Reduction of new heterotopic ossification (HO) in the open-label, phase 3 MOVE trial of palovarotene for fibrodysplasia ossificans progressiva (FOP)

Pignolo, Robert J.<sup>1,*</sup>; Hsiao, Edward C.<sup>2,*</sup>; Mukaddam, Mona Al<sup>3</sup>; Baujat, Geneviève<sup>4</sup>; Berglund, Staffan K.<sup>5</sup>; Brown, Matthew A.<sup>6,7</sup>; Cheung, Angela M.<sup>8</sup>; Cunto, Carmen De<sup>9</sup>; Delai, Patricia<sup>10</sup>; Haga, Nobuhiko<sup>11</sup>; Kannu, Peter<sup>12</sup>; Keen, Richard<sup>13</sup>; Sang, Kim-Hanh Le Quan<sup>4</sup>; Mancilla, Edna E.<sup>14</sup>; Marino, Rose<sup>15</sup>; Strahs, Andrew<sup>15</sup>; Kaplan, Frederick S.<sup>3</sup>

Affiliations

¹Department of Medicine, Mayo Clinic, Rochester, MN, USA

²Division of Endocrinology and Metabolism, the UCSF Metabolic Bone Clinic, the Eli and Edythe Broad Institute for Regeneration Medicine, and the Institute of Human Genetics, Department of Medicine, and the UCSF Program in Craniofacial Biology, University of California-San Francisco, San Francisco, CA, USA

³Departments of Orthopaedic Surgery & Medicine, The Center for Research in FOP and Related Disorders,

⁴Département de Génétique, Institut IMAGINE and Hôpital Universitaire Necker-Enfants Malades, Paris, France

⁵Department of Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden

⁶Faculty of Life Sciences and Medicine, King’s College London, London, UK

⁷Genomics England Ltd, London, UK

⁸Department of Medicine and Joint Department of Medical Imaging, University Health Network, University of Toronto, Toronto, ON, Canada

⁹Pediatric Rheumatology Section, Department of Pediatrics, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina

¹⁰Centro de Pesquisa Clinica, Hospital Israelita Albert Einstein, São Paulo, Brazil

¹¹Department of Rehabilitation Medicine, The University of Tokyo Hospital, Tokyo, Japan

¹²Hospital for Sick Children, Toronto, ON, Canada

¹³Centre for Metabolic Bone Disease, Royal National Orthopaedic Hospital, Stanmore, UK

¹⁴Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

¹⁵Ipsen, Cambridge, MA, USA

Abstract and keywords

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 analyses met futility criteria; dosing was paused. An independent Data Monitoring Committee recommended trial continuation. Post hoc 18-month interim analyses utilized BcPM with square-root transformation and HO data collapsed to equalize MOVE and NHS visit schedules, BcPM without transformation, and weighted linear mixed-effects (wLME) models, alongside prespecified analysis. Safety was assessed throughout. Eighteen-month interim analyses included 97 MOVE and 101 NHS individuals with post-baseline WBCT. 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 using WBCT 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.

Keywords: FIBRODYSPLASIA OSSIFICANS PROGRESSIVA; CLINICAL TRIAL; THERAPEUTICS

Links

DOI: 10.1002/jbmr.4762

PubMed: 36583535

WoS: 000922691300001

History

Received: 2022-08-10

Revised: 2022-12-22

Accepted: 2022-12-28

Cited Works (7)

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