In-Home Evaluation of Episodic Administration of Palovarotene in Fibrodysplasia Ossificans Progressiva (FOP) Subjects

Fibrodysplasia Ossificans Progressiva (FOP) is a rare, severely disabling disease characterized by painful, recurrent episodes of soft tissue swelling (flare-ups) that result in abnormal bone formation (heterotopic ossification or HO) in muscles, tendons, and ligaments. Flare-ups begin early in life and may occur spontaneously or after soft tissue trauma, vaccinations, or influenza infections. Recurrent flare-ups progressively restrict movement by locking joints leading to cumulative loss of function and disability. Mouse models of FOP have demonstrated the ability of retinoic acid receptor gamma (RARγ) agonists such as palovarotene to prevent HO following injury. This 36-month study will evaluate the long-term safety and efficacy of episodic treatment with palovarotene for flare-ups in FOP subjects who successfully complete two flare-up treatment periods (6 weeks duration) and two follow-up periods (6 weeks duration) in Study PVO-1A-202.

The primary objective of this Phase 2, open-label, multicenter, single-arm, extension study is to investigate the safety and efficacy of episodic treatment with palovarotene in FOP subjects with flare-ups.

Secondary objectives are:

The effect of episodic treatment of flare-ups with palovarotene on range of motion (ROM) as assessed by the subject global assessment of movement.

* The effect of episodic treatment of flare-ups with palovarotene on ROM as assessed by the Cumulative Analogue Joint Involvement Scale for FOP (CAJIS) for subjects with video-conferencing capability.
* The effect of episodic treatment of flare-ups with palovarotene on the total burden of heterotopic ossification (HO) as assessed by low-dose whole body computerized tomography (WBCT), excluding the head; and whole body dual energy x-ray absorptiometry (DEXA).
* The effect of episodic treatment of flare-ups with palovarotene on physical function using age-appropriate forms of the FOP-Physical Function Questionnaire (FOP-PFQ).
* The effect of episodic treatment of flare-ups with palovarotene on physical and mental health using age appropriate forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale.
* The effects of episodic treatment of flare-ups with palovarotene on pain and swelling associated with the flare-up using numeric rating scales (NRS) or the Faces Pain Scale-Revised (FPS-R) in subjects under 8 years of age.
* The use of assistive devices and adaptations for daily living by FOP subjects.

The follow-up portion of the study will consist of a Screening visit that will correspond to the last day (Study Day 84) of Study PVO-1A-202 and bi-annual assessments at Months 6, 12, 18, 24, 30, and 36.

Subjects experiencing a new, distinct flare-up during the 36-month follow-up will be evaluated and if eligible, receive palovarotene at the weight-adjusted equivalent of 10 mg for 14 days followed by 5 mg for at least 28 days. Any subject who received a lower dosing regimen due to tolerability issues during Study PVO-1A-202 will receive that tolerated dose.

For each flare-up there will be two periods:

1. A Screening period to occur within 7 days of the start of a new, distinct flare-up. The first dose of palovarotene will be taken within 10 days of the flare-up onset to allow for shipment of study medication to the subject's home.
2. A treatment period of at least 6 weeks duration. Subjects experiencing a new, distinct flare-up will be evaluated

Eligibility Criteria:
Inclusion Criteria:

For study enrollment

* Completed Study PVO-1A-202 having been treated with palovarotene (ie, 6 weeks on-treatment and 6-weeks follow-up) for two flare-ups.
* Written, signed, and dated informed consent or age-appropriate subject/parent assent (this must be performed according to local regulations).

For treatment with palovarotene for subsequent flare-ups

* Symptomatic onset of a new, distinct flare-up within 10 days of the first dose of study drug. Symptoms must be reported by the subject, be consistent with their previous flare-ups, and include a subject-reported onset date. The flare-up must be confirmed by the physician at screening via telephone contact and/or video-conferencing.
* Females of child-bearing potential (FOCBP) must have a negative blood (or urine) pregnancy test (with sensitivity of at least 50 mIU/mL) prior to administration of palovarotene. Male and FOCBP subjects must agree to remain abstinent during treatment and for 1 month after treatment or, if sexually active, to use two highly effective methods of birth control during and for 1 month after treatment. Additionally, sexually active FOCBP subjects must already be using two highly effective methods of birth control 1 month before treatment is to start. Specific risk of the use of retinoids during pregnancy, and the agreement to remain abstinent or use two highly effective methods of birth control will be clearly defined in the informed consent, and the subject or legally authorized representatives (eg, parents, caregivers, or legal guardians) must specifically sign this section.
* Subjects must be accessible for treatment with palovarotene and follow-up.

Exclusion Criteria:

For study enrollment

* 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.

For treatment with palovarotene for subsequent flare-ups:

* Weight \<20 kg.
* The flare-up is at a completely ankylosed joint.
* Intercurrent non-healed fracture at any location.
* If currently using vitamin A or beta carotene, multivitamins containing vitamin A or beta carotene, or herbal preparations, fish oil, and unable or unwilling to discontinue use of these products during palovarotene treatment.
* Exposure to synthetic oral retinoids in the past 30 days prior to screening (signature of the informed consent or age-appropriate subject assent).
* Concurrent treatment with tetracycline or any tetracycline derivatives due to the potential increased risk of pseudotumor cerebri
* History of allergy or hypersensitivity to retinoids or lactose.
* Female subjects who are breastfeeding.
* Subjects with uncontrolled cardiovascular, hepatic, pulmonary, gastrointestinal, endocrine, metabolic, ophthalmologic, immunologic, psychiatric, clinically significant abnormal laboratory findings, or other significant disease.
* Simultaneous participation in another interventional clinical research study within the past 4 weeks (except for Study PVO-1A-202).
* Subjects experiencing suicidal ideation (type 4 or 5) or any suicidal behavior within the past month prior to Screening as defined by the Columbia Suicide Severity Rating Scale.
* 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.