A Narrative Review of Phase II and III Clinical Trials for the Pharmacological Treatment of Fibrodysplasia Ossificans Progressiva (FOP): Efficacy, Safety, and Challenges in Treatment Strategies.

Abstract

Background: Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disorder marked by progressive heterotopic ossification (HO), causing severe disability and reduced life expectancy. Despite advancements in understanding its pathophysiology, effective treatments remain limited. Promising pharmacological approaches include retinoic acid receptor γ (RARγ) agonists, such as palovarotene, and monoclonal antibodies targeting activin A, like garetosmab. However, the rarity of FOP complicates the generation of robust clinical evidence.

Methods: This narrative review analysed data from Phase II and III clinical trials on ClinicalTrials.gov, including completed and terminated interventional studies evaluating pharmacological treatments for FOP. Key trial details were systematically extracted and reviewed, including design, interventions, outcomes, and adverse events.

Results: Five trials met the inclusion criteria, focusing on palovarotene and garetosmab. Palovarotene significantly reduced HO progression, particularly during active disease phases or flare-ups. Garetosmab showed potential in preventing new HO lesions and reducing lesion activity. However, both treatments posed safety concerns, including premature epiphyseal fusion in younger patients (palovarotene) and systemic adverse events (garetosmab). Terminated trials revealed logistical and ethical challenges, such as recruitment difficulties, small sample sizes, and limitations of placebo-controlled designs.

Conclusion: Pharmacological advances, including palovarotene and garetosmab, show promise in managing FOP. Nevertheless, safety concerns and the complexities of clinical trial implementation highlight the need for innovative approaches to ensure effective and equitable treatments. Future research should prioritise long-term safety, efficacy, and patient-centred outcomes to improve FOP management.