TY - JOUR
T1 - The natural history of fibrodysplasia ossificans progressiva
T2 - A prospective, global 36-month study
AU - Pignolo, Robert J.
AU - Baujat, Geneviève
AU - Brown, Matthew A.
AU - De Cunto, Carmen
AU - Hsiao, Edward C.
AU - Keen, Richard
AU - Al Mukaddam, Mona
AU - Le Quan Sang, Kim Hanh
AU - Wilson, Amy
AU - Marino, Rose
AU - Strahs, Andrew
AU - Kaplan, Frederick S.
N1 - Funding Information:
R.J.P. is a research investigator at Clementia Pharmaceuticals/Ipsen and Regeneron Pharmaceuticals, Inc and is part of the advisory board as President of the International Clinical Council on Fibrodysplasia Ossificans Progressiva. G.B. is part of the advisory boards of Clementia Pharmaceuticals/Ipsen, FOP European Consortium, and International Clinical Council on FOP and is a speaker at Clementia Pharmaceuticals/Ipsen. M.A.B. is part of the advisory boards of AbbVie, Janssen, Pfizer, UCB Pharma, and Novartis; receives grant support from AbbVie; is a research investigator at AbbVie, Clementia Pharmaceuticals/Ipsen, Janssen, Novartis, Pathios Therapeutics Ltd, and Regeneron Pharmaceuticals, Inc; and is a speaker at AbbVie, United States, Janssen, Novartis, Switzerland, Pfizer, United States, Regeneron Pharmaceuticals, Inc, United States, and UCB Pharma, United Kingdom. C.D.C. is a research investigator at Clementia Pharmaceuticals/Ipsen and is a speaker at Novartis. E.C.H. is part (all voluntary) of the Fibrous Dysplasia Foundation Advisory Board, International Fibrodysplasia Ossificans Progressiva Association (IFOPA), United States Registry Medical Advisory Board, and International Clinical Council on FOP Advisory Board; receives clinical research support from Clementia Pharmaceuticals/Ipsen, France, Neurocrine Biosciences Inc, United States, and Regeneron Pharmaceuticals, Inc; and is a research investigator at Clementia Pharmaceuticals/Ipsen. R.K. is a research investigator at Clementia Pharmaceuticals/Ipsen, Kyowa Kirin, and Regeneron Pharmaceuticals, Inc and is part of the IFOPA Fibrodysplasia Ossificans Progressiva Registry Medical Advisory Board and International Clinical Council on Fibrodysplasia Ossificans Progressiva Advisory Board. M.A.M. receives research support from Clementia Pharmaceuticals/Ipsen and Regeneron Pharmaceuticals, Inc; is a non-paid consultant for BioCryst Pharmaceuticals, Inc, United States, Blueprint Medicines, Daiichi Sankyo, Incyte, and Keros Therapeutics; is part (all voluntary) of the IFOPA Registry Medical Advisory Board, Incyte Advisory Board, and International Clinical Council on FOP Advisory Board; and receives non-restricted educational fund from Excel and Catalyst sponsored by Ipsen. K.-H.L.Q.S. is a coordinator of Ipsen FOP-program and multiple osteochondromas-trial. A.W., R.M., and A.S. are employees of Ipsen. F.S.K. is a research investigator at Clementia/Ipsen and Regeneron Pharmaceuticals, Inc, is part of the IFOPA Medical Advisory Board, is a Founder and immediate past President of the International Clinical Council on FOP, and is the Chair of the Publications Committee of the International Clinical Council. In April 2019, Ipsen acquired Clementia Pharmaceuticals.The authors thank the International Fibrodysplasia Ossificans Progressiva Association and the local fibrodysplasia ossificans progressiva patient associations; the patients involved in the study as well as their caregivers; and the care teams, investigators, and research staff at participating institutions. The authors extend their thanks to Donna Grogan for her extensive contributions to the study, data collection and analysis, and drafting of the manuscript. The authors thank Oliver Palmer, Arianna Psichas, and Amelia Frizell-Armitage of Costello Medical, United Kingdom, for providing medical writing support, which was sponsored by Ipsen in accordance with Good Publication Practice guidelines. The study was sponsored by Ipsen. Conceptualization and Methodology: A.W. A.S. E.C.H. F.S.K. M.A.B. R.J.P.; Data Curation: A.W. R.M.; Formal Analysis: A.W. A.S. R.M.; Investigation: R.J.P. G.B. M.A.B. C.D.C. E.C.H. R.K. M.A.M.; Data Interpretation: R.J.P. G.B. M.A.B. C.D.C. E.C.H. R.K. M.A.M. K.-H.L.Q.S. A.W. R.M. A.S. F.S.K.; Writing-original draft: A.W.; Writing-review and editing: R.J.P. G.B. M.A.B. C.D.C. E.C.H. R.K. M.A.M. K.-H.L.Q.S. A.W. R.M. A.S. F.S.K. All study sites obtained ethics approval from local institutional review boards and complied with all applicable national, ethics, and regulatory guidelines. The study was conducted according to the guidelines of Good Clinical Practice and the International Conference on Harmonization and is in full compliance with the Declaration of Helsinki and its 2013 amendment. Informed consent or assent was obtained from all participants as required by the institutional review boards.
Funding Information:
The authors thank the International Fibrodysplasia Ossificans Progressiva Association and the local fibrodysplasia ossificans progressiva patient associations; the patients involved in the study as well as their caregivers; and the care teams, investigators, and research staff at participating institutions. The authors extend their thanks to Donna Grogan for her extensive contributions to the study, data collection and analysis, and drafting of the manuscript. The authors thank Oliver Palmer, Arianna Psichas, and Amelia Frizell-Armitage of Costello Medical, United Kingdom, for providing medical writing support, which was sponsored by Ipsen in accordance with Good Publication Practice guidelines. The study was sponsored by Ipsen .
Publisher Copyright:
© 2022 The Authors
PY - 2022/12
Y1 - 2022/12
N2 - Purpose: We report the first prospective, international, natural history study of the ultra-rare genetic disorder fibrodysplasia ossificans progressiva (FOP). FOP is characterized by painful, recurrent flare-ups, and disabling, cumulative heterotopic ossification (HO) in soft tissues. Methods: Individuals aged ≤65 years with classical FOP (ACVR1R206H variant) were assessed at baseline and over 36 months. Results: In total, 114 individuals participated; 33 completed the study (mean follow up: 26.8 months). Median age was 15.0 (range: 4-56) years; 54.4% were male. During the study, 82 (71.9%) individuals reported 229 flare-ups (upper back: 17.9%, hip: 14.8%, shoulder: 10.9%). After 84 days, 14 of 52 (26.9%) imaged flare-ups had new HO at the flare-up site (mean new HO volume: 28.8 × 103 mm3). Mean baseline low-dose whole-body computed tomography (excluding head) HO volume was 314.4 × 103 mm3; lowest at 2 to <8 years (68.8 × 103 mm3) and increasing by age (25-65 years: 575.2 × 103 mm3). The mean annualized volume of new HO was 23.6 × 103 mm3/year; highest at 8 to <15 and 15 to <25 years (21.9 × 103 and 41.5 × 103 mm3/year, respectively) and lowest at 25 to 65 years (4.6 × 103 mm3/year). Conclusion: Results from individuals receiving standard care for up to 3 years in this natural history study show the debilitating effect and progressive nature of FOP cross-sectionally and longitudinally, with greatest progression during childhood and early adulthood.
AB - Purpose: We report the first prospective, international, natural history study of the ultra-rare genetic disorder fibrodysplasia ossificans progressiva (FOP). FOP is characterized by painful, recurrent flare-ups, and disabling, cumulative heterotopic ossification (HO) in soft tissues. Methods: Individuals aged ≤65 years with classical FOP (ACVR1R206H variant) were assessed at baseline and over 36 months. Results: In total, 114 individuals participated; 33 completed the study (mean follow up: 26.8 months). Median age was 15.0 (range: 4-56) years; 54.4% were male. During the study, 82 (71.9%) individuals reported 229 flare-ups (upper back: 17.9%, hip: 14.8%, shoulder: 10.9%). After 84 days, 14 of 52 (26.9%) imaged flare-ups had new HO at the flare-up site (mean new HO volume: 28.8 × 103 mm3). Mean baseline low-dose whole-body computed tomography (excluding head) HO volume was 314.4 × 103 mm3; lowest at 2 to <8 years (68.8 × 103 mm3) and increasing by age (25-65 years: 575.2 × 103 mm3). The mean annualized volume of new HO was 23.6 × 103 mm3/year; highest at 8 to <15 and 15 to <25 years (21.9 × 103 and 41.5 × 103 mm3/year, respectively) and lowest at 25 to 65 years (4.6 × 103 mm3/year). Conclusion: Results from individuals receiving standard care for up to 3 years in this natural history study show the debilitating effect and progressive nature of FOP cross-sectionally and longitudinally, with greatest progression during childhood and early adulthood.
KW - Fibrodysplasia ossificans progressiva
KW - Natural history study
UR - http://www.scopus.com/inward/record.url?scp=85138833026&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85138833026&partnerID=8YFLogxK
U2 - 10.1016/j.gim.2022.08.013
DO - 10.1016/j.gim.2022.08.013
M3 - Article
C2 - 36152026
AN - SCOPUS:85138833026
SN - 1098-3600
VL - 24
SP - 2422
EP - 2433
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 12
ER -