An Efficacy and Safety Study of Palovarotene for the Treatment of Fibrodysplasia Ossificans Progressiva.

One of the primary objectives was to evaluate the efficacy of palovarotene in decreasing new HO in participants with FOP as assessed by low-dose, whole body computed tomography (WBCT), excluding head, compared to untreated participants from Clementia's FOP natural history study (Study PVO-1A-001, NHS). The other primary objective was to evaluate the safety of palovarotene in participants with FOP.

This study was conducted in three parts. Part A was the main part of the study, Part B, the 2-year (24-month) extension and Part C was an up-to-2-year post last dose of study treatment follow-up for skeletally immature participants.

Participants in Part A and B received a chronic/flare-up dosing regimen of palovarotene for up to 4 years (48 months) as follows:

* Chronic treatment: orally administered 5 mg palovarotene once daily.
* Flare-up treatment: orally administered 20 mg palovarotene once daily for 4 weeks (28 days) followed by orally administered 10 mg palovarotene once daily for 8 weeks (56 days). Flare-up treatment may be extended until the Investigator determines that the flare-up has resolved.

Note that all dosing was weight-adjusted in skeletally immature participants (those under the age of 18 years with less than 90% skeletal maturity on hand/wrist x-rays performed at Screening).

In part C, participants who were enrolled in Parts A or B who discontinued the study and were skeletally immature were invited back to participate in the off-treatment safety follow-up. No new participants were enrolled into Part C.

• Palovarotene (Drug): Palovarotene was taken orally once daily at approximately the same time each day following a meal.

Primary outcomes

• Annualized New Heterotopic Ossification (HO) [Baseline (within one month of screening/Day 1) and up to 24 months]: The annualized new HO was assessed by low-dose, whole body computed tomography (WBCT), excluding head. The weighted linear mixed effect method without square-root transformation and negatives included was used for annualized new HO analysis.

Secondary outcomes

• Percentage of Participants With Any New HO [From Baseline (Day 1) up to end of 4-year follow-up period (approximately 57 months)]: The new HO was assessed by WBCT scan. The percentage of participants with any new HO (volume > 0 mm\^3) were analyzed using the Bayesian distribution. Results are presented for overall ITT period.
• Number of Body Regions With New HO [From Baseline (Day 1) up to end of 4-year follow-up period (approximately 57 months)]: All participants were analyzed for number of body regions with any new HO (new HO > 0 mm\^3). The presence of HO across various body regions was analyzed using WBCT scan. Results are presented for overall ITT period
• Percentage of Participants With Flare-Ups [Month 12]: Flare-up as an event with one or more flare-up symptoms, and regardless of flare-up symptom onset. Flare-up was evaluated remotely, or by telephone or video-conferencing, unless the Investigator deemed that a site visit was necessary.
• Ratio of Flare-Up Per Participant-Month of Exposure [From Baseline (Day 1) up to end of 4-year follow-up period (approximately 57 months)]: Flare-up as an event with one or more flare-up symptoms, and regardless of flare-up symptom onset. Flare-up was evaluated remotely, or by telephone or video-conferencing, unless the Investigator deemed that a site visit was necessary. The flare-up rate per participant-month exposure was analyzed using a negative binomial regression. Results are presented for overall ITT period.

Sex: All, ages: 4 Years to any

Key Inclusion Criteria:

* Written, signed, and dated informed subject/parent consent; and for subjects who are minors, age-appropriate assent (performed according to local regulations).
* Males or females at least 4 years of age.
* No flare-up symptoms within the past 4 weeks, including at the time of enrollment.
* Abstinent or using two highly effective forms of birth control.
* Accessible for treatment and follow-up; able to undergo all study procedures including low-dose WBCT (excluding head) without sedation.

Key Exclusion Criteria:

* Weight <10 kg.
* Concomitant medications that are strong inhibitors or inducers of cytochrome P450 (CYP450) 3A4 activity; or kinase inhibitors such as imatinib.
* Amylase or lipase >2x above the upper limit of normal (ULN) or with a history of chronic pancreatitis.
* Elevated aspartate aminotransferase or alanine aminotransferase >2.5x ULN.
* Fasting triglycerides >400 mg/dL with or without therapy.
* Female subjects who are breastfeeding.
* Subjects with uncontrolled cardiovascular, hepatic, pulmonary, gastrointestinal, endocrine, metabolic, ophthalmologic, immunologic, psychiatric, or other significant disease.
* Simultaneous participation in another clinical research study (other than palovarotene studies) within 4 weeks prior to Screening; or within five half-lives of the investigational agent, whichever is longer.
* Any reason that, in the opinion of the Investigator, would lead to the inability of the subject and/or family to comply with the protocol.

Participant flow

Outcome results

• Annualized New Heterotopic Ossification (HO) (Primary), Mean, cubic millimeters (mm^3): Palovarotene 9427.1 +/- 3084.0; Untreated (PVO-1A-001) 23720.2 +/- 4850.0
• Percentage of Participants With Any New HO (Secondary), Number, percentage of participants: Palovarotene 83.5
• Number of Body Regions With New HO (Secondary), Mean, body regions: Palovarotene 3.0 +/- 1.68
• Percentage of Participants With Flare-Ups (Secondary), Number, percentage of participants: Palovarotene 64.6
• Ratio of Flare-Up Per Participant-Month of Exposure (Secondary), Mean, ratio of flare-up: Palovarotene 0.2 +/- 0.40

Adverse events

Time frame: Treatment-emergent adverse events are collected from first date of palovarotene intake up to end of 4-year follow-up period (approximately 57 months) for study PVO-1A-301. For study PVO-1A-001, adverse events (AEs) were collected from study day 1 up to approximately 37 months. While no pharmacological intervention was applied in this observational study (PVO-1A-001), safety issues resulting only from any study-related procedure were recorded as AEs. MedDRA version 21.0 for PVO-1A-001 study.

Serious adverse events by term

Other adverse events by term

Limitations and caveats: A valid comparison of AEs from observational study (PVO-1A-001) was not made since AEs were only captured as related to study procedures.

• Shimono K, Tung WE, Macolino C, Chi AH, Didizian JH, Mundy C, Chandraratna RA, Mishina Y, Enomoto-Iwamoto M, Pacifici M, Iwamoto M. Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-gamma agonists. Nat Med. 2011 Apr;17(4):454-60. doi: 10.1038/nm.2334. Epub 2011 Apr 3. PMID 21460849
• Results publication: Lindborg CM, Al Mukaddam M, Baujat G, Cho TJ, De Cunto CL, Delai PLR, Eekhoff EMW, Haga N, Hsiao EC, Morhart R, de Ruiter R, Scott C, Seemann P, Szczepanek M, Tabarkiewicz J, Pignolo RJ, Kaplan FS. Most Fractures Treated Nonoperatively in Individuals With Fibrodysplasia Ossificans Progressiva Heal With a Paucity of Flareups, Heterotopic Ossification, and Loss of Mobility. Clin Orthop Relat Res. 2023 Dec 1;481(12):2447-2458. doi: 10.1097/CORR.0000000000002672. Epub 2023 May 8. PMID 37156007
• Results publication: Pignolo RJ, Hsiao EC, Al Mukaddam M, Baujat G, Berglund SK, Brown MA, Cheung AM, De Cunto C, Delai P, Haga N, Kannu P, Keen R, Le Quan Sang KH, Mancilla EE, Marino R, Strahs A, Kaplan FS. Reduction of New Heterotopic Ossification (HO) in the Open-Label, Phase 3 MOVE Trial of Palovarotene for Fibrodysplasia Ossificans Progressiva (FOP). J Bone Miner Res. 2023 Mar;38(3):381-394. doi: 10.1002/jbmr.4762. Epub 2023 Jan 25. PMID 36583535

• Study Protocol (PDF, 2020-10-30)
• Statistical Analysis Plan (PDF, 2022-12-13)

• Ipsen Medical Director, Study director, Ipsen

NIH grants: 2017