An Efficacy and Safety Study of Palovarotene for the Treatment of MO

Multiple osteochondromas is a rare condition where children develop multiple benign
cartilage-capped bony tumors called osteochondromas on bones throughout the body, resulting
in pain, deformity, limb length discrepancy, disability, and eventually arthritis and
possible malignancy. The primary objective is to compare the efficacy of two dosage regimens
of palovarotene with placebo to prevent the formation of new osteochondromas in pediatric MO
subjects with exostosin 1 or exostosin 2 gene mutations. Osteochondroma formation will be
assessed by whole body magnetic resonance imaging (MRI). Secondary efficacy objectives are to
compare the effect of palovarotene on the volume of osteochondromas as assessed by MRI; and
on the annualized rate of new or worsening deformities and MO-related surgeries. The overall
safety of palovarotene and the effects of palovarotene on linear growth, bone growth plates,
bone mineral density, quality of life, and pain due to osteochondromas will also be studied.

Key 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 disease-causing exostosin 1 or 2 gene mutations.

- Male or female from 2 to 14 years of age.

- Female subjects must be premenarchal at screening.

- A bone age at screening of 14 years or less.

- Symptomatic MO, defined as five or more clinically-evident osteochondromas and a new
or enlarged osteochondroma that occurred in the preceding 12 months, five or more
clinically-evident osteochondromas and the presence of a painful osteochondroma, a
skeletal deformity, a joint limitation, or prior surgery for a MO-related
complication.

- The ability to undergo whole body MRI with or without sedation/general anesthesia.

- Use of two effective methods of birth control during treatment, and for 1 month after
treatment discontinuation, unless committed to true abstinence from heterosexual sex.
Sexually active females of child-bearing potential must also agree to start effective
methods of birth control at screening.

Key Exclusion Criteria:

- Weight under 10 kg.

- Other syndromic conditions such as Langer-Giedion or Potocki-Shaffer.

- Any subject with neurologic signs suggestive of spinal cord impingement.

- Concomitant medications that are strong inhibitors or inducers of cytochrome P450 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 or alanine aminotransferase above 2.5×ULN.

- Any surgical implant that is contraindicated for MRI.