ESPE Yearbook of Paediatric Endocrinology

JBMR Plus, (2025). 9(1), ziae147. https://doi.org/10.1093/jbmrpl/ziae147

Brief Summary: This review outlines the development of palovarotene (Sohonos), a selective retinoic acid receptor (RAR) agonist, as a potential treatment for fibrodysplasia ossificans progressiva (FOP), a rare and debilitating genetic condition characterised by progressive heterotopic ossification (HO). It outlines the drug’s mechanism of action and the rationale behind its use in preclinical studies. It also summarises the findings of clinical trials, including data from the pivotal Phase 3 MOVE trial, which ultimately supported the drug’s regulatory approval in the United States.

Commentary: This review describes how the study of retinoid signalling biology led to a real-world treatment. The drug’s targeted inhibition of chondrogenesis and downstream ossification processes, hallmarks of HO in FOP, makes it a uniquely mechanism-based therapy. By modulating SMAD signalling and suppressing progenitor cell recruitment, palovarotene directly interferes with the ectopic skeletal cascade that defines the disease.

Palovarotene was investigated as a potential therapy to reduce heterotopic ossification (HO) in FOP. Despite the absence of a statistically significant effect in Phase 2 studies, a Phase 3 MOVE trial of palovarotene was conducted. This single-arm, open-label study compared patients treated with palovarotene with natural history controls. Subjects aged 4+ years were treated with either a daily dose or a flare-up dose of palovarotene. Annualised change in new HO formation was assessed using low-dose CT scans. The data from the MOVE trial were then compared with those from the FOP Natural History Study (NHS). Although the primary analysis was complicated by limitations in the statistical model and discrepancies in the imaging schedule, post hoc analyses indicated a 60% reduction in new HO volume. Notably, a matched-pair analysis revealed a reduction in HO formation among patients who transitioned from the natural history cohort to palovarotene treatment. These findings were pivotal in securing FDA approval in 2023.

However, this treatment has also been linked to serious adverse events, prompting the European Medicines Agency to reject it. Notably, 21 out of 57 children under the age of 14 experienced premature physeal closure (PPC), resulting in a partial clinical hold and age-related prescribing restrictions. People with FOP may already have reduced bone density, increasing the risk of osteoporosis-related fractures at a young age. Palovarotene may also interfere with fracture healing by inhibiting osteogenesis.

Further clinical trials are needed to clarify the efficacy and safety of palovarotene treatment in patients with FOP.