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S Sheng - One of the best experts on this subject based on the ideXlab platform.

  • investigating Sirukumab for rheumatoid arthritis 2 year results from the phase iii sirround d study
    RMD Open, 2018
    Co-Authors: Carter Thorne, Tsutomu Takeuchi, George Karpouzas, S Sheng, Regina Kurrasch
    Abstract:

    Objectives The phase III, multicentre, randomised, double-blind, placebo-controlled, parallel-group SIRROUND-D study evaluated long-term efficacy and safety of the interleukin (IL)-6 inhibitor, Sirukumab, in patients with active rheumatoid arthritis (RA) refractory to disease-modifying antirheumatic drugs (DMARDs). Methods Patients were randomised 1:1:1 to Sirukumab 100  mg every 2 weeks (q2w), 50  mg every 4 weeks or placebo q2w subcutaneously. Patients initially randomised to placebo were rerandomised at Weeks 18, 40 or 52 to one of the Sirukumab groups until Week 104. Results Of 1670 randomised patients, 1402 were included in the full analysis set and 1269 in the radiographic analysis set at Week 104. American College of Rheumatology scores, Disease Activity Score based on C-reactive protein, Clinical Disease Activity Index and clinically meaningful improvements in patient-reported outcomes were sustained at Week 104 among patients initially randomised to Sirukumab. Placebo patients subsequently rerandomised to Sirukumab showed clinical improvements at Week 104 that were comparable to results among patients initially randomised to Sirukumab. Radiographic progression from Week 52 to Week 104 was comparable between all groups whether initially randomised to Sirukumab or subsequently rerandomised to Sirukumab from placebo. No new safety signals were identified in the extended exposure period compared with the initial 52 weeks of treatment. Conclusions Sirukumab treatment resulted in sustained reductions in clinical signs and symptoms and minimal progression in radiographic damage over 2 years among patients with RA refractory to DMARDs. The safety profile of Sirukumab was as expected for an anti-IL-6 agent, with no new signals reported.

  • Sirukumab for rheumatoid arthritis the phase iii sirround d study
    Annals of the Rheumatic Diseases, 2017
    Co-Authors: Tsutomu Takeuchi, Carter Thorne, George Karpouzas, S Sheng, Weichun Xu
    Abstract:

    Objectives Interleukin-6 (IL-6) is implicated in rheumatoid arthritis (RA) pathophysiology. Unlike IL-6 receptor inhibitors, Sirukumab is a human monoclonal antibody that selectively binds to the IL-6 cytokine. The phase III, multicentre, randomised, double-blind, placebo-controlled, parallel-group SIRROUND-D study (ClinicalTrials.gov identifier NCT01604343) evaluated the efficacy and safety of Sirukumab in patients with active RA refractory to disease-modifying antirheumatic drugs. Methods Patients were randomised 1:1:1 to treatment with Sirukumab 100 mg every 2 weeks, 50 mg every 4 weeks or placebo every 2 weeks subcutaneously. Results through week 52 are reported. Results Of 1670 randomised patients, significantly more patients achieved American College of Rheumatology 20% (ACR20) response at week 16 (coprimary endpoint) with Sirukumab 100 mg every 2 weeks (53.5%) or 50 mg every 4 weeks (54.8%) versus placebo (26.4%; both p Conclusions Sirukumab 100 mg every 2 weeks and 50 mg every 4 weeks led to significant reductions in RA symptoms, inhibition of structural damage progression and physical function and quality of life improvements, with an expected safety profile. Trial registration number NCT01604343; Results.

  • AB0378 Improvements in Measures of Work Productivity/interference and General Health Status with Sirukumab Treatment in Patients with Active Rheumatoid Arthritis despite Disease-Modifying Anti-Rheumatic Drug Treatment
    Annals of the Rheumatic Diseases, 2016
    Co-Authors: T Takeuchi, Carter Thorne, George Karpouzas, S Sheng, Weichun Xu, S Peterson, K Mcquarrie, R Ganguly
    Abstract:

    Background Treatment-related improvements in the ability to perform work and general health status are key outcomes from the perspective of a patient with rheumatoid arthritis (RA). Sirukumab is a human monoclonal antibody that selectively binds to the IL-6 cytokine with high affinity and is under development for RA and other diseases. Objectives To evaluate the effects of Sirukumab on work productivity/interference and general health status in patients with active RA refractory to conventional, synthetic disease-modifying anti-rheumatic drugs (DMARDs). Methods In a randomized, double-blind, Phase 3 global study, patients with active RA and inadequate response to DMARDs were randomly assigned (1:1:1) to treatment with Sirukumab SC 50 mg q4w, Sirukumab SC 100 mg q2w, or placebo SC q2w. Patients on placebo with insufficient ( Results Mean WLQ production loss scores improved significantly from baseline for both Sirukumab 50 mg q4w and 100 mg q2w compared with placebo at Weeks 24 and 52 (all P P P ≤0.002). Conclusions In patients with active RA refractory to DMARDs, Sirukumab treatment was associated with significant improvements in work-related productivity and general health status, consistent with disease improvement demonstrated with Sirukumab treatment. Disclosure of Interest T. Takeuchi Grant/research support from: Astellas Pharma, Bristol–Myers K.K., Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahikasei Pharma Corp., and Taisho Toyama Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Ltd, Consultant for: Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., and Asahi Kasei Medical K.K.,abbivie GK, Daiichi Sankyo Co.,Ltd., Bristol–Myers K.K., Nipponkayaku Co.Ltd., Speakers bureau: AbbVie GK., Bristol–Myers K.K., Chugai Pharmaceutical Co,. Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., and Takeda Pharmaceutical Co., Ltd., Astellas Pharma, and Diaichi Sankyo Co., Ltd., Celtrion, Nipponkayaku Co. Ltd, G. Karpouzas: None declared, C. Thorne Grant/research support from: Abbvie, Amgen, Celgene, Lilly, Novartis, Pfizer, Sanofi, and UCB, Consultant for: Abbvie, Amgen, Celgene, Centocor, Genzyme, Hospira, Janssen, Lilly, Medexus/Medac, Merck, Novartis, Pfizer, Sanofi, and UCB, Speakers bureau: Medexus/Medac, K. McQuarrie Employee of: Janssen Research & Development, LLC, S. Sheng Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, W. Xu Employee of: Janssen Research & Development, LLC, S. Peterson Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, R. Ganguly Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, C. Han Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, K. Fei Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, B. Hsu Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC

  • sat0145 efficacy and safety of Sirukumab in patients with active rheumatoid arthritis despite disease modifying anti rheumatic drug treatment results of a randomized double blind placebo controlled study
    Annals of the Rheumatic Diseases, 2016
    Co-Authors: T Takeuchi, George Karpouzas, S Sheng, C Thorne, Weichun Xu
    Abstract:

    Background Sirukumab, a human monoclonal antibody that selectively binds to the IL-6 cytokine with high affinity, is under development for rheumatoid arthritis (RA) and other diseases. Objectives To evaluate efficacy and safety of Sirukumab in patients (pts) with RA refractory to conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs). Methods In this Phase 3 global study, 1,670 pts with active RA and inadequate response to DMARDs were randomized (1:1:1) to Sirukumab subcutaneous (SC) 50mg q4w, Sirukumab SC 100mg q2w, or placebo SC q2w. Pts on placebo with insufficient improvement ( Results For both co-primary endpoints, Sirukumab 50mg q4w and 100mg q2w showed significant improvement vs placebo (Table; all P P P Conclusions In DMARD-inadequate responders, Sirukumab SC 50mg q4w and 100mg q2w reduced signs/symptoms of RA, inhibited radiographic progression, and improved health-related quality of life. The safety profile of Sirukumab was consistent with the known safety profile of anti-IL-6 treatment. Disclosure of Interest T. Takeuchi Grant/research support from: Astellas Pharma, Bristol–Myers K.K., Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahikasei Pharma Corp., and Taisho Toyama Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Ltd, Consultant for: Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., and Asahi Kasei Medical K.K.,abbivie GK, Daiichi Sankyo Co.,Ltd., Bristol–Myers K.K., Nipponkayaku Co.Ltd., Speakers bureau: AbbVie GK., Bristol–Myers K.K., Chugai Pharmaceutical Co,. Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., and Takeda Pharmaceutical Co., Ltd., Astellas Pharma, and Diaichi Sankyo Co., Ltd., Celtrion, Nipponkayaku Co. Ltd, C. Thorne Grant/research support from: Abbvie, Amgen, Celgene, Lilly, Novartis, Pfizer, Sanofi, and UCB, Consultant for: Abbvie, Amgen, Celgene, Centocor, Genzyme, Hospira, Janssen, Lilly, Medexus/Medac, Merck, Novartis, Pfizer, Sanofi, and UCB, Speakers bureau: Medexus/Medac, G. Karpouzas Consultant for: Janssen, Speakers bureau: Janssen, S. Sheng Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, W. Xu Employee of: Janssen Research & Development, LLC, R. Rao Shareholder of: GSK, Employee of: GSK, K. Fei Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, B. Hsu Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC

  • sat0158 response and radiographic progression in biologic naive and biologic experienced patients with rheumatoid arthritis treated with Sirukumab
    Annals of the Rheumatic Diseases, 2016
    Co-Authors: C Thorne, George Karpouzas, S Sheng, Weichun Xu, T Takeuchi, Stephen Xu, Regina Kurrasch
    Abstract:

    Background Efficacy and safety of Sirukumab, a selective, high-affinity human monoclonal antibody to IL-6, have recently been evaluated in a global Phase 3 study in patients (pts) with active rheumatoid arthritis (RA) refractory to conventional disease-modifying anti-rheumatic drugs (DMARDs). Objectives To compare efficacy and radiographic progression of Sirukumab in subgroups of pts with active RA despite DMARD treatment who previously received biologic therapy (biologic-experienced) and who previously only received synthetic DMARDs (biologic-naive). Methods Pts were randomized (1:1:1) to Sirukumab subcutaneous (SC) 50mg q4w, Sirukumab SC 100mg q2w, or placebo SC q2w. Pts on placebo with insufficient ( Results Improvements were observed in all outcomes for Sirukumab vs placebo, regardless of prior biologic use (all P P P =0.02). No differences between prior biologic-naive and -experienced pts were observed in either Sirukumab dose group for the co-primary endpoints (both P ≥0.1) as well as for Wk 24 ACR50 response, DAS28 (CRP) remission, or Wk 52 mean DAS28 change from BL (all P ≥0.1). Conclusions Both Sirukumab doses significantly reduced RA signs/symptoms and inhibited radiographic progression vs placebo within prior biologic use categories, with comparable efficacy observed between biologic-naive and -experienced pts for both Sirukumab doses. Disclosure of Interest C. Thorne Grant/research support from: Abbvie, Amgen, Celgene, Lilly, Novartis, Pfizer, Sanofi, and UCB, Consultant for: Abbvie, Amgen, Celgene, Centocor, Genzyme, Hospira, Janssen, Lilly, Medexus/Medac, Merck, Novartis, Pfizer, Sanofi, and UCB, Speakers bureau: Medexus/Medac, G. Karpouzas Consultant for: Janssen, Speakers bureau: Janssen, T. Takeuchi Grant/research support from: Astellas Pharma, Bristol–Myers K.K., Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahikasei Pharma Corp., and Taisho Toyama Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Ltd, Consultant for: Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., and Asahi Kasei Medical K.K.,abbivie GK, Daiichi Sankyo Co.,Ltd., Bristol–Myers K.K., Nipponkayaku Co.Ltd., Speakers bureau: AbbVie GK., Bristol–Myers K.K., Chugai Pharmaceutical Co,. Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., and Takeda Pharmaceutical Co., Ltd., Astellas Pharma, and Diaichi Sankyo Co., Ltd., Celtrion, Nipponkayaku Co. Ltd, S. Sheng Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, W. Xu Employee of: Janssen Research & Development, LLC, S. Xu Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, R. Kurrasch Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, K. Fei Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, B. Hsu Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC

Yoshiya Tanaka - One of the best experts on this subject based on the ideXlab platform.

  • efficacy and safety of Sirukumab in japanese patients with active rheumatoid arthritis who were refractory or intolerant to anti tumor necrosis factor therapy subgroup analysis of a randomized double blind multicenter phase 3 study sirround t
    Modern Rheumatology, 2019
    Co-Authors: Yoshiya Tanaka, Tsutomu Takeuchi, Hisashi Yamanaka, Masayoshi Harigai, Toshikazu Nakano, Koshiro Akagi, Yoshifumi Ukyo
    Abstract:

    OBJECTIVE: To evaluate the efficacy and safety of Sirukumab, a human anti-interleukin six monoclonal antibody, in Japanese patients with rheumatoid arthritis who were refractory to anti-tumor necrosis factor therapy. METHODS: This subgroup analysis, based on a double-blind, placebo-controlled, 52-week phase 3, global study (SIRROUND-T) assessed the American College of Rheumatology (ACR) 20 response at week 16 (primary endpoint). Secondary endpoints: ACR 50, Disease Activity Score in 28 joints-C reactive protein, Health Assessment Questionnaire-Disability Index and safety were assessed. Results 116/878 patients received Sirukumab 50 mg/4 weeks (q4w, n = 35), 100 mg/2 weeks (q2w, n = 44) or placebo (n = 37) subcutaneously. Significantly more patients achieved ACR 20 response at week 16 with Sirukumab (50 mg q4w:20 [57.1%]; p < .001, 100 mg q2w:24 [54.5%]; p = .001) versus placebo (7 [18.9%]); consistent significant improvement in secondary endpoints at week 24 and 52 was observed. At week 24, incidence of treatment-emergent adverse events (TEAEs) was numerically higher with Sirukumab groups (50 mg q4w:29 [82.9%]; 100 mg q2w:38 [86.4%] versus placebo (28 [75.7%]); however, at week 52, Sirukumab combined groups had comparable incidence of TEAEs. CONCLUSION: Efficacy findings through 52 weeks were comparable between Sirukumab doses in Japanese patients and consistent with primary SIRROUND-T study results. No new safety signals were observed.

  • Sirukumab in rheumatoid arthritis refractory to sulfasalazine or methotrexate a randomized phase 3 safety and efficacy study in japanese patients
    Arthritis Research & Therapy, 2018
    Co-Authors: Tsutomu Takeuchi, Hisashi Yamanaka, Masayoshi Harigai, Toshikazu Nakano, Yoshifumi Ukyo, Ryo Tamamura, Yuichi Kato, Yoshiya Tanaka
    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.

  • efficacy and safety of Sirukumab in japanese patients with moderate to severe rheumatoid arthritis inadequately controlled by disease modifying anti rheumatic drugs subgroup analysis of a phase 3 study
    Modern Rheumatology, 2018
    Co-Authors: Tsutomu Takeuchi, Yoshiya Tanaka, Hisashi Yamanaka, Masayoshi Harigai, Toshikazu Nakano, Koshiro Akagi, Yoshifumi Ukyo
    Abstract:

    AbstractObjective: To evaluate the efficacy and safety of Sirukumab in Japanese patients with active rheumatoid arthritis (RA) uncontrolled by disease-modifying antirheumatic drugs.Methods: This subgroup analysis based on a double-blind, placebo-controlled, 52-week phase 3 study (SIRROUND-D) assessed American College of Rheumatology (ACR) 20 response at week 16 and van der Heijde-modified Sharp score (vdH-S) at week 52 (coprimary endpoints).Results: A total of 168 (Japanese)/1670 patients received Sirukumab 50 mg/4 weeks (q4w, n = 58), 100 mg/every 2 weeks (q2w, n = 54), or placebo (n = 56) subcutaneously. Significantly more patients achieved ACR20 response at week 16 with Sirukumab (50 mg q4w: 69.0%; 100mg q2w: 66.7%) vs. placebo (21.4%; p < .001). Median change from baseline in total vdH-S score at week 52 was significantly lower with Sirukumab (50 mg q4w: 0.3, p = .024; 100 mg q2w: 0.0, p = .002) vs. placebo (1.3). Sirukumab consistently showed greater improvements in secondary endpoints at weeks 24 an...

  • Efficacy and safety of Sirukumab in Japanese patients with moderate to severe rheumatoid arthritis inadequately controlled by disease modifying anti-rheumatic drugs: Subgroup analysis of a phase 3 study
    Modern Rheumatology, 2018
    Co-Authors: Tsutomu Takeuchi, Yoshiya Tanaka, Hisashi Yamanaka, Masayoshi Harigai, Toshikazu Nakano, Koshiro Akagi, Yoshifumi Ukyo
    Abstract:

    AbstractObjective: To evaluate the efficacy and safety of Sirukumab in Japanese patients with active rheumatoid arthritis (RA) uncontrolled by disease-modifying antirheumatic drugs.Methods: This subgroup analysis based on a double-blind, placebo-controlled, 52-week phase 3 study (SIRROUND-D) assessed American College of Rheumatology (ACR) 20 response at week 16 and van der Heijde-modified Sharp score (vdH-S) at week 52 (coprimary endpoints).Results: A total of 168 (Japanese)/1670 patients received Sirukumab 50 mg/4 weeks (q4w, n = 58), 100 mg/every 2 weeks (q2w, n = 54), or placebo (n = 56) subcutaneously. Significantly more patients achieved ACR20 response at week 16 with Sirukumab (50 mg q4w: 69.0%; 100mg q2w: 66.7%) vs. placebo (21.4%; p 

  • fri0214 long term efficacy and safety of Sirukumab in patients with active rheumatoid arthritis despite anti tumor necrosis factor therapy results of the randomized phase 3 sirround t study
    Annals of the Rheumatic Diseases, 2017
    Co-Authors: Yoshiya Tanaka, Regina Kurrasch, Daniel Aletaha, Prasheen Agarwal, S Popik
    Abstract:

    Background Sirukumab, a selective, high-affinity human monoclonal antibody to the interleukin-6 (IL-6) cytokine, is under development for rheumatoid arthritis (RA) and other diseases. Objectives To evaluate long-term efficacy and safety of Sirukumab in patients (pts) with RA refractory or intolerant to anti-tumor necrosis factor (TNF) agents. Methods This phase 3 study included pts ≥18 years with moderate to severe active RA, and a lack of benefit to ≥1 anti-TNF or intolerance to ≥2 anti-TNFs. Eligible pts were initially randomized 1:1:1 to Sirukumab subcutaneous (SC) 50mg q4w, Sirukumab SC 100mg q2w, or placebo SC q2w for 24 wks. Placebo-treated pts with Results 878 pts were initially randomized to placebo (n=294), Sirukumab 50 mg q4w (n=292), or Sirukumab 100 mg q2w (n=292). Of placebo-treated pts, 94 met EE criteria at Wk 18 and 158 crossed over at Wk 24 and were re-randomized to Sirukumab. 60% of pts had received ≥2 prior biologics, including non-TNF–targeted biologics. RA signs and symptoms and patient-reported outcomes (PROs [SF-36 scores]) improved significantly with Sirukumab versus placebo through Wk 24. Improvements were maintained through Wk 52 with no dose response (Table 1). Through Wk 52 in the combined Sirukumab 50mg q4w and 100mg q2w groups, respectively, an adverse event (AE) was reported for 79.6% and 81.3% of pts and a serious AE was reported for 14.2% and 13.2% of pts; injection-site reactions and alanine aminotransferase increases were the most commonly reported AEs. Conclusions In this population intolerant or refractory to anti-TNFs/other biologics, Sirukumab SC 50mg q4w and 100mg q2w were well tolerated and reduced signs and symptoms of RA and improved PROs through 52 wks of treatment, also among pts who switched from placebo to Sirukumab. Disclosure of Interest Y. Tanaka Grant/research support from: Mitsubishi-Tanabe, Takeda, Daiichi-Sankyo, Chugai, Bristol-Myers, MSD, Astellas, Abbvie, and Eisai, Speakers bureau: Abbvie, Chugai, Daiichi-Sankyo, Bristol-Myers, Mitsubishi-Tanabe, Astellas, Takeda, Pfizer, Teijin, Asahi-kasei, YL Biologics, Sanofi, Janssen, Eli Lilly, and GlaxoSmithKline, D. Aletaha Grant/research support from: AbbVie, Pfizer, Grunenthal, Merck Medac, UCB, Mitsubishi/Tanabe, Janssen, and Roche, Consultant for: AbbVie, Pfizer, Grunenthal, Merck Medac, UCB, Mitsubishi/Tanabe, Janssen, and Roche, P. Agarwal Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, R. Kurrasch Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, P. Tak Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, S. Popik Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC

Yanli Zhuang - One of the best experts on this subject based on the ideXlab platform.

  • exposure response modeling analyses for Sirukumab a human monoclonal antibody targeting interleukin 6 in patients with moderately to severely active rheumatoid arthritis
    The Journal of Clinical Pharmacology, 2018
    Co-Authors: Yan Xu, Yanli Zhuang, Zhenhua Xu, Chuanpu Hu, Amarnath Sharma, Honghui Zhou
    Abstract:

    To characterize the dose-exposure-response relationship of Sirukumab, an anti-interleukin 6 human monoclonal antibody, in the treatment of moderately to severely active rheumatoid arthritis (RA), we conducted exposure-response (E-R) modeling analyses based on data from two pivotal phase 3 placebo-controlled trials of Sirukumab in patients with RA who were inadequate responders to nonbiologic disease-modifying antirheumatic drugs or anti-tumor necrosis factor α agents. A total of 2176 patients were included for the analyses and received subcutaneous administration of either placebo or Sirukumab 50 mg every 4 weeks or 100 mg every 2 weeks. The clinical endpoints were 20%, 50%, and 70% improvement in the American College of Rheumatology response criteria (ie, ACR20, ACR50, and ACR70), and 28-joint Disease Activity Index Score (DAS28) using C-reactive protein. To provide a thorough assessment of the Sirukumab E-R relationship, 2 pharmacokinetic/pharmacodynamic modeling approaches were implemented, including joint longitudinal modeling (ie, indirect response modeling of the time course of the 2 clinical endpoints) and landmark analyses (ie, direct linking of selected pharmacokinetic parameters to response at week 16 or 24). Results from both modeling analyses were generally consistent, and collectively suggested that the Sirukumab subcutaneous dose of 50 mg every 4 weeks would produce near-maximal efficacy. No covariates identified in the E-R modeling analyses would have a significant impact on dose-response. Despite body weight and comorbid diabetes having significant effect on Sirukumab exposure, simulations suggested that their effect on efficacy was small. Our work provides a comprehensive evaluation of Sirukumab E-R to support dose recommendations in patients with RA.

  • Joint longitudinal model development: application to exposure–response modeling of ACR and DAS scores in rheumatoid arthritis patients treated with Sirukumab
    Journal of Pharmacokinetics and Pharmacodynamics, 2018
    Co-Authors: Chuanpu Hu, Yanli Zhuang, Zhenhua Xu, Yan Xu, Amarnath Sharma, Liping Zhang, Honghui Zhou
    Abstract:

    Exposure–response modeling is important to optimize dose and dosing regimen in clinical drug development. The joint modeling of multiple endpoints is made possible in part by recent progress in latent variable indirect response (IDR) modeling for ordered categorical endpoints. This manuscript presents the results of joint modeling of continuous and ordered categorical endpoints in the latent variable IDR modeling framework through the sharing of model parameters, with an application to the exposure–response modeling of Sirukumab. Sirukumab is a human anti- interleukin-6 (IL-6) monoclonal antibody that binds soluble human IL-6 thus blocking IL-6 signaling, which plays a major role in the pathophysiology of rheumatoid arthritis (RA). A phase 2 clinical trial was conducted in patients with active RA despite methotrexate therapy, who received subcutaneous (SC) administration of either placebo or Sirukumab of 25, 50 or 100 mg every 4 weeks (q4w) or 100 mg every 2 weeks (q2w). Major efficacy endpoints were the 20, 50, and 70% improvement in the American College of Rheumatology (ACR20, ACR50, and ACR70) disease severity criteria, and the 28-joint disease activity score using C-reactive protein (DAS28). The ACR endpoints were treated as ordered categorical and DAS28 as continuous. The results showed that, compared with the common approach of separately modeling the endpoints, the joint model could describe the observed data better with fewer parameters through the sharing of random effects, and thus more precisely characterize the dose–response relationship. The implications on future dose and dosing regimen optimization are discussed in contrast with those from landmark analysis.

  • confirmatory population pharmacokinetic analysis for Sirukumab a human monoclonal antibody targeting interleukin 6 in patients with moderately to severely active rheumatoid arthritis
    The Journal of Clinical Pharmacology, 2018
    Co-Authors: Yan Xu, Yanli Zhuang, Zhenhua Xu, Chuanpu Hu, Honghui Zhou
    Abstract:

    The population pharmacokinetics of Sirukumab, a human immunoglobulin G1κ monoclonal antibody against interleukin-6, were characterized in patients with moderately to severely active rheumatoid arthritis in 4 phase 3 studies (SIRROUND-D, -T, -H, and -M). A total of 17 034 serum concentrations were analyzed from 1991 rheumatoid arthritis patients who received subcutaneous administration of Sirukumab 50 mg every 4 weeks or 100 mg every 2 weeks. A stepwise confirmatory population PK analysis was conducted to accommodate the staged data release and the sparse sampling nature of phase 3 studies and to assess the potential covariate influences in an unbiased and timely manner. The base model, that is, a 1-compartment linear model with first-order absorption and first-order elimination, was prespecified based on prior information from a phase 2 study along with information about phase 3 study design. The covariate model was also prespecified based on pharmacological/physiological relevance and sample size. After the primary covariate analysis, a simplified model was produced by removing covariates with effect sizes <10%. The estimated apparent clearance (CL/F) and volume of distribution were 0.641 L/day and 16.1 L, respectively, at standard body weights of 70 kg. The terminal elimination half-life was approximately 17.4 days. Sirukumab CL/F and volume of distribution increased with body weight, and CL/F was higher in patients with diabetic comorbidity. Simulations suggest that the effects of diabetic comorbidity and weight on Sirukumab exposure were additive. To fully understand the clinical relevance including potential dose adjustment, current covariate findings need to be evaluated concurrently with the efficacy and safety data.

  • joint longitudinal model development application to exposure response modeling of acr and das scores in rheumatoid arthritis patients treated with Sirukumab
    Journal of Pharmacokinetics and Pharmacodynamics, 2018
    Co-Authors: Chuanpu Hu, Yanli Zhuang, Zhenhua Xu, Yan Xu, Amarnath Sharma, Liping Zhang, Honghui Zhou
    Abstract:

    Exposure-response modeling is important to optimize dose and dosing regimen in clinical drug development. The joint modeling of multiple endpoints is made possible in part by recent progress in latent variable indirect response (IDR) modeling for ordered categorical endpoints. This manuscript presents the results of joint modeling of continuous and ordered categorical endpoints in the latent variable IDR modeling framework through the sharing of model parameters, with an application to the exposure-response modeling of Sirukumab. Sirukumab is a human anti- interleukin-6 (IL-6) monoclonal antibody that binds soluble human IL-6 thus blocking IL-6 signaling, which plays a major role in the pathophysiology of rheumatoid arthritis (RA). A phase 2 clinical trial was conducted in patients with active RA despite methotrexate therapy, who received subcutaneous (SC) administration of either placebo or Sirukumab of 25, 50 or 100 mg every 4 weeks (q4w) or 100 mg every 2 weeks (q2w). Major efficacy endpoints were the 20, 50, and 70% improvement in the American College of Rheumatology (ACR20, ACR50, and ACR70) disease severity criteria, and the 28-joint disease activity score using C-reactive protein (DAS28). The ACR endpoints were treated as ordered categorical and DAS28 as continuous. The results showed that, compared with the common approach of separately modeling the endpoints, the joint model could describe the observed data better with fewer parameters through the sharing of random effects, and thus more precisely characterize the dose-response relationship. The implications on future dose and dosing regimen optimization are discussed in contrast with those from landmark analysis.

  • Exposure‐Response Modeling Analyses for Sirukumab, a Human Monoclonal Antibody Targeting Interleukin 6, in Patients With Moderately to Severely Active Rheumatoid Arthritis
    The Journal of Clinical Pharmacology, 2018
    Co-Authors: Yan Xu, Yanli Zhuang, Zhenhua Xu, Chuanpu Hu, Amarnath Sharma, Honghui Zhou
    Abstract:

    To characterize the dose-exposure-response relationship of Sirukumab, an anti-interleukin 6 human monoclonal antibody, in the treatment of moderately to severely active rheumatoid arthritis (RA), we conducted exposure-response (E-R) modeling analyses based on data from two pivotal phase 3 placebo-controlled trials of Sirukumab in patients with RA who were inadequate responders to nonbiologic disease-modifying antirheumatic drugs or anti-tumor necrosis factor α agents. A total of 2176 patients were included for the analyses and received subcutaneous administration of either placebo or Sirukumab 50 mg every 4 weeks or 100 mg every 2 weeks. The clinical endpoints were 20%, 50%, and 70% improvement in the American College of Rheumatology response criteria (ie, ACR20, ACR50, and ACR70), and 28-joint Disease Activity Index Score (DAS28) using C-reactive protein. To provide a thorough assessment of the Sirukumab E-R relationship, 2 pharmacokinetic/pharmacodynamic modeling approaches were implemented, including joint longitudinal modeling (ie, indirect response modeling of the time course of the 2 clinical endpoints) and landmark analyses (ie, direct linking of selected pharmacokinetic parameters to response at week 16 or 24). Results from both modeling analyses were generally consistent, and collectively suggested that the Sirukumab subcutaneous dose of 50 mg every 4 weeks would produce near-maximal efficacy. No covariates identified in the E-R modeling analyses would have a significant impact on dose-response. Despite body weight and comorbid diabetes having significant effect on Sirukumab exposure, simulations suggested that their effect on efficacy was small. Our work provides a comprehensive evaluation of Sirukumab E-R to support dose recommendations in patients with RA.

Honghui Zhou - One of the best experts on this subject based on the ideXlab platform.

  • exposure response modeling analyses for Sirukumab a human monoclonal antibody targeting interleukin 6 in patients with moderately to severely active rheumatoid arthritis
    The Journal of Clinical Pharmacology, 2018
    Co-Authors: Yan Xu, Yanli Zhuang, Zhenhua Xu, Chuanpu Hu, Amarnath Sharma, Honghui Zhou
    Abstract:

    To characterize the dose-exposure-response relationship of Sirukumab, an anti-interleukin 6 human monoclonal antibody, in the treatment of moderately to severely active rheumatoid arthritis (RA), we conducted exposure-response (E-R) modeling analyses based on data from two pivotal phase 3 placebo-controlled trials of Sirukumab in patients with RA who were inadequate responders to nonbiologic disease-modifying antirheumatic drugs or anti-tumor necrosis factor α agents. A total of 2176 patients were included for the analyses and received subcutaneous administration of either placebo or Sirukumab 50 mg every 4 weeks or 100 mg every 2 weeks. The clinical endpoints were 20%, 50%, and 70% improvement in the American College of Rheumatology response criteria (ie, ACR20, ACR50, and ACR70), and 28-joint Disease Activity Index Score (DAS28) using C-reactive protein. To provide a thorough assessment of the Sirukumab E-R relationship, 2 pharmacokinetic/pharmacodynamic modeling approaches were implemented, including joint longitudinal modeling (ie, indirect response modeling of the time course of the 2 clinical endpoints) and landmark analyses (ie, direct linking of selected pharmacokinetic parameters to response at week 16 or 24). Results from both modeling analyses were generally consistent, and collectively suggested that the Sirukumab subcutaneous dose of 50 mg every 4 weeks would produce near-maximal efficacy. No covariates identified in the E-R modeling analyses would have a significant impact on dose-response. Despite body weight and comorbid diabetes having significant effect on Sirukumab exposure, simulations suggested that their effect on efficacy was small. Our work provides a comprehensive evaluation of Sirukumab E-R to support dose recommendations in patients with RA.

  • Joint longitudinal model development: application to exposure–response modeling of ACR and DAS scores in rheumatoid arthritis patients treated with Sirukumab
    Journal of Pharmacokinetics and Pharmacodynamics, 2018
    Co-Authors: Chuanpu Hu, Yanli Zhuang, Zhenhua Xu, Yan Xu, Amarnath Sharma, Liping Zhang, Honghui Zhou
    Abstract:

    Exposure–response modeling is important to optimize dose and dosing regimen in clinical drug development. The joint modeling of multiple endpoints is made possible in part by recent progress in latent variable indirect response (IDR) modeling for ordered categorical endpoints. This manuscript presents the results of joint modeling of continuous and ordered categorical endpoints in the latent variable IDR modeling framework through the sharing of model parameters, with an application to the exposure–response modeling of Sirukumab. Sirukumab is a human anti- interleukin-6 (IL-6) monoclonal antibody that binds soluble human IL-6 thus blocking IL-6 signaling, which plays a major role in the pathophysiology of rheumatoid arthritis (RA). A phase 2 clinical trial was conducted in patients with active RA despite methotrexate therapy, who received subcutaneous (SC) administration of either placebo or Sirukumab of 25, 50 or 100 mg every 4 weeks (q4w) or 100 mg every 2 weeks (q2w). Major efficacy endpoints were the 20, 50, and 70% improvement in the American College of Rheumatology (ACR20, ACR50, and ACR70) disease severity criteria, and the 28-joint disease activity score using C-reactive protein (DAS28). The ACR endpoints were treated as ordered categorical and DAS28 as continuous. The results showed that, compared with the common approach of separately modeling the endpoints, the joint model could describe the observed data better with fewer parameters through the sharing of random effects, and thus more precisely characterize the dose–response relationship. The implications on future dose and dosing regimen optimization are discussed in contrast with those from landmark analysis.

  • confirmatory population pharmacokinetic analysis for Sirukumab a human monoclonal antibody targeting interleukin 6 in patients with moderately to severely active rheumatoid arthritis
    The Journal of Clinical Pharmacology, 2018
    Co-Authors: Yan Xu, Yanli Zhuang, Zhenhua Xu, Chuanpu Hu, Honghui Zhou
    Abstract:

    The population pharmacokinetics of Sirukumab, a human immunoglobulin G1κ monoclonal antibody against interleukin-6, were characterized in patients with moderately to severely active rheumatoid arthritis in 4 phase 3 studies (SIRROUND-D, -T, -H, and -M). A total of 17 034 serum concentrations were analyzed from 1991 rheumatoid arthritis patients who received subcutaneous administration of Sirukumab 50 mg every 4 weeks or 100 mg every 2 weeks. A stepwise confirmatory population PK analysis was conducted to accommodate the staged data release and the sparse sampling nature of phase 3 studies and to assess the potential covariate influences in an unbiased and timely manner. The base model, that is, a 1-compartment linear model with first-order absorption and first-order elimination, was prespecified based on prior information from a phase 2 study along with information about phase 3 study design. The covariate model was also prespecified based on pharmacological/physiological relevance and sample size. After the primary covariate analysis, a simplified model was produced by removing covariates with effect sizes <10%. The estimated apparent clearance (CL/F) and volume of distribution were 0.641 L/day and 16.1 L, respectively, at standard body weights of 70 kg. The terminal elimination half-life was approximately 17.4 days. Sirukumab CL/F and volume of distribution increased with body weight, and CL/F was higher in patients with diabetic comorbidity. Simulations suggest that the effects of diabetic comorbidity and weight on Sirukumab exposure were additive. To fully understand the clinical relevance including potential dose adjustment, current covariate findings need to be evaluated concurrently with the efficacy and safety data.

  • joint longitudinal model development application to exposure response modeling of acr and das scores in rheumatoid arthritis patients treated with Sirukumab
    Journal of Pharmacokinetics and Pharmacodynamics, 2018
    Co-Authors: Chuanpu Hu, Yanli Zhuang, Zhenhua Xu, Yan Xu, Amarnath Sharma, Liping Zhang, Honghui Zhou
    Abstract:

    Exposure-response modeling is important to optimize dose and dosing regimen in clinical drug development. The joint modeling of multiple endpoints is made possible in part by recent progress in latent variable indirect response (IDR) modeling for ordered categorical endpoints. This manuscript presents the results of joint modeling of continuous and ordered categorical endpoints in the latent variable IDR modeling framework through the sharing of model parameters, with an application to the exposure-response modeling of Sirukumab. Sirukumab is a human anti- interleukin-6 (IL-6) monoclonal antibody that binds soluble human IL-6 thus blocking IL-6 signaling, which plays a major role in the pathophysiology of rheumatoid arthritis (RA). A phase 2 clinical trial was conducted in patients with active RA despite methotrexate therapy, who received subcutaneous (SC) administration of either placebo or Sirukumab of 25, 50 or 100 mg every 4 weeks (q4w) or 100 mg every 2 weeks (q2w). Major efficacy endpoints were the 20, 50, and 70% improvement in the American College of Rheumatology (ACR20, ACR50, and ACR70) disease severity criteria, and the 28-joint disease activity score using C-reactive protein (DAS28). The ACR endpoints were treated as ordered categorical and DAS28 as continuous. The results showed that, compared with the common approach of separately modeling the endpoints, the joint model could describe the observed data better with fewer parameters through the sharing of random effects, and thus more precisely characterize the dose-response relationship. The implications on future dose and dosing regimen optimization are discussed in contrast with those from landmark analysis.

  • Exposure‐Response Modeling Analyses for Sirukumab, a Human Monoclonal Antibody Targeting Interleukin 6, in Patients With Moderately to Severely Active Rheumatoid Arthritis
    The Journal of Clinical Pharmacology, 2018
    Co-Authors: Yan Xu, Yanli Zhuang, Zhenhua Xu, Chuanpu Hu, Amarnath Sharma, Honghui Zhou
    Abstract:

    To characterize the dose-exposure-response relationship of Sirukumab, an anti-interleukin 6 human monoclonal antibody, in the treatment of moderately to severely active rheumatoid arthritis (RA), we conducted exposure-response (E-R) modeling analyses based on data from two pivotal phase 3 placebo-controlled trials of Sirukumab in patients with RA who were inadequate responders to nonbiologic disease-modifying antirheumatic drugs or anti-tumor necrosis factor α agents. A total of 2176 patients were included for the analyses and received subcutaneous administration of either placebo or Sirukumab 50 mg every 4 weeks or 100 mg every 2 weeks. The clinical endpoints were 20%, 50%, and 70% improvement in the American College of Rheumatology response criteria (ie, ACR20, ACR50, and ACR70), and 28-joint Disease Activity Index Score (DAS28) using C-reactive protein. To provide a thorough assessment of the Sirukumab E-R relationship, 2 pharmacokinetic/pharmacodynamic modeling approaches were implemented, including joint longitudinal modeling (ie, indirect response modeling of the time course of the 2 clinical endpoints) and landmark analyses (ie, direct linking of selected pharmacokinetic parameters to response at week 16 or 24). Results from both modeling analyses were generally consistent, and collectively suggested that the Sirukumab subcutaneous dose of 50 mg every 4 weeks would produce near-maximal efficacy. No covariates identified in the E-R modeling analyses would have a significant impact on dose-response. Despite body weight and comorbid diabetes having significant effect on Sirukumab exposure, simulations suggested that their effect on efficacy was small. Our work provides a comprehensive evaluation of Sirukumab E-R to support dose recommendations in patients with RA.

Michael E Weinblatt - One of the best experts on this subject based on the ideXlab platform.

  • Sirukumab a human anti interleukin 6 monoclonal antibody a randomised 2 part proof of concept and dose finding phase ii study in patients with active rheumatoid arthritis despite methotrexate therapy
    Annals of the Rheumatic Diseases, 2014
    Co-Authors: Josef S Smolen, S Sheng, Michael E Weinblatt, Yanli Zhuang
    Abstract:

    Objectives The safety and efficacy of Sirukumab, an anti-interleukin-6 (IL-6) monoclonal antibody, were evaluated in a 2-part, placebo-controlled phase II study of patients with active rheumatoid arthritis (RA) despite methotrexate therapy. Methods In Part A (proof-of-concept), 36 patients were randomised to placebo or Sirukumab 100 mg every 2 weeks (q2w) through week 10, with crossover treatment during weeks 12–22. In Part B (dose finding), 151 patients were randomised to Sirukumab (100 mg q2w, 100 mg q4w, 50 mg q4w, or 25 mg q4w) through week 24, or placebo through week 10 with crossover to Sirukumab 100 mg q2w (weeks 12–24). The proportion of patients with an American College of Rheumatology 50 (ACR50) response and the change from baseline in the 28-joint count disease activity score using C-reactive protein (DAS28-CRP) were determined. Safety was evaluated through week 38 in both parts. Results The primary endpoint (ACR50 at week 12 in Part B) was achieved only with Sirukumab 100 mg q2w versus placebo (26.7% vs 3.3%; p=0.026). Greater improvements in mean DAS28-CRP at week 12 were observed with Sirukumab 100 mg q2w versus placebo in Parts A (2.1 vs 0.6, p Conclusions Sirukumab-treated patients experienced improvements in the signs/symptoms of RA. Safety results through 38 weeks were consistent with other IL-6 inhibitors. Trial registration number NCT00718718.

  • op0025 results from a multicenter international randomized double blind placebo controlled phase 2 study of Sirukumab a human anti il 6 monoclonal antibody in patients with active rheumatoid arthritis despite methotrexate therapy
    Annals of the Rheumatic Diseases, 2013
    Co-Authors: S Sheng, Michael E Weinblatt, Josef S Smolen
    Abstract:

    Objectives To assess remission rates from a phase 2 study of Sirukumab, a human monoclonal antibody against the cytokine interleukin-6 (formerly named CNTO 136), using the new provisional 2011 ACR/EULAR rheumatoid arthritis (RA) remission criteria. Methods In the dose-ranging part of a 2-part, multicenter, randomized, double blind, placebo controlled, phase 2 study, pts with active RA despite methotrexate (MTX) were randomized equally to receive SC injections of placebo q2w at wks 0-10 and Sirukumab 100 mg q2w at wks 12-24 (n=30), Sirukumab 100 mg q2w at wks 0-24 (n=30), Sirukumab 100 mg q4w at wks 0-24 (n=30), Sirukumab 50 mg q4w at wks 0-24 (n=30), or Sirukumab 25 mg q4w at wks 0-24 (n=31). RA remission rates were prospectively assessed using the DAS28 (CRP) remission criteria and retrospectively assessed using the 2011 ACR/EULAR remission criteria (Boolean-and SDAI-based) at wks 12, 24, and 38. The 2011 ACR/EULAR remission criteria used in this study were: Boolean-based (68-joint TJC ≤1, 66-joint SJC ≤1, CRP ≤1 mg/dL, PGA ≤1 on a 1-10 cm VAS), index-based (SDAI score [ie, 28-joint TJC + 28-joint SJC + PGA + physician’s global assessment + CRP mg/dL] ≤3.3). Results At wk 12 (pre-crossover), more pts were in remission with Sirukumab than with placebo according to both Boolean- and SDAI-based ACR/EULAR criteria (2% vs 0% and 6% vs 3%, Table). The percentage of pts in remission according to all 3 criteria increased to a peak at wk 24 in the Sirukumab 100 mg q2w and q4w treatment groups and remained higher than wk-12 rates at wk 38, 14 wks after the last dose of Sirukumab. Pts who received Sirukumab 100 mg q2w throughout the study achieved the highest remission rates according to all 3 remission criteria at all time points, including a statistically significant difference compared with placebo according to DAS28 remission criteria at wk 12 (20% vs 0%, p=0.024) and Boolean-based ACR/EULAR remission in 4/30 (13%) pts and SDAI-based ACR/EULAR remission in 7/30 (23%) pts at both wk 24 and wk 38. As expected, the more stringent 2011 ACR/EULAR remission criteria resulted in generally lower remission rates than the DAS28 remission criteria at all time points. Lower remission rates were seen for all groups at all time points with the Boolean-based vs the SDAI-based definition. Conclusions Higher remission rates according to both the 2011 ACR/EULAR and the DAS28 (CRP) criteria were achieved with Sirukumab at SC dose regimens ranging from 25-100 mg q2w-q4w compared with placebo. After placebo crossover to Sirukumab, all groups achieved increasing remission rates over time with continued Sirukumab treatment. The highest Sirukumab dose regimen (100 mg q2w) achieved the highest remission rates. The 2011 ACR/EULAR criteria were more stringent than the DAS28 (CRP) criteria; and the Boolean-based definition was more stringent than the SDAI-based definition. Disclosure of Interest B. Hsu Employee of: Janssen Research & Development, LLC, S. Sheng Employee of: Janssen Research & Development, LLC, M. Weinblatt Grant/Research support from: Investigators for Janssen Research & Development, LLC sponsored clinical study, J. Smolen Grant/Research support from: Investigators for Janssen Research & Development, LLC sponsored clinical study

  • fri0181 Sirukumab a human anti il 6 monoclonal antibody improves physical function in patients with active ra despite methotrexate therapy results from a 2 part proof of concept dose ranging randomized double blind placebo controlled phase 2 study
    Annals of the Rheumatic Diseases, 2013
    Co-Authors: C F Chiou, S Sheng, Josef S Smolen, Michael E Weinblatt
    Abstract:

    Background Sirukumab (formerly named CNTO136) is a human mAb that binds with high affinity to the cytokine IL-6. In the proof of concept part (Part A) of this multicenter, randomized, double blind, PBO controlled, phase 2 study, 100mg Sirukumab SC injections q2w were generally well tolerated and efficacious Objectives The phase 2 dose-ranging Part B was initiated after Part A to determine efficacious and safe Sirukumab dose regimens. Methods In Part B, pts with active RA despite MTX were randomized equally to: (1) PBO q2wk at wks 0–10, then Sirukumab 100 mg q2wk at wks12–24; (2) Sirukumab 100 mg q2wk at wks 0–24; (3) Sirukumab 100 mg q4wk at wks 0–24; (4) Sirukumab 50 mg q4wk at wks 0–24; or (5) Sirukumab 25 mg q4wk at wks 0–24. As reported previously, the primary endpoint (ACR50 response at wk 12) was achieved by the 100 mg q2wk and 50 mg q4wk doses. We now report specific changes observed through wk12 in the Health Assessment Questionnaire disability index (HAQ-DI), the physical component summary (PCS) score of the Short Form-36 (SF-36) scales, and individual ACR core components other than HAQ-DI. Two improvement thresholds (≥0.25 and ≥0.30) were used to define HAQ-DI response. Clinical response was assessed using the Disease Activity Score (employing 28 joints and C-reactive protein, DAS28-CRP) and Clinical Disease Activity Index (CDAI). The study was only powered for the primary endpoint. An intent-to-treat analysis of pts according to original treatment assignments was conducted, with imputation of missing data by carrying forward the last observation and treatment failure rules for non-responders. Results In Part B, 151 pts were randomized and treated. At baseline, mean age: 53±11 yrs, mean weight: 69±15 kg, mean DAS28 (CRP): 5.9±0.9, and median serum CRP: 1.7 mg/dL. Mean baseline HAQ-DI scores (1.54±0.64) were comparable between treatment groups; mean SF-36 PCS score (31.55±7.78) was notably below the general population norm. At wk12, a higher proportion of pts achieved HAQ-DI response, significantly greater improvement in HAQ-DI was observed in the combined Sirukumab group (mean±sd: 0.42±0.53) compared to PBO (0.15±0.56) (p=0.012). No apparent Sirukumab dose response was observed. HAQ-DI response was observed as early as wk2 and increased over time through wk24 in all 5 treatment groups. At wk12, greater improvement in SF-36 PCS score was observed in the combined Sirukumab group compared with PBO (p=0.038). Also, statistically significant improvement in the combined Sirukumab group vs. PBO was observed for each of the ACR core components, except for tender joint count, which trended toward improvement (p=0.06). Pain (p=0.010), physician global (p=0.005), and CRP (p Conclusions In this Phase 2 study of patients with active RA despite MTX therapy, Sirukumab in combination with MTX, improved physical function as well as reduced multiple other signs and symptoms of RA. Disclosure of Interest B. Hsu: None Declared, C.-F. Chiou: None Declared, S. Sheng Employee of: Janssen Research & Development, LLC, J. Smolen Grant/Research support from: Investigators for Janssen Research & Development, LLC sponsored clinical study, M. Weinblatt Grant/Research support from: Investigators for Janssen Research & Development, LLC sponsored clinical study

  • thu0100 results from a 2 part proof of concept dose ranging randomized double blind placebo controlled phase 2 study of Sirukumab a human anti il 6 monoclonal antibody in patients with active rheumatoid arthritis despite methotrexate therapy
    Annals of the Rheumatic Diseases, 2013
    Co-Authors: S Sheng, Josef S Smolen, Michael E Weinblatt
    Abstract:

    Objectives To determine the efficacy and safety of SC Sirukumab (SRM) dose regimens & to describe PK & PD in active RA pts in a Ph2 dose-ranging Part B study. Methods Pts w/ active RA despite MTX were randomized: (1) PBO q2w at wks 0–10, then SRM 100mg q2w at wks 12–24; (2) SRM 100mg q2w at wks 0–24; (3) SRM 100mg q4w at wks 0–24; (4) SRM 50mg q4w at wks 0–24; or (5) SRM 25mg q4w at wks 0–24. Primary endpt ACR50 at wk12, compared btw each active grp vs PBO. Key secondary endpts: change from baseline (BL) in DAS28 (CRP) at wk12, serum SRM PK, & % change from BL in serum CRP at wk2. Results In Part B, 151 pts were randomized & treated. 85% female, 60% Caucasian, 21% Japanese. At BL, mean age:53±11yrs, mean weight:69±15kg, mean DAS28 (CRP):5.9±0.9, & median serum CRP:1.7mg/dL. 26 (87%) PBO pts crossed over to SRM 100mg q2w at wk12. At wk12, SRM sig improved ACR50 (overall p=0.010) & sig decreased DAS28 (p 80% from BL w/ SRM at wk2 & remained suppressed thru wk24. Thru wk38, AEs occurred more often w/ SRM than PBO (81 vs 67%), including minor infections/infestations (31 vs 13%), GI disorders (19 vs 10%), & injection site reactions (16 vs 3%). Leukopenia (19, 13% [1 NCI Gr 3]), neutropenia (5, 3% [3 Gr 3]), thrombocytopenia (3, 2% [1 Gr 3, 1 Gr 4]), & lymphopenia (2, 1%, [1 Gr 3, 1 Gr 4]) were reported w/ SRM. ALT (8 Gr 3, 7%) & AST (1 Gr 3, 1%) elevations not associated w/ increased bilirubin; & sustained increase from BL starting at wk2 in total cholesterol (mean SRM vs PBO: 19%±17% vs -5%±12%) & LDL (20%±20% vs -4%±22%) were seen w/ SRM. These lab abnormalities occurred w/o dose relationship or short term clinical sequelae. SAEs were more common w/ PBO (4, 13%) than SRM (13, 9%); majority were infections. 1 pt died of unrelated brain aneurysm. 4/136 (3%; 2 100mg q4w, 2 PBO→100mg q2w) evaluable pts had antibodies to SRM thru wk38; 3 of these pts were ACR50 responders at wk24, 0 had injection site reactions. Conclusions SRM was efficacious & generally well tolerated. SRM PK were linear over SC regimens ranging from 25 to 100mg. Disclosure of Interest B. Hsu Employee of: Janssen Research & Development, LLC, S. Sheng Employee of: Janssen Research & Development, LLC, J. Smolen Grant/Research support from: Investigators for Janssen Research & Development, LLC sponsored clinical study, M. Weinblatt Grant/Research support from: Investigators for Janssen Research & Development, LLC sponsored clinical study