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

Tsutomu Takeuchi, Hisashi Yamanaka, Masayoshi Harigai, Ryo Tamamura, Yuichi Kato, Yoshifumi Ukyo, Toshikazu Nakano, Benjamin Hsu, Yoshiya Tanaka, Tsutomu Takeuchi, Hisashi Yamanaka, Masayoshi Harigai, Ryo Tamamura, Yuichi Kato, Yoshifumi Ukyo, Toshikazu Nakano, Benjamin Hsu, 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.

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.

Keywords: Biologicals; Disease-modifying anti-rheumatic drugs; Interleukin-6; Rheumatoid arthritis; Sirukumab.

Conflict of interest statement

Ethics approval and consent to participate

The study protocol was approved by the institutional review board (Keio University Hospital) of the lead investigator (TT) and by the institutional review boards of each of the 20 other participating study sites. The study was conducted in accordance with the Declaration of Helsinki consistent with Good Clinical Practices and applicable regulatory requirements. All participants provided written informed consent.

Consent for publication

Not applicable.

Competing interests

TT has received research grants 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, Asahi Kasei Pharma Corp., Taisho Toyama Pharmaceutical Co. Ltd and SymBio Pharmaceuticals Ltd; has received consulting fees from Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., Asahi Kasei Medical K.K., AbbVie GK, Daiichi Sankyo Co. Ltd, Bristol-Myers K.K. and Nippon Kayaku Co. Ltd; and has received speaking fees from AbbVie GK, Bristol-Myers K.K., Chugai Pharmaceutical Co. Ltd, Eisai Co. Ltd, Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Takeda Pharmaceutical Co. Ltd, Astellas Pharma, Daiichi Sankyo Co. Ltd, Celtrion and Nippon Kayaku Co. Ltd.

HY has received research grants from AbbVie, Asahi Kasei, Astellas, AstraZeneca, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, GlaxoSmithKline, Janssen Pharmaceutical Product, L.P., Mitsubishi Tanabe, MSD, Nippon Kayaku, Pfizer Inc., Santen, Taisho Toyama, Takeda and Teijin; has received consulting fees from AbbVie, Astellas, AstraZeneca, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Mitsubishi Tanabe, Nippon Kayaku, Pfizer Inc., Takeda and Teijin; and has served on a speakers’ bureau for AbbVie, Astellas, Bristol-Myers Squibb, Chugai, Eisai, Mitsubishi Tanabe, Pfizer Inc., Takeda and Teijin.

MH has received research grants from AbbVie Japan, Astellas Pharma, Bristol-Myers Squibb, Chugai Pharmaceutical, Eisai, Mitsubishi Tanabe Pharma, Ono Pharmaceuticals, Santen Pharmaceutical, Takeda Pharmaceutical, UCB Japan and Teijin Pharma; and has received consulting fees from AbbVie Japan, Janssen Pharma, Chugai Pharmaceutical, Teijin Pharma, Eli Lilly Japan and Zenyaku Kogyo.

YT has received research grants from Mitsubishi-Tanabe, Takeda, Daiichi-Sankyo, Chugai, Bristol-Myers, MSD, Astellas, Abbvie and Eisai; and has received consulting fees from Abbvie, Chugai, Daiichi-Sankyo, Bristol-Myers, Mitsubishi-Tanabe, Astellas, Takeda, Pfizer, Teijin, Asahi Kasei, YL Biologics, Sanofi, Janssen, Eli Lilly and GlaxoSmithKline.

RT, YK, YU and TN are employees of Janssen Pharmaceutical K.K.

BH is an employee and stockholder of Johnson & Johnson.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Study design and patient disposition

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