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Bone Abstracts (2019) 7 OC27 | DOI: 10.1530/boneabs.7.OC27

ICCBH2019 Oral Communications (1) (27 abstracts)

Palovarotene inhibits the development of new heterotopic ossification in fibrodysplasia ossificans progressiva (FOP)

Frederick Kaplan 1 , Edward C Hsiao 2 , Geneviève Baujat 3 , Richard Keen 4 , Carmen De Cunto 5 , Maja Di Rocco 6 , Matthew A Brown 7 , Mona M Al Mukaddam 1 , Donna R Grogan 8 & Robert J Pignolo 9

1University of Pennsylvania, Philadelphia, Pennsylvania, USA; 2University of California San Francisco, San Francisco, California, USA; 3Institut IMAGINE and Hôpital Necker-Enfants Malades, Paris, France; 4Royal National Orthopaedic Hospital, Stanmore, UK; 5Hospital Italiano de Buenos Aires, Buenos Aires, Argentina; 6Giannina Gaslini Institute, Genoa, Italy; 7Queensland University of Technology, Queensland, Australia; 8Clementia Pharmaceuticals Inc, Newton, Massachusetts, USA, 9Mayo Clinic, Rochester, New York, USA.

Objective: FOP is a rare, severely disabling disease characterized by episodic flare-ups and accumulation of heterotopic ossification (HO) leading to restricted movement, physical disability, and early death. Data from two Phase 2 interventional studies and one natural history study (NHS) were used to evaluate whether palovarotene could reduce HO following an FOP flare-up.

Methods: HO volume at the flare-up site was determined by CT at baseline and 12 weeks post-baseline; baseline edema was determined by MRI/US. Palovarotene regimens included: flare-up only 10/5 mg for 2/4 weeks (48 flare-ups/27 subjects; mean/median age (range)=23/22 years (9–44); 52%male); flare-up only 20/10 mg for 4/8+ weeks (18 flare ups/12 subjects; 14/11 years (7–34); 33%male); 5 mg daily (chronic) plus 20/10 regimen during flare-up (33 flare-ups/23 subjects; 25/25 years (13 46); 35%male). The comparator pooled data from a randomized placebo group and untreated NHS flare-ups (49 flare-ups/41 subjects; 17/14 years (4 53); 49%male). Flare-ups most commonly occurred in the hip, knee, lower back, and shoulder in all groups. All imaging was interpreted by a blinded, central laboratory using pre-specified procedures.

Results: The difference in new HO volume between the 20/10 flare-up regimen (3,045 mm3) and placebo/untreated flare-ups (11,014 mm3) was statistically significant (95% CI=27,379 mm3, 2,253 mm3; P=0.02; ANOVA with BCa bootstrap and covariate adjustment), representing a 72% reduction in new HO volume. Reductions versus controls were similar with the chronic/flare-up (3,018 mm3; P=0.16) and 10/5 flare-up regimens (2,731 mm3; P=0.05). The proportion of flare-ups with baseline edema that formed new HO was 40% in the placebo/untreated group, 60% in the 10/5 group, 50% in the 20/10 group, and 27% in the chronic/flare-up group. Dose-related increases in adverse events, mainly mucocutaneous in nature, were observed. There were no apparent effects on ECG findings or on growth in skeletally immature subjects.

Conclusions: Data from 148 prospectively assessed flare-ups demonstrated an ~70% decrease in new HO volume at week 12 following palovarotene administration when compared to the placebo/untreated control. The impact of the chronic/flare-up regimen on whole body HO volume is being evaluated in a Phase 3 trial. Palovarotene was tolerated at the doses administered. We thank the FOP community and clinical research teams

Disclosure: Donna Grogan is an employee of Clementia Pharmaceuticals Inc.

Volume 7

9th International Conference on Children's Bone Health


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