Safety and efficacy of abatacept in early diffuse cutaneous systemic sclerosis (ASSET): open-label extension of a phase 2, double-blind randomised trial

Lorinda Chung, Cathie Spino, Richard McLain, Sindhu R. Johnson, Christopher P. Denton, Jerry A. Molitor, Virginia D. Steen, Robert Lafyatis, Robert W. Simms, Suzanne Kafaja, Tracy M. Frech, Vivien Hsu, Robyn T. Domsic, Janet E. Pope, Jessica K. Gordon, Maureen D. Mayes, Nora Sandorfi, Faye N. Hant, Elana J. Bernstein, Soumya ChatterjeeFlavia V. Castelino, Ali Ajam, Yannick Allanore, Marco Matucci-Cerinic, Michael L. Whitfield, Oliver Distler, Ora Singer, Amber Young, Vivek Nagaraja, David A. Fox, Daniel E. Furst, Dinesh Khanna

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Abatacept was well tolerated by patients with early diffuse cutaneous systemic sclerosis in a phase 2, double-blind randomised trial, with potential efficacy at 12 months. We report here the results of an open-label extension for 6 months. Methods: Patients (aged ≥18 years) with diffuse cutaneous systemic sclerosis of less than 3 years' duration from their first non-Raynaud's symptom were enrolled into the ASSET trial (A Study of Subcutaneous Abatacept to Treat Diffuse Cutaneous Systemic Sclerosis), which is a double-blind trial at 22 sites in Canada, the UK, and the USA. After completion of 12 months of treatment with either abatacept or placebo, patients received a further 6 months of abatacept (125 mg subcutaneous every week) in an open-label extension. The primary endpoint of the double-blind trial was modified Rodnan Skin Score (mRSS) at 12 months, which was reassessed at 18 months in the open-label extension. The primary analysis included all participants who completed the double-blind trial and received at least one dose of open-label treatment (modified intention to treat). This trial is registered with ClinicalTrials.gov, NCT02161406. Findings: Between Sept 22, 2014, and March 15, 2017, 88 participants were randomly allocated in the double-blind trial either abatacept (n=44) or placebo (44); 32 patients from each treatment group completed the 6-month open-label extension. Among patients assigned abatacept, a mean improvement from baseline in mRSS was noted at 12 months (−6·6 [SD 6·4]), with further improvement seen during the open-label extension period (−9·8 [8·1] at month 18). Participants assigned placebo had a mean improvement from baseline in mRSS at 12 months (−3·7 [SD 7·6]), with a further improvement at month 18 (−6·3 [9·3]). Infections during the open-label extension phase occurred in nine patients in the placebo–abatacept group (12 adverse events, one serious adverse event) and in 11 patients in the abatacept–abatacept group (14 adverse events, one serious adverse event). Two deaths occurred during the 12-month double-blind period in the abatacept group, which were related to scleroderma renal crisis; no deaths were recorded during the open-label extension. Interpretation: During the 6-month open-label extension, no new safety signals for abatacept were identified in the treatment of diffuse cutaneous systemic sclerosis. Clinically meaningful improvements in mRSS and other outcome measures were observed in both the abatacept and placebo groups when patients transitioned to open-label treatment. These data support further studies of abatacept in diffuse cutaneous systemic sclerosis. Funding: Bristol-Myers Squibb and National Institutes of Health.

Original languageEnglish (US)
Pages (from-to)e743-e753
JournalThe Lancet Rheumatology
Volume2
Issue number12
DOIs
StatePublished - Dec 2020

Bibliographical note

Funding Information:
This investigator-initiated clinical trial was funded by Bristol-Myers Squibb and the National Institutes of Health (National Institute of Allergy and Infectious Diseases Clinical and Autoimmunity Center of Excellence, grant 5-UM1-AI-110557 to the University of Michigan; and National Institute of Arthritis and Musculoskeletal and Skin Diseases, grants K24-AR-063120 and R01-AR-07047 to DK). We thank the patients who participated in this trial and the research coordinators for their hard work and contributions.

Funding Information:
LC is on the advisory board and steering committee for Bristol-Myers Squibb, during the conduct of the study; the advisory board for Eicos and Mitsubishi Tanabe, outside of the submitted work; the data safety monitoring board for Reata, outside of the submitted work; and reports grants from and is on the advisory board for Boehringer Ingelheim, outside of the submitted work. CS reports statistical consultant fees from Eicos, outside of the submitted work. SRJ reports clinical trial support from Bayer, Corbus, GlaxoSmithKline, Bristol-Myers Squibb, and Ikaria, outside of the submitted work; and clinical trial support from and is on the advisory board for Boehringer Ingelheim, outside of the submitted work. CPD reports grants and personal fees from GlaxoSmithKline, Bristol-Myers Squibb, Inventiva, and CSL Behring, during the conduct of the study; and personal fees from Roche, Horizon, Sanofi, Boehringer Ingelheim, and Galapagos, during the conduct of the study. JAM reports clinical trial support from Bristol-Myers Squibb, during the conduct of the study; personal fees from Eicos, outside of the submitted work; personal fees, consulting fees, and clinical trial support from Boehringer Ingelheim, outside of the submitted work; and clinical trial support from Corbus and Kadmon, outside of the submitted work. VDS reports grants, is a site principal investigator for a trial in scleroderma, and is on the advisory board for Corbus and Bayer, during the conduct of the study; grants and is on a steering committee for a trial in scleroderma for CSL Behring, during the conduct of the study; is on the advisory board for Forbius, during the conduct of the study; reports grants and consultancy, advisory board, and site principal investigator for a trial in scleroderma and lung disease for Boehringer Ingelheim, outside of the submitted work; is site principal investigator for a scleroderma and Raynaud's trial and is on a steering committee for Eisocs, outside of the submitted work; and reports grants from Reata, outside of the submitted work. RL reports grants from Bristol-Myers Squibb, during the conduct of the study; personal fees from Bristol-Myers Squibb, Formation, Sanofi, Biocon, Boehringer-Mannheim, Merck, and Genentech/Roche, outside of the submitted work; and grants from Corbus, Formation, Elpidera, Regeneron, Pfizer, and Kiniksa, outside of the submitted work. RWS reports grants from Bristol-Myers Squibb, GlaxoSmithKline, Corbus, Boehringer Ingelheim, EMD Serono, Actelion, Roche, and Sanofi, during the conduct of the study. SK reports clinical trial support from the University of California at Los Angeles Division of Rheumatology, during the conduct of the study. RTD reports personal fees from Formation, Eicos, and Corbus, outside of the submitted work. JEP reports grants and honoraria for consulting from Bristol-Myers Squibb and Boehringer Ingelheim, during the conduct of the study; and grants from Merck, during the conduct of the study. JKG reports grants from the University of Michigan, during the conduct of the study; and grants from Eicos and Cumberland Pharmaceuticals, outside of the submitted work. MDM reports personal fees from Medtelligence, Actelion Pharma, Astellas, and Mitsubishi-Tanabe, outside of the submitted work; grants from Bayer, Reata, Sanofi, Corbus, and GlaxoSmithKline, outside of the submitted work; and grants and personal fees from Boehringer Ingelheim, Eicos, and Galapagos Pharma, outside of the submitted work. EJB reports grants from the National Institutes of Health (NIH), outside of the submitted work; grants and personal fees from Boehringer Ingelheim and Eicos, outside of the submitted work; and grants from Pfizer, outside of the submitted work. YA reports grants and personal fees from Inventiva and Sanofi, during the conduct of the study; and personal fees from Bayer, Bristol-Myers Squibb, Chemomab, Curzion, and Roche, during the conduct of the study. MM-C has received consulting fees or honorarium from Inventiva, Bayer, Boehringer, CSL Behring, Corbus, Galapagos, Mitsubishi, Samsung, Regeneron, Acceleron, MSD, Chemomab, Lilly, Pfizer, and Roche, outside of the submitted work. MLW reports grants from NIH, during the conduct of the study; grants and personal fees from Bristol-Myers Squibb, during the conduct of the study; grants and personal fees from Celdara Medical, outside of the submitted work; personal fees from Acceleron, AbbVie, and Boehringer Ingelheim, outside of the submitted work; and grants and personal fees from Corbus, outside of the submitted work. OD reports personal fees from AbbVie, Actelion, Acceleron Pharma, Amgen, AnaMar, Baecon Discovery, and Blade Therapeutics, outside of the submitted work; personal fees from Catenion, Competitive Drug Development, CSL Behring, ChemomAb, Curzion Pharmaceuticals, Ergonex, Galapagos, Glenmark Pharmaceuticals, GlaxoSmithKline, Inventiva, Italfarmaco, iQone, iQvia, Lilly, Medac, Medscape, MSD, Novartis, Pfizer, Roche, Sanofi, Target BioScience, and UCB, outside of the submitted work; grants and personal fees from Bayer, Boehringer Ingelheim, and Mitsubishi Tanabe, outside of the submitted work; and has a patent (mir-29 for the treatment of systemic sclerosis) issued to US8247389, EP2331143. VN reports clinical trial support from Bristol-Myers Squibb, during the conduct of the study. DAF reports grants from NIH (National Institute of Allergy and Infectious Diseases Clinical and Autoimmunity Center of Excellence), Immune Tolerance Network, Bristol-Myers Squibb, and Pfizer, outside of the submitted work; and personal fees from CSL Behring, outside of the submitted work. DEF reports grants from Bristol-Myers Squibb, during the conduct of the study; grants and personal fees from Acetlion, Amgen, Bristol-Myers Squibb, Corbus, Galapagos, GlaxoSmithKline, NIH, Novartis, and Pfizer, outside of the submitted work; grants from Sanofi and Genentech/Roche, outside of the submitted work; and fees for Continuing Medical Education (CME) presentations, outside of the submitted work. DK reports grants and personal fees from Bristol-Myers Squibb, during the conduct of the study; grants from NIH, Immune Tolerance Network, and Bayer, outside of the submitted work; grants from Bristol-Myers Squibb, Horizon, and Pfizer, outside of the submitted work; personal fees from Acceleron, Acetlion, Amgen, Blade Therapeutics, Boehringer Ingelheim, CSL Behring, Corbus, Cytori, Galapagos, Genentech/Roche, GlaxoSmithKline, Horizon, Merck, Mitsubishi Tanabe, Regeneron, Sanofi-Aventis, United Therapeutics, and Eicos, outside of the submitted work; CME support from Impact PH, outside of the submitted work; holds stock in Eicos; and declares personal fees from and is Chief Medical Officer for CiviBioPharma/Eicos, outside of the submitted work. All other authors declare no competing interests.

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