On August 16, 2023, the FDA accelerated the approval of palovarotene (Sohonos; Ipsen Biopharmaceuticals) for the reduction in volume of new heterotopic ossification in female patients aged ≥8 years and in male patients aged ≥10 years who have been diagnosed with fibrodysplasia ossificans progressiva (FOP).
The FDA granted palovarotene capsules fast-track and breakthrough therapy designations, as well as priority review for this indication.
Palovarotene is an oral selective retinoic acid receptor gamma agonist and is the first drug approved for the treatment of patients with FOP.
FOP is a rare, autosomal dominant disorder in which connective tissue, such as muscle, tendons, and ligaments, progressively turn into bone tissue, forming bone outside the skeleton (extraskeletal or heterotopic bone) that limits movement. This process typically becomes noticeable in early childhood, starting with the neck and shoulders and proceeding down the body and into the limbs. Extraskeletal bone formation causes progressive loss of mobility as the joints become affected. An inability to fully open the mouth may cause difficulty in speaking and eating. An estimated 400 people in the United States have FOP. By age 30, the majority of patients require the use of a wheelchair and full-time care.
“FOP is life-altering to the individuals diagnosed and their families. There’s not a day that goes by where those impacted don’t worry about the debilitating physical pain of muscle that is replaced by bone, another joint locking or the relentless emotional toll of losing the ability to do an activity they love, or hold a loved one close,” noted Michelle Davis, Executive Director of the International FOP Association, in a press release. “The first treatment for FOP has been proven to reduce the volume of new abnormal bone growth, which may result in better health outcomes for people living with FOP,” she added.
The FDA approval of palovarotene was based on safety and efficacy data from clinical trials, including the pivotal phase 3 MOVE study (NCT03312634), an open-label, multicenter study that compared 18-month data for 107 patients with FOP who received oral palovarotene and were compared with treatment-naïve patients. The study results demonstrated that palovarotene effectively reduced the annualized heterotopic ossification volume compared with the standard of care (ie, palliative care).
“As a clinician caring for patients with FOP, I personally see the daily challenges and stresses that our patients and their families must contend with,” Edward C. Hsiao, MD, PhD, Division of Endocrinology and Metabolism, University of California, San Francisco, said in a press release. “The published Phase III MOVE study showed that Sohonos can decrease new heterotopic ossification, and that palovarotene can be tolerated by many patients with FOP.”
The full safety and efficacy data reviewed by the FDA came from clinical trials that enrolled a total of 164 patients with FOP, including 139 female patients aged ≥8 years and male patients aged ≥10 years (mean age, 19 years; range, 8-61 years; 51% male). Most of the patients received a daily dose of 5-mg oral palovarotene for 4 weeks (or 20 mg for a flare up), followed by 10 mg for 8 weeks, for a total of 12 weeks of treatment. In patients whose skeleton was <90% mature, all of the doses were reduced according to the patient’s body weight.
The most common (>10%) adverse events with palovarotene include dry skin, dry lips, arthralgia, pruritus, pain in extremity, rash, alopecia, erythema, headache, back pain, skin exfoliation, nausea, musculoskeletal pain, myalgia, dry eyes, hypersensitivity, peripheral edema, and fatigue.
Serious adverse events with palovarotene were reported in 15% (n=21) of the patients (female patients aged ≥8 years; male patients aged ≥10 years), with the most common event being premature epiphyseal closure. Adverse events leading to the permanent discontinuation of palovarotene treatment occurred in 11 patients, with dry skin being the most common (n=2) event. Mucocutaneous adverse events leading to dose reductions were more frequent in the patients who received the 20-mg/10-mg flare-up dose (37%) than in the patients who received the long-term dose of 5 mg/10 mg (4%).
Treatment with palovarotene is associated with metabolic bone disorders that may decrease vertebral bone mineral content and bone density; patients should be assessed periodically for spinal fracture. In addition, patients receiving palovarotene should be advised about the potential for mood disorders, including suicidal ideation, as well as night blindness that can impair nighttime driving.
Palovarotene was approved with a boxed warning about the risk for embryo-fetal toxicity and premature epiphyseal closure in pediatric patients. Palovarotene is contraindicated in patients who are pregnant. Patients should conduct a pregnancy test 1 week before initiating treatment with palovarotene and periodically during therapy for female patients of reproductive potential. Monitoring linear growth in growing pediatric patients is also recommended.
The recommended dosage of palovarotene for patients aged ≥14 years is 5 mg once daily for 4 weeks, followed by 10 mg once daily for 8 weeks, for a total of 12 weeks; if a patient has a flare up in the first 4 weeks, the dose should be increased to 20 mg daily, followed by 10 mg for the next 8 weeks. The dose for patients aged ≤14 years is between 2.5 mg and 5 mg daily, based on body weight. The prescribing information for palovarotene should be consulted for dosing in patients aged ≤14 years.
Before taking palovarotene, all growing pediatric patients should undergo skeletal maturity baseline assessments. Continued monitoring is recommended every 6 to 12 months, until patients reach skeletal maturity or final adult height.