Druggable targets, clinical trial design and proposed pharmacological management in fibrodysplasia ossificans progressiva

ABSTRACT Introduction: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by heterotopic ossification, congenital skeletal abnormalities especially of the great toes, and several features of accelerated aging. Missense mutations in the in the gene for ACVR1/ALK2 encoding Activin A receptor type I/Activin-like kinase 2, a bone morphogenetic protein (BMP) type I receptor are responsible for all known cases of FOP. Progression of the condition is relentless and occurs clinically via episodic inflammatory exacerbations or flare-ups and/or spontaneously (without flare-ups). Areas covered: The current pharmacological targets, potential designs for clinical trials, and possible treatment approaches using experimental and repurposed agents for FOP are reviewed [PubMed 2000–2019, using FOP as a key search term]. Expert opinion: The growing number of pharmacological interventions for FOP includes blocking the activity of the mutant FOP receptor, quenching inflammatory triggers, inhibiting connective tissue progenitor cells that give rise to ectopic endochondral ossification, and minimizing the micro-environmental factors that promote lesion progression. In light of the rarity of FOP, new approaches to clinical trial design, including delayed start and n = 1 designs, are considered. Finally, a schema for pharmacological management of FOP in anticipation of approved medications and the availability of repurposed drugs is proposed.