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- Title
Reduction of New Heterotopic Ossification (HO) in the Open-Label, Phase 3 MOVE Trial of Palovarotene for Fibrodysplasia Ossificans Progressiva (FOP).
- Authors
Pignolo, Robert J.; Hsiao, Edward C.; Al Mukaddam, Mona; Baujat, Geneviève; Berglund, Staffan K.; Brown, Matthew A.; Cheung, Angela M.; De Cunto, Carmen; Delai, Patricia; Nobuhiko Haga; Kannu, Peter; Keen, Richard; Kim-Hanh Le Quan Sang; Mancilla, Edna E.; Marino, Rose; Strahs, Andrew; Kaplan, Frederick S.
- Abstract
Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, severely disabling genetic disorder of progressive heterotopic ossification (HO). The single-arm, open-label, phase 3 MOVE trial (NCT03312634) assessed efficacy and safety of palovarotene, a selective retinoic acid receptor gamma agonist, in patients with FOP. Findings were compared with FOP natural history study (NHS; NCT02322255) participants untreated beyond standard of care. Patients aged =4 years received palovarotene once daily (chronic: 5 mg; flare-up: 20 mg for 4 weeks, then 10 mg for =8 weeks; weight-adjusted if skeletally immature). The primary endpoint was annualized change in new HO volume versus NHS participants (by low-dose whole-body computed tomography [WBCT]), analyzed using a Bayesian compound Poisson model (BcPM) with square-root transformation. Twelve-month interim analysesmet futility criteria; dosing was paused. An independent DataMonitoring Committee recommended trial continuation. Post hoc 18-month interim analyses utilized BcPM with square-root transformation and HO data collapsed to equalizeMOVE and NHS visit schedules, BcPM without transformation, andweighted linearmixed-effects (wLME)models, alongside prespecified analysis. Safety was assessed throughout. Eighteen-month interim analyses included 97 MOVE and 101 NHS individuals with post-baselineWBCT. BcPM analyses without transformation showed 99.4% probability of any reduction in new HO with palovarotene versus NHS participants (with transformation: 65.4%). Mean annualized new HO volume was 60% lower in MOVE versus the NHS wLME results were similar (54% reduction fitted; nominal p = 0.039). All palovarotene-treated patients reported =1 adverse event (AE); 97.0% reported =1 retinoid-associated AE; 29.3% reported =1 serious AE, including premature physeal closure (PPC)/epiphyseal disorder in 21/57 (36.8%) patients aged <14 years. Post hoc computational analyses usingWBCT showed decreased vertebral bone mineral density, content, and strength, and increased vertebral fracture risk in palovarotene-treated patients. Thus, post hoc analyses showed evidence for efficacy of palovarotene in reducing new HO in FOP, but high risk of PPC in skeletally immature patients. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
- Subjects
GREAT Britain. National Health Service; FIBRODYSPLASIA ossificans progressiva; CLINICAL trials; HETEROTOPIC ossification; RETINOIC acid receptors; ADRENERGIC beta agonists; BONE density
- Publication
Journal of Bone & Mineral Research, 2023, Vol 38, Issue 3, p381
- ISSN
0884-0431
- Publication type
Article
- DOI
10.1002/jbmr.4762