1. Safety and efficacy of the miR-124 upregulator ABX464 (obefazimod, 50 and 100 mg per day) in patients with active rheumatoid arthritis and inadequate response to methotrexate and/or anti-TNFα therapy: a placebo-controlled phase II study
- Author
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Claire Daien, Marek Krogulec, Paul Gineste, Jean-Marc Steens, Laurence Desroys du Roure, Sophie Biguenet, Didier Scherrer, Julien Santo, Hartmut Ehrlich, Patrick Durez, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), NZOZ Lecznica MAK-MED S.C [Nadarzyn, Poland], Laboratoires pharmaceutiques Abivax [Paris] (LPAP), Medical Consultant [Brussels, Belgium] (MC), Abivax, Laboratoires pharmaceutiques Abivax [Montpellier] (LPAM), Cliniques Universitaires Saint-Luc [Bruxelles], MORNET, Dominique, UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, and UCL - (SLuc) Service de rhumatologie
- Subjects
[SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system ,antirheumatic agents ,rheumatoid ,Immunology ,Genetics and Molecular Biology ,General Biochemistry, Genetics and Molecular Biology ,methotrexate ,Rheumatology ,arthritis ,[SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system ,[SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,General Biochemistry ,[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,Immunology and Allergy - Abstract
ObjectiveThis phase 2a randomised, double blind, placebo controlled, parallel group study evaluated the safety and efficacy of a first-in-class drug candidate ABX464 (obefazimod, 50 mg and 100 mg per day), which upregulates the biogenesis of the mRNA inhibitor micro-RNA (miR)-124, in combination with methotrexate (MTX) in 60 patients (1:1:1 ratio) with moderate-to-severe active rheumatoid arthritis (RA) who have inadequate response to MTX or/and to an anti-tumour necrosis factor alpha (TNFα) therapy.MethodsThe primary end point was the safety of ABX464; efficacy endpoints included the proportion of patients achieving American College of Rheumatology (ACR)20/50/70 responses, disease activity scores (DAS) 28, simplified disease activity score, clinical disease activity score), European League Against Rheumatism response, DAS28 low disease activity or remission.ResultsABX464 50 mg was safe and well tolerated. Two serious adverse events were reported (one on placebo group and one on ABX464 100 mg). Eleven patients were withdrawn for AEs (9 patients on 100 mg, 1 on 50 mg and 1 on placebo). Drug discontinuation was mainly due to gastrointestinal disorders. No cases of opportunistic infection, no malignancies and no death were reported. Compared with placebo, ABX464 50 mg showed significantly higher proportions of patients achieving ACR20 and ACR50 responses at week 12. DAS28-C reactive protein (CRP) and DAS28-erythrocyte sedimentation rate decreased significantly and rates of categorical DAS28-CRP response or CDAI remission increased significantly on ABX464 at week 12. A significant upregulation of miR-124 was observed in blood for every patient dosed with ABX464.ConclusionABX464 50 mg was safe, well tolerated and showed a promising efficacy. Mild-to-moderate gastrointestinal AEs led to a high drop-out rate of patients on ABX464 100 mg, which may not be a relevant dose to use. These findings warrant exploration of ABX464 at 50 mg per day or less for treating patients with RA.Trial registration namePhase IIa randomised, double blind, placebo controlled, parallel group, multiple dose study on ABX464 in combination with MTX, in patients with moderate to severe active RA who have inadequate response to MTX or/and to an anti- TNFα therapy or intolerance to anti-TNFα therapy.EUDRACT number: 2018-004677-27Trial registration numberNCT03813199.
- Published
- 2022