Clinical Trials

Inclusion Criteria:

• Written, signed, and dated informed subject/parent consent and age-appropriate assent (performed according to local regulations).
• A clinical diagnosis of MO with a disease-causing Ext1 or Ext2 mutations confirmed by a central laboratory.
• Male and female subjects with a chronological age of 2-14 years, inclusive.
• Female subjects must be premenarchal at screening.
• Bone age at screening of ≤14 years, 0 months per the Greulich-Pyle method as assessed by a central reader.
• Symptomatic MO, defined as the occurrence of any one of the following at screening:
  • Five or more clinically-evident OCs and the presence of a new or enlarging OC in the preceding 12 months;
  • Five or more clinically-evident OCs and the presence of a painful OC;
  • A skeletal deformity;
  • A joint limitation;
  • Prior surgery for a MO-related complication.
• If a subject had a prior surgery for MO, the subject should not be screened until at least 8 weeks post-surgery to allow for at least 12 weeks of stabilization of symptoms prior to first dose. Surgical orthopedic implants are allowed if they were in situ for ≥ 12 weeks prior to the baseline MRI.
• If a subject is currently receiving pain medications, the dose must be stable (i.e., < 20% variance) for 2 weeks prior to screening.
• The ability to undergo whole body MRI with or without sedation/general anesthesia.
• Male and female subjects of child bearing potential who are heterosexually active must agree to use two effective methods of birth control, one of which must be highly effective during treatment and for 1 month after treatment discontinuation, unless they commit to true abstinence from heterosexual sex.  Heterosexually active females of child bearing potential (FOCBP), must also agree to start effective methods of birth control at screening. An FOCBP is defined as a female who is ≥13 years of age or is post-menarchal, whichever is earlier.
• Subjects must be accessible for treatment with study drug and follow-up.

Exclusion Criteria:

• Weight < 10 kg.
• Other known syndromic conditions such as Langer-Giedion or Potocki-Shaffer syndromes.
• Any subject with neurologic signs suggestive of spinal cord impingement.
• If subject is 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. For eligibility, no washout is required prior to the first dose of study drug.
• Exposure to synthetic oral retinoids within 4 weeks prior to enrollment.
• Concurrent treatment with tetracycline or any tetracycline derivatives, due to the potential increased risk of pseudotumor cerebri.
• History of allergy or hypersensitivity to retinoids, gelatin, or lactose (other than lactose intolerance).
• Concomitant medications that are strong inhibitors or inducers of cytochrome P450 (CYP450) 3A4 activity.
• Amylase or lipase > 2 times the above the upper limit of normal (> 2 × ULN) or with a history of chronic pancreatitis.
• Elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5x ULN.
• Fasting triglycerides > 400 mg/dL with or without therapy.
• Subjects with uncontrolled cardiovascular, renal, hepatic, pulmonary, gastrointestinal, endocrine, metabolic, ophthalmologic, immunologic, psychiatric, or other significant disease. These include subjects requiring glucocorticoid at doses > 0.2 mg/kg or up to 10 mg prednisone equivalent daily.
• Subjects experiencing suicidal ideation (type 4 or 5) or any suicidal behavior within the past month or any suicidal behavior within the past year as defined by the Columbia-Suicide Severity Rating Scale (C-SSRS).
• Subjects unable or unwilling to complete the study or all study-related procedures, including imaging.
• Any surgical implant that is contraindicated for MRI. Dental braces are permitted.
• Participation in any clinical research study within 4 weeks prior to enrollment or simultaneous participation in any clinical research study.
• 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.