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.

KEYWORDS:

• Fibrodysplasia ossificans progressiva
• heterotopic ossification
• ACVR1
• ALK2
• kinase inhibitors
• clinical trials

Article highlights

• Current pharmacological targets, potential designs for clinical trials, and possible treatment approaches using experimental and repurposed agents for FOP are reviewed.

• The status of FOP drug development is updated.

• Discovery phase studies on pharmacologic agents targeting a wide spectrum of mechanisms are described.

• Expert opinion is given on approaches to clinical trial design and pharmacological management of FOP in anticipation of approved medications and availability of repurposed drugs.

• Combination therapy or drug cocktails are proposed as the mainstay of future FOP management, with episodic treatment using additional interventions at the time of a breakthrough flare-up.

Acknowledgments

We acknowledge the International FOP Association (IFOPA) for sharing information regarding current drug development that was presented during the 2019 FOP Drug Development Forum in Orlando, Florida.

Declaration of interest

The authors are principle investigators on the current FOP clinical trials sponsored by Clementia/Ipsen Pharmaceuticals and Regeneron Pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported in part by the Radiant Hope Foundation (to RJP), the Robert and Arlene Kogod Professorship in Geriatric Medicine (to RJP) and the Isaac and Rose Nassau Professorship of Orthopaedic Molecular Medicine (to FSK).