mg q4w and 100 mg q2w was generally tolerable and with measurable efficacy in Japanese patients with RA refractory to methotrexate and sulfasalazine. TRIAL REGISTRATION:NCT01689532 . Registered 18 September 2012.

SUBMITTER: Takeuchi T

PROVIDER: S-EPMC5842593 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic inflammatory status, joint destruction, disability, and pain. Methotrexate (MTX) has been confirmed to reduce disease activity and delay or stabilize the development of bone erosions. However, major drawbacks are that patients show great interindividual variability in response to MTX and the unpredictable occurrence of side effects. A strategy for personalized MTX treatment to predict its efficacy and toxicity has not yet been determined. To establish personalized MTX therapy in Japanese patients with rheumatoid arthritis, we performed a preliminary study for predicting better methotrexate efficacy including single-nucleotide polymorphisms (SNPs) for MTX-related transporters/enzymes. METHODS:Disease control status (good or poor) was judged by the number of Disease Activity Scores (DAS28) of <2 for 6-12 months. The response index R was calculated by the improved area under the curve (AUC) of the DAS28 score for 0-3 or 0-6 months by dividing the cumulative dose of MTX during 0-3 or 0-6 months, respectively. Genotyping of alleles of RFC1 80G?>?A, RFC1 -43 T?>?C, FPGS 1994G?>?A, GGH 401C?>?T, MTHFR 1298A?>?C, and TYMS 3'-UTR (-6/+6) was performed using the real-time PCR system. RESULTS:Seven of 21 patients were judged as good responders in terms of disease control, and the remainder as poor responders. For 0-3 months after starting MTX administration, the median cumulative dose and improved DAS28 AUC in the good and poor response groups were 96.0 mg and 25.4 and 118.0 mg and 23.4, respectively. For 0-6 months, the median cumulative dose and improved DAS28 AUC in the good and poor response groups were 192.0 mg and 51.0 and 214.0 mg and 47.6, respectively. Statistically significant differences between the 2 groups in the 0-6-month period were observed in DAS28 AUC improvement and index R. A slight tendency for a correlation between G/G genotypes and A allele genotypes in RFC1 80 genotypes was observed, although it did not reach statistical significance. CONCLUSION:This study suggested that aggressive RA treatment with MTX from the early period of administration is necessary to obtain a good response after 6 months, although no SNPs predicting a better treatment response to MTX were identified.

Project description:ObjectiveTofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). The phase III, 24-month, placebo-controlled Oral Rheumatoid Arthritis (ORAL) Scan trial was undertaken to evaluate the efficacy, including inhibition of structural progression, and safety of tofacitinib in patients with active RA and an inadequate response to methotrexate (MTX). Month 24 data from the completed study are reported here.MethodsPatients were randomized 4:4:1:1 to receive tofacitinib 5 mg or 10 mg twice daily, or placebo, switched to tofacitinib 5 mg or 10 mg twice daily, with stable background MTX. Patients receiving placebo switched to tofacitinib at month 3 (nonresponders) or month 6 (remaining patients). Clinical efficacy, structural progression, and treatment-emergent adverse events were evaluated. Analyses were performed on the full analysis set with observed data or nonresponder imputation with no advancement penalty for clinical efficacy, and imputation by linear extrapolation for structural progression.ResultsOverall, 797 patients were treated; 539 (67.6%) completed 24 months of treatment. Responses according to the American College of Rheumatology criteria for 20% improvement (ACR20), ACR50, and ACR70; the proportion of patients in whom remission or low disease activity was achieved according to the 4-variable Disease Activity Score in 28 joints using the erythrocyte sedimentation rate, Clinical Disease Activity Index, or Simplified Disease Activity Index; Boolean remission; and Health Assessment Questionnaire disability index scores were maintained from month 12 to 24 and were similar between tofacitinib dosages. Limited structural damage was observed at months 12 and 24. Safety events were similar in type and frequency for both tofacitinib dosages, and were consistent with those previously reported.ConclusionOur findings indicate that clinical and radiographic treatment effects are sustained in months 12-24 in patients with RA receiving tofacitinib 5 mg or 10 mg twice daily plus MTX. The safety profile is consistent with that of other tofacitinib studies.

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Sirukumab in rheumatoid arthritis refractory to sulfasalazine or methotrexate: a randomized phase 3 safety and efficacy study in Japanese patients.

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