ASP5094, a humanized monoclonal antibody against integrin alpha-9, did not show efficacy in patients with rheumatoid arthritis refractory to methotrexate: results from a phase 2a, randomized, double-blind, placebo-controlled trial

Tsutomu Takeuchi, Yoshiya Tanaka, Jay Erdman, Yuichiro Kaneko, Masako Saito, Chieri Higashitani, Ronald Smulders, Christopher Lademacher, Tsutomu Takeuchi, Yoshiya Tanaka, Jay Erdman, Yuichiro Kaneko, Masako Saito, Chieri Higashitani, Ronald Smulders, Christopher Lademacher

Abstract

Background: Rheumatoid arthritis (RA) is a chronic, debilitating autoimmune condition characterized by joint synovial inflammation. Current treatments include methotrexate (MTX), biologic agents, and Janus kinase (JAK) inhibitors. However, these agents are not efficacious in all patients and there are concerns regarding side effects and risk of infection as these treatments target immune-related pathways. Overexpression and activation of integrin alpha-9 (α9) on fibroblast-like synoviocytes are associated with RA disease onset and exacerbation. The humanized immunoglobulin G1 monoclonal antibody ASP5094 was designed to inhibit human α9 and is currently under investigation for the treatment of RA.

Methods: This phase 2a, multicenter, randomized, placebo-controlled, double-blind, parallel-group study (NCT03257852) evaluated the efficacy, safety, and biological activity of intravenous ASP5094 10 mg/kg in patients with moderate to severe RA that was refractory to MTX. Patients received ASP5094 or placebo every 4 weeks for a total of three administrations. Both treatment groups used concomitant MTX. The primary efficacy endpoint was the proportion of patients who responded per American College of Rheumatology 50% improvement using C-reactive protein (ACR50-CRP) after 12 weeks of treatment. Biological activity of ASP5094 was assessed via pharmacokinetics and pharmacodynamics of known downstream effectors of α9. Safety was also assessed.

Results: Sixty-six patients were enrolled and randomized to placebo (n = 33) or ASP5094 (n = 33). In the primary efficacy analysis, ACR50-CRP response rates were 6.3% and 18.2% at week 12 in the ASP5094 and placebo groups, respectively; a difference of - 11.9, which was not significant (2-sided P value = 0.258). No trends in ACR50 response rates were observed in subgroups based on demographics or baseline disease characteristics, and no significant differences between placebo and ASP5094 were identified in secondary efficacy or pharmacodynamic endpoints, despite achievement of target serum concentrations of ASP5094. Most treatment-emergent adverse events were mild to moderate in severity, and ASP5094 was considered safe and well tolerated overall.

Conclusion: Although no notable safety signals were observed in this study, ASP5094 was not efficacious in patients with moderate to severe RA with an inadequate response to MTX.

Trial registration: ClinicalTrials.gov, NCT03257852 . Registered on 22 Aug. 2017.

Keywords: Antibodies, Monoclonal, Humanized; Antirheumatic agents; Arthritis, Rheumatoid; Biological products; Extracellular matrix proteins; Integrin alpha-9, human; Integrins; Methotrexate; Synovial membrane; Synoviocytes.

Conflict of interest statement

T. Takeuchi reports grants from Astellas Pharma, Inc.; Chugai Pharmaceutical Co, Ltd.; Daiichi-Sankyo Co., Ltd.; Takeda Pharmaceutical Co., Ltd.; AbbVie GK; Asahikasei Pharma Corp.; Mitsubishi Tanabe Pharma Co.; Pfizer Japan Inc.; Eisai Co., Ltd.; AYUMI Pharmaceutical Corporation; Nipponkayaku Co. Ltd.; Novartis Pharma K.K.; and Shionogi & Co., LTD and personal fees from Astellas Pharma, Inc.; AbbVie GK; AYUMI Pharmaceutical Corporation; Eisai Co., Ltd.; Gilead Sciences, Inc.; GlaxoSmithKline K.K.; Sanofi K.K.; Taiho Pharmaceutical Co., Ltd.; Mitsubishi Tanabe Pharma Co.; Daichi Sankyo Co. Ltd.; Chugai Pharmaceutical Co., Ltd.; Taisho Pharmaceutical Co., Ltd.; Eli Lilly Japan K.K.; Novartis Pharma K.K.; Boehringer-Ingelheim Co., Ltd.; Nipponkayaku Co. Ltd.; Pfizer Japan Inc.; Bristol-Myers K.K.; Janssen Pharmaceutical K.K.; and UCB Japan Co. Ltd.

Y. Tanaka reports personal fees from Daiichi-Sankyo; Astellas Pharma, Inc.; Chugai; Eli Lilly; Pfizer; AbbVie; YL Biologics; Bristol-Myers; Takeda; Mitsubishi-Tanabe; Novartis; Eisai; Janssen; and Teijin and grants from Asahi-kasei, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, Bristol-Myers, UCB, Daiichi-Sankyo, Eisai, Ono.

C. Lademacher, J. Erdman, Y. Kaneko, M. Saito, C. Higashitani, and R. Smulders are employees of Astellas Pharma, Inc.

Figures

Fig. 1
Fig. 1
Study design
Fig. 2
Fig. 2
Patient disposition. aProvided informed consent
Fig. 3
Fig. 3
Change from baseline in a DAS28-CRP, b DAS28-ESR, c SDAI, and d CDAI scores over time. CDAI, Clinical Disease Activity Index; CRP, c-reactive protein; DAS28, Disease Activity Score in 28 joints; ESR, erythrocyte sedimentation rate; SDAI, Simplified Disease Activity Index

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