Palovarotene for Fibrodysplasia Ossificans Progressiva (FOP): Results of a Randomized, Placebo-Controlled, Double-Blind Phase 2 Trial

Robert J Pignolo, Geneviève Baujat, Edward C Hsiao, Richard Keen, Amy Wilson, Jeff Packman, Andrew L Strahs, Donna R Grogan, Frederick S Kaplan, Robert J Pignolo, Geneviève Baujat, Edward C Hsiao, Richard Keen, Amy Wilson, Jeff Packman, Andrew L Strahs, Donna R Grogan, Frederick S Kaplan

Abstract

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by progressive heterotopic ossification (HO), often heralded by flare-ups, leading to reduced movement and life expectancy. This placebo-controlled, double-blind trial (NCT02190747) evaluated palovarotene, an orally bioavailable selective retinoic acid receptor gamma agonist, for prevention of HO in patients with FOP. Patients experiencing a flare-up were enrolled in two cohorts: (1) patients ≥15 years were randomized 3:1 to palovarotene 10/5 mg (weeks 1-2/3-6) or placebo; (2) patients ≥6 years were randomized 3:3:2 to palovarotene 10/5 mg, palovarotene 5/2.5 mg (weeks 1-2/3-6), or placebo. Cohort data were pooled. The primary endpoint was the proportion of responders (no/minimal new HO at flare-up body region by plain radiograph) at week 6. Change from baseline in HO volume and new HO incidence were assessed by computed tomography (CT) at week 12. Tissue edema was assessed by magnetic resonance imaging (MRI) or ultrasound. Forty patients (aged 7-53 years) were enrolled (placebo: n = 10; palovarotene 5/2.5 mg: n = 9; palovarotene 10/5 mg: n = 21). Disease history was similar between groups. In the per-protocol population, the proportion of responders at week 6 by plain radiograph was 100% with palovarotene 10/5 mg; 88.9% with palovarotene 5/2.5 mg; 88.9% with placebo (Cochran-Armitage trend test: p = 0.17). At week 12, the proportions were 95.0% with palovarotene 10/5 mg; 88.9% with palovarotene 5/2.5 mg; 77.8% with placebo (Cochran-Armitage trend test: p = 0.15). Week 12 least-squares mean (LSmean) new HO volume, assessed by CT, was 3.8 × 103 mm3 with palovarotene 10/5 mg; 1.3 × 103 mm3 with palovarotene 5/2.5 mg; 18.0 × 103 mm3 with placebo (pairwise tests versus placebo: p ≤ 0.12). Palovarotene was well-tolerated. No patients discontinued treatment or required dose reduction; one patient had dose interruption due to elevated lipase. Although these findings were not statistically significant, they support further evaluation of palovarotene for prevention of HO in FOP in larger studies. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Keywords: CELL/TISSUE SIGNALING; CLINICAL TRIALS; FIBRODYSPLASIA OSSIFICANS PROGRESSIVA; HETEROTOPIC OSSIFICATION; RADIOLOGY.

Conflict of interest statement

RJP: Research investigator: Clementia/Ipsen, Regeneron; Advisory board: International FOP Association (IFOPA) Medical Advisory Board; President of the International Clinical Council on FOP. GB: Advisory board: Clementia/Ipsen, FOP European Consortium, International Clinical Council on FOP; Speaker: Clementia/Ipsen; ECH: Research investigator: Clementia/Ipsen; Receives clinical trials support through his institution from Clementia/Ipsen; Prior research support from Neurocrine Biosciences and Regeneron; Serves in a volunteer capacity on the International Clinical Council on FOP, the medical advisory board of the Fibrous Dysplasia Foundation, and the medical registry advisory board of the IFOPA. RK: Research investigator: Ipsen/Clementia, Kyowa Kirin, Regeneron; Advisory board: IFOPA FOP Registry Medical Advisory Board, International Clinical Council on FOP. AW: Employee of Clementia at the time the study was conducted. JP: Employee of Clementia at the time the study was conducted. ALS: Employee of Ipsen. DRG: Chief Medical Officer of Clementia and a shareholder at the time these data were obtained. FSK: Research investigator: Clementia/Ipsen, Regeneron; Advisory Board: IFOPA Medical Advisory Board; Founder and Past President of the International Clinical Council on FOP. In April 2019, Ipsen acquired Clementia Pharmaceuticals.

© 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Figures

Fig. 1
Fig. 1
Schematic showing the randomization of patients in Cohorts 1 and 2. aIncludes eight patients with eligible flare‐ups randomized in a 3:1 ratio to either PVO 10/5 mg or placebo. bTreatment and dosing regimens for Cohort 2 were based on the data available for Cohort 1. During the Data Monitoring Committee review, enrollment continued during the interim between randomization of the last patient in Cohort 1 and the start of Cohort 2 to allow eligible patients to participate; an additional eight patients with eligible flare‐ups were randomized in a 3:1 ratio to either PVO 10/5 mg or placebo. PVO = palovarotene.
Fig. 2
Fig. 2
Patient disposition. aMinimum required compliance with treatment: ≥80%; excluded patient compliance: 60%. PVO = palovarotene.
Fig. 3
Fig. 3
Incidence of new HO at the flare‐up body region at week 6 and week 12 as assessed by CT scan and/or plain radiograph (global read). (A) All evaluable flare‐ups. (B) Flare‐ups with baseline edema. Per protocol analysis set. In the global read, the presence/absence of new HO was determined after full evaluation of all images across all modalities and time points. (A) Primary analysis: one‐sided Cochran‐Armitage test of trend for all evaluable flare‐ups at week 6 and 12. CT = computed tomography; HO = heterotopic ossification; PVO = palovarotene.
Fig. 4
Fig. 4
Volume of new HO at the flare‐up body region as measured by CT scan (primary read). (A) All flare‐ups (LSmean). (B) All flare‐ups (individual observations). (C) Patients with flare‐ups and new HO >0 mm3 (LSmean). Per protocol analysis set. In the primary read, each imaging modality was assessed independently for HO. p values are from pairwise tests from a repeated measures mixed model. (A) The volume of new HO was not evaluable in one patient at week 6 and three patients week 12, all in the PVO 10/5 mg group. (B) Squares represent individual observations. Whiskers extend to maximum and minimum values due to small interquartile ranges of data. (C) Flare‐up body regions: placebo: 2 hip, 1 knee; PVO 5/2.5 mg: 1 shoulder/elbow, 1 knee; PVO 10/5 mg: 3 hip, 1 knee. CT = computed tomography; HO = heterotopic ossification; LSmean = least squares mean; PVO = palovarotene; SD = standard deviation; SE = standard error.

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