E-Poster Presentation 30th Australian and New Zealand Bone and Mineral Society Annual Scientific Meeting 2020

Measuring outcomes in ultra-rare diseases: methodology of the palovarotene fibrodysplasia ossificans progressiva (FOP) clinical development program (#112)

Robert J. Pignolo 1 , Geneviève Baujat 2 , Matthew A. Brown 3 , Carmen De Cunto 4 , Maja Di Rocco 5 , Edward C Hsiao 6 , Richard Keen 7 , Mona Al Mukaddam 8 , Andrew Strahs 9 , Donna R. Grogan 9 , Rose Marino 9 , Frederick S. Kaplan 8 , Shane Patella 10
  1. Department of Medicine, Mayo Clinic, Rochester, MN, USA
  2. Département de Génétique, Institut IMAGINE and Hôpital Necker-Enfants Malades, Paris, France
  3. Guy’s & St. Thomas’ NHS Foundation Trust and King’s College London , NIHR Biomedical Research Centre, London, UK
  4. Pediatric Rheumatology Section, Department of Pediatrics, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
  5. Unit of Rare Diseases, Department of Pediatrics, Giannina Gaslini Institute, Genoa, Italy
  6. Division of Endocrinology and Metabolism, UCSF Metabolic Bone Clinic, Institute of Human Genetics, and UCSF Program in Craniofacial Biology, Department of Medicine, University of California-San Francisco, San Francisco, CA, USA
  7. Centre for Metabolic Bone Disease, Royal National Orthopaedic Hospital, Stanmore, UK
  8. Departments of Orthopaedic Surgery & Medicine, The Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  9. Ipsen, Newton, MA, USA
  10. Ipsen, Glen Waverley, VIC, Australia

Background: FOP is an ultra-rare genetic disorder characterized by heterotopic ossification (HO) of soft and connective tissues (often preceded by flare-ups), cumulative disability, and shortened life expectancy. Palovarotene is a highly selective retinoic acid receptor-gamma agonist under investigation for treatment of FOP. Conducting FOP trials have multiple challenges, including low number of confirmed cases worldwide, limited understanding of disease progression, the need to identify disease-specific biomarkers and optimize assessment of HO progression.

 

Objective: To describe the challenges encountered when conducting clinical trials in FOP.

 

Methods: Here, we describe the methodology of: a non-interventional, prospective, protocol-specified, longitudinal natural history study (NHS; NCT02322255); a multicenter, randomized, double‑blind, placebo-controlled phase II trial (NCT02190747); an ongoing open-label extension (OLE) to the phase II trial (NCT02279095) (Table). Studies were designed adaptively. Palovarotene doses were administered episodically (high dose for 2 or 4-weeks, followed by low dose for 4 or ≥8-weeks, from flare-up onset) or daily. In the double-blind period of the phase II trial, participants were randomized in two cohorts: 0:3:1 (aged ≥15years) or 3:3:2 (≥6years) to palovarotene 5/2.5mg, palovarotene 10/5mg or placebo, episodically for 2-weeks then 4-weeks. HO incidence and volume are assessed annually by low dose whole-body computer tomography and/or at 12-weeks during the course of flare-ups (defined as ≥2 [≥1 in OLE Part C] or pain, swelling, stiffness, decreased range of motion, redness, or warmth). Other clinical, functional and patient-reported outcomes are assessed using FOP-specific measures, including the Cumulative Analogue Joint Involvement Scale (CAJIS) and FOP Physical Function Questionnaire (FOP-PFQ). Studies were approved by independent ethics committees. 151 unique participants were enrolled.

 

Conclusions: Novel methodological approaches are needed to develop disease-modifying treatments for serious, ultra-rare diseases. HO is the main cause of disability in patients with FOP. This program may inform development of new treatments in rare diseases.

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