Abstract
Original language | English |
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Pages (from-to) | 2615-2624 |
Number of pages | 10 |
Journal | Nature medicine |
Volume | 29 |
Issue number | 10 |
Early online date | 2023 |
DOIs | |
Publication status | Published - Oct 2023 |
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In: Nature medicine, Vol. 29, No. 10, 10.2023, p. 2615-2624.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Garetosmab in fibrodysplasia ossificans progressiva
T2 - a randomized, double-blind, placebo-controlled phase 2 trial
AU - di Rocco, Maja
AU - Forleo-Neto, Eduardo
AU - Pignolo, Robert J.
AU - Keen, Richard
AU - Orcel, Philippe
AU - Funck-Brentano, Thomas
AU - Roux, Christian
AU - Kolta, Sami
AU - Madeo, Annalisa
AU - Bubbear, Judith S.
AU - Tabarkiewicz, Jacek
AU - Szczepanek, Małgorzata
AU - Bachiller-Corral, Javier
AU - Cheung, Angela M.
AU - Dahir, Kathryn M.
AU - Botman, Esmée
AU - Raijmakers, Pieter G.
AU - Mukaddam, Mona Al
AU - Tile, Lianne
AU - Portal-Celhay, Cynthia
AU - Sarkar, Neena
AU - Hou, Peijie
AU - Musser, Bret J.
AU - Boyapati, Anita
AU - Mohammadi, Kusha
AU - Mellis, Scott J.
AU - Rankin, Andrew J.
AU - Economides, Aris N.
AU - Trotter, Dinko Gonzalez
AU - Herman, Gary A.
AU - O’Meara, Sarah J.
AU - DelGizzi, Richard
AU - Weinreich, David M.
AU - Yancopoulos, George D.
AU - Eekhoff, E. Marelise W.
AU - Kaplan, Frederick S.
N1 - Funding Information: M.D.R. is a principal investigator (PI) of Regeneron Pharmaceuticals and Ipsen trials. E.F.-N., C.P.-C., N.S., P.H., B.J.M., A.B., K.M., S.J.M., A.J.R., A.N.E., D.G.T., G.A.H., S.J.O., R.D., D.M.W. and G.D.Y. are employees of and hold stocks and shares in Regeneron Pharmaceuticals. R.J.P. is a PI of the Regeneron Pharmaceuticals LUMINA-1 and Clementia/Ipsen MOVE trials; a founding member and immediate past president of the International Clinical Council on FOP; and chair of the International Clinical Council Publications Committee. R.K. is a PI of clinical trials sponsored by Clementia/Ipsen and Regeneron Pharmaceuticals and is a non-paid member of the International Clinical Council on FOP and IFOPA registry advisory board. P.O. is a PI of clinical trials sponsored by Regeneron Pharmaceuticals. T.F.-B. is a sub-investigator of the Regeneron Pharmaceuticals LUMINA-1 trial and PI of IPSEN FALKON trial. C.R. has received research grants to their institution from Regeneron Pharmaceuticals. S.K. is a sub-investigator of the Regeneron Pharmaceuticals LUMINA-1 trial. A.M. is a sub-investigator in clinical trials sponsored by Regeneron Pharmaceuticals and Clementia-Ipsen. J.S.B. is a sub-investigator of the Regeneron Pharmaceuticals LUMINA-1 and Clementia/Ipsen MOVE trials. J.T. received grants to their institution (University Rzeszów) as a speaker for Merck and Novartis, and is a hired scientific expert for SoftSystem. M.S. is a speaker for Roche. J.B.-C. is an investigator of a clinical trial sponsored by Regeneron Pharmaceuticals. A.M.C. received a grant to their institution (University Health Network) for a clinical trial. K.M.D. is a PI on the Regeneron Pharmaceuticals LUMINA-1 trial. This project 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. E.B. is a sub-investigator of the Regeneron Pharmaceuticals LUMINA-1 trial at Amsterdam UMC, The Netherlands. P.G.R. is a sub-investigator of the Regeneron Pharmaceuticals LUMINA-1 trial at Amsterdam UMC, The Netherlands. M.A.M. is a PI of clinical trials sponsored by Clementia/Ipsen, Regeneron Pharmaceuticals and Incyte; and is a non-paid member of the International Clinical Council on FOP and IFOPA registry advisory board. L.T. received a grant to their institution (University Health Network) for a clinical trial (as a sub-investigator). E.M.W.E. receives subsidies/financing FOP research from the Dutch FOP Patient Foundation, IFOPA, Regeneron Pharmaceuticals, EU-IMI (AZ) and Clementia/Ipsen; holds non-paid board memberships for the International Clinical Council on FOP, IFOPA registry advisory board, Dutch Society for Endocrinology (NVE) BoNe; is a representative for Amsterdam Bone Center and Rare Bone Expert Center, European FOP consortium investigators; is a member of the ERN BOND and ASBMR committee; and is lead clinical PI on the Regeneron Pharmaceuticals LUMINA-1 trial. F.S.K. is a founding member and past president of the International Clinical Council on FOP; a member of the Medical Advisory Board of the IFOPA Global Registry; and a global PI on the Regeneron Pharmaceuticals LUMINA-1 and the Clementia/Ipsen MOVE trials. Funding Information: We thank the patients and their families for their participation in this study, as well as the healthcare professionals and investigators who treated these patients and made this study possible. We acknowledge the contributions of the LUMINA-1 consortium study site investigators (listed in the Supplementary Information ). We also acknowledge K. Niswender, E. Sherwood, L. Howard and M. Black at Vanderbilt University Medical Center. We acknowledge the contributions of S. Kallish, K.S. Toder and R. Jurek at the University of Pennsylvania. We acknowledge M. Andisik for assistance with assay development and clinical bioanalysis, S. McAfee and J. Zylstra for assistance with assay development and H. Marini and J. Rodriguez for assistance with clinical bioanalysis; all from Regeneron Pharmaceuticals. We thank D. O’Donovan for the safety figure concept and R. Attre and D. Srinivasan from Regeneron Pharmaceuticals for assistance with development of the manuscript. Medical writing support under the direction of the authors was provided by C. Ridley from Prime Global (Knutsford, UK) according to Good Publication Practice guidelines (https://www.acpjournals.org/doi/10.7326/M22-1460 ) and funded by Regeneron Pharmaceuticals. The authors were involved in the study design and collection, analysis and interpretation of data. All authors had full access to all the data in this study and take complete responsibility for the integrity of the data and the accuracy of the data analysis. The study was funded by Regeneron Pharmaceuticals. The sponsor was involved in the study design and collection, analysis and interpretation of data, as well as checking the accuracy of the data provided in the manuscript. Funding Information: We thank the patients and their families for their participation in this study, as well as the healthcare professionals and investigators who treated these patients and made this study possible. We acknowledge the contributions of the LUMINA-1 consortium study site investigators (listed in the ). We also acknowledge K. Niswender, E. Sherwood, L. Howard and M. Black at Vanderbilt University Medical Center. We acknowledge the contributions of S. Kallish, K.S. Toder and R. Jurek at the University of Pennsylvania. We acknowledge M. Andisik for assistance with assay development and clinical bioanalysis, S. McAfee and J. Zylstra for assistance with assay development and H. Marini and J. Rodriguez for assistance with clinical bioanalysis; all from Regeneron Pharmaceuticals. We thank D. O’Donovan for the safety figure concept and R. Attre and D. Srinivasan from Regeneron Pharmaceuticals for assistance with development of the manuscript. Medical writing support under the direction of the authors was provided by C. Ridley from Prime Global (Knutsford, UK) according to Good Publication Practice guidelines ( https://www.acpjournals.org/doi/10.7326/M22-1460 ) and funded by Regeneron Pharmaceuticals. The authors were involved in the study design and collection, analysis and interpretation of data. All authors had full access to all the data in this study and take complete responsibility for the integrity of the data and the accuracy of the data analysis. The study was funded by Regeneron Pharmaceuticals. The sponsor was involved in the study design and collection, analysis and interpretation of data, as well as checking the accuracy of the data provided in the manuscript. Publisher Copyright: © 2023, The Author(s).
PY - 2023/10
Y1 - 2023/10
N2 - Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by heterotopic ossification (HO) in connective tissues and painful flare-ups. In the phase 2 LUMINA-1 trial, adult patients with FOP were randomized to garetosmab, an activin A-blocking antibody (n = 20) or placebo (n = 24) in period 1 (28 weeks), followed by an open-label period 2 (28 weeks; n = 43). The primary end points were safety and for period 1, the activity and size of HO lesions. All patients experienced at least one treatment-emergent adverse event during period 1, notably epistaxis, madarosis and skin abscesses. Five deaths (5 of 44; 11.4%) occurred in the open-label period and, while considered unlikely to be related, causality cannot be ruled out. The primary efficacy end point in period 1 (total lesion activity by PET–CT) was not met (P = 0.0741). As the development of new HO lesions was suppressed in period 1, the primary efficacy end point in period 2 was prospectively changed to the number of new HO lesions versus period 1. No placebo patients crossing over to garetosmab developed new HO lesions (0% in period 2 versus 40.9% in period 1; P = 0.0027). Further investigation of garetosmab in FOP is ongoing. ClinicalTrials.gov identifier NCT03188666 .
AB - Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by heterotopic ossification (HO) in connective tissues and painful flare-ups. In the phase 2 LUMINA-1 trial, adult patients with FOP were randomized to garetosmab, an activin A-blocking antibody (n = 20) or placebo (n = 24) in period 1 (28 weeks), followed by an open-label period 2 (28 weeks; n = 43). The primary end points were safety and for period 1, the activity and size of HO lesions. All patients experienced at least one treatment-emergent adverse event during period 1, notably epistaxis, madarosis and skin abscesses. Five deaths (5 of 44; 11.4%) occurred in the open-label period and, while considered unlikely to be related, causality cannot be ruled out. The primary efficacy end point in period 1 (total lesion activity by PET–CT) was not met (P = 0.0741). As the development of new HO lesions was suppressed in period 1, the primary efficacy end point in period 2 was prospectively changed to the number of new HO lesions versus period 1. No placebo patients crossing over to garetosmab developed new HO lesions (0% in period 2 versus 40.9% in period 1; P = 0.0027). Further investigation of garetosmab in FOP is ongoing. ClinicalTrials.gov identifier NCT03188666 .
UR - http://www.scopus.com/inward/record.url?scp=85172773623&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41591-023-02561-8
DO - https://doi.org/10.1038/s41591-023-02561-8
M3 - Article
C2 - 37770652
SN - 1078-8956
VL - 29
SP - 2615
EP - 2624
JO - Nature medicine
JF - Nature medicine
IS - 10
ER -