Garetosmab, an inhibitor of activin A, reduces heterotopic ossification and flare-ups in adults with fibrodysplasia ossificans progressiva: a randomized, double-blind, placebo-controlled phase 2 trial

Background Fibrodysplasia ossificans progressiva (FOP), an ultra-rare disorder caused by mutations in the gene encoding activin A receptor type 1 ( ACVR1) , is characterized by painful flare-ups and cumulative heterotopic ossification (HO). Garetosmab, a fully-human monoclonal antibody blocking activin A, prevents HO in FOP mice. Methods LUMINA-1 ([NCT03188666][1]) was a phase 2, multi-center, randomized, double-blind, placebo-controlled study evaluating the safety, tolerability, and effects on HO of intravenous (IV) garetosmab 10 mg/kg every 4 weeks (Q4W). Adult patients with FOP were randomized to garetosmab or placebo for 28 weeks (Period\_1), followed by an open-label period (Period\_2). After Period\_2, patients were allowed to stay on garetosmab in an open-label extension. For Period\_1, primary endpoints were HO total lesion activity (HO-TLA) by 18F-sodium fluoride positron emission tomography (18F-NaF PET) and HO total lesion volume by computed tomography (CT). The Period\_2 primary endpoint compared the number of new lesions in Period\_2 versus Period_1. The safety primary endpoint was incidence and severity of TEAEs through the end of the Period 1 at week 28. Findings Patients (n=44) were randomized to garetosmab (n=20) or placebo (n=24). In Period_1, there was a trend for garetosmab to decrease HO-TLA versus placebo (24.6%; P =0.07), primarily driven by near complete prevention of new lesions (97% decrease by 18F-NaF PET, post-hoc P =0.009; 90% relative reduction by CT, post-hoc P =0.017); flare-ups were significantly reduced ( P =0.0005). For placebo patients transitioning to garetosmab in Period\_2, no patients developed new HO lesions (0% in Period\_2 versus 40.9% in Period\_1; P =0.0027) by CT. All 44 patients met primary safety endpoint of at least one TEAE during Period 1. Garetosmab was associated with more adverse events than placebo: mild recurrent epistaxis, madarosis, and skin/soft tissue infections. Overall, the AEs were predominantly mild in severity, with no effect on patients’ ability to receive garetosmab. Five deaths (5/44; 11.4%) occurred either in Period\_2 or the open-label extension. The deaths were associated with baseline disease severity in some, preexisting comorbidities in others and occurred following 8-16 doses (median: 15) of garetosmab in the open label/follow-up periods. Interpretation Garetosmab reduced flare-ups and prevented new HO lesions in FOP patients. Although side effects were mild to moderate, there were a relatively high number of deaths for a small study; the deaths were not related to epistaxis and considered unlikely to be related to garetosmab. Funding Regeneron Pharmaceuticals, Inc. ### Competing Interest Statement Maja Di Rocco: PI of Regeneron Pharmaceuticals Inc. and Ipsen trials. Eduardo Forleo-Neto: employee of and holds stocks and shares in Regeneron Pharmaceuticals Inc. Robert J. Pignolo: PI of the Regeneron Pharmaceuticals Inc. LUMINA-1 and Clementia/Ipsen MOVE trials, founding member and immediate past president of the International Clinical Council (ICC) on FOP, and chair of the ICC Publications Committee. Richard Keen: PI of clinical trials sponsored by Clementia/Ipsen and Regeneron Pharmaceuticals Inc; non-paid member of the International Clinical Council on FOP and IFOPA registry advisory board. Philippe Orcel: PI of clinical trial sponsored by Regeneron Pharmaceuticals Inc. Thomas Funck-Brentano: is a sub-investigator of the Regeneron Pharmaceuticals Inc. LUMINA-1 trial and PI of IPSEN FALKON trial Christian Roux: research grants, for the institution, from Regeneron Pharmaceuticals Inc. Sami Kolta: sub-investigator of the Regeneron Pharmaceuticals Inc. LUMINA-1 trial. Annalisa Madeo: sub-Investigator in clinical trials sponsored by Regeneron Pharmaceuticals Inc. and Clementia-Ipsen. Judith S. Bubbear: sub-investigator of the Regeneron Pharmaceuticals Inc. LUMINA-1 and Clementia/Ipsen MOVE trials. Jacek Tabarkiewicz: grants to institution (UR), speaker for Merck, Novartis; hired scientific expert for SoftSystem. Małgorzata Szczepanek: speaker for Roche. Javier Bachiller-Corral: investigator of clinical trial sponsored by Regeneron Pharmaceuticals Inc. Angela M. Cheung: grant to institution (UHN) for clinical trial, no personal COI. Kathryn M. Dahir: PI on the Regeneron Pharmaceuticals Inc. Trial. This project described was supported by CTSA award No. UL1 TR002243 from the National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors/sponsor and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. Esmee Botman: is a sub-investigator of the Regeneron Pharmaceuticals Inc. LUMINA-1 trial at the Amsterdam UMC, the Netherlands. Pieter G Raijmakers: is a sub-investigator of the Regeneron Pharmaceuticals Inc. LUMINA-1 trial at the Amsterdam UMC, the Netherlands. Mona Al Mukaddam: PI of clinical trials sponsored by Clementia/Ipsen, Regeneron Pharmaceuticals Inc. and Incyte; non-paid member of the International Clinical Council on FOP and IFOPA registry advisory board. Lianne Tile: grant to institution (UHN) for clinical trial (sub-investigator), no personal COI. Cynthia Portal-Celhay: employee of and holds stocks and shares in Regeneron Pharmaceuticals Inc. Melissa Simek-Lemos: employee of and holds stocks and shares in Regeneron Pharmaceuticals Inc. Neena Sarkar: employee of and holds stocks and shares in Regeneron Pharmaceuticals Inc. Peijie Hou: employee of and holds stocks and shares in Regeneron Pharmaceuticals Inc. Bret Musser: employee of and holds stocks and shares in Regeneron Pharmaceuticals Inc. Anita Boyapati: employee of and holds stocks and shares in Regeneron Pharmaceuticals Inc. Scott Mellis: employee of and holds stocks and shares in Regeneron Pharmaceuticals Inc. Andrew J. Rankin: employee of and holds stocks and shares in Regeneron Pharmaceuticals Inc. Aris N. Economides: employee of and holds stocks and shares in Regeneron Pharmaceuticals Inc. Dinko Gonzalez Trotter: employee of and holds stocks and shares in Regeneron Pharmaceuticals Inc. Gary Herman: employee of and holds stocks and shares in Regeneron Pharmaceuticals Inc. David M. Weinreich: employee of and holds stocks and shares in Regeneron Pharmaceuticals Inc. George D. Yancopolous: employee of and holds stocks and shares in Regeneron Pharmaceuticals Inc. E. Marelise W. Eekhoff: subsidies/financing FOP research: Dutch FOP Patient Foundation, IFOPA, Regeneron Pharmaceuticals Inc., EU-IMI (AZ), Clementia/Ipsen (i.e., general lecture). Non-paid Board memberships: the International Clinical Council on FOP, IFOPA registry advisory board, Dutch Society for Endocrinology (NVE) BoNe; Representative: Amsterdam Bone Center and Rare Bone Expert Center, European FOP consortium. Member of ERN BOND and of an ASBMR committee. Frederick S. Kaplan: founding member and past president of the International Clinical Council on FOP, member of the Medical Advisory Board of the IFOPA Global Registry and global principal investigator on the Regeneron LUMINA-1 and the Clementia/Ipsen MOVE trials. ### Clinical Trial NCT03188666 ### Funding Statement The study was funded by Regeneron Pharmaceuticals, Inc. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The trial was approved by the following Institutional Review Boards: University Health Network 700 University Ave.10th Floor, Suite 1056, Toronto Ontario, M5G1Z5, Canada; Comité de Protection des Personnes (CPP) Ile-de-F, 78 rue du Général Leclerc, Le Kremlin Bicentre, Paris France, 94275; Comitato Etico Regione Liguria, IRCCS Ospedale Policlinico, San Martino, Largo Rosanna Benzi, 10, Genova Italy, 16132; Science committee AMS, Attn. Dr. R.T.de Jongh, VUmc, internal medicine, room 4A35, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands; METC VUmc BS7, Kamer H-443, Postbus 7057, Amsterdam Netherlands, 1007 MD; Komisja Bioetyczna Uniwersytetu Rzeszowskiego ul. Warszawska 26A, 35-205, Rzeszow Poland; Comité de Ética de la Investigación con medicamentos del Hospital Universitario Ramón y Cajal. Ctra. Colmenar, km. 9,100, Madrid Spain, 28034; London - Central Research Ethics Committee, 3rd Floor, Barlow House, 4 Minshull Street, Manchester UK, M13DZ; University of Pennsylvania, Office of Regulatory, 3624 Market Street, Suite 301 S, Philadelphia PA, 19104, United States; Mayo Clinic Institutional Review Board, 200 First Street SW, Rochester Minnesota, 55905, United States; Vanderbilt University 1313 21st Ave., South, Suite 505, Nashville Tennessee, 37232, United States. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Qualified researchers may request access to study documents that support the methods and findings reported in this manuscript. Individual anonymized patient data will be considered for sharing once the product and indication has been approved by major health authorities (eg, FDA, EMA, PMDA, etc), if there is legal authority to share the data and there is not a reasonable likelihood of patient re-identification. Submit requests to . [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03188666&atom=%2Fmedrxiv%2Fearly%2F2023%2F01%2F13%2F2023.01.11.23284254.atom