FDA approves Ipsen’s palovarotene for ultra-rare disease

The FDA gave a nod of approval to Ipsen’s treatment for the ultra-rare disease fibrodysplasia ossificans progressiva though regulators have expressed concerns at least twice about the safety and efficacy of the drug.

“For the first time doctors have an approved medicine available to them, shown to reduce the formation of new, abnormal bone growth, known as heterotopic ossification (HO), which causes debilitating mobility challenges and has a devastating impact on the lives of people with FOP,” Howard Mayer, head of R&D at Ipsen, said in a statement.

Fibrodysplasia ossificans progressiva is a congenital disease that leads to the ongoing formation of bone tissue in muscles, tendons and ligaments. As it builds up, patients’ joints freeze up, and they lose movement. It eventually leads to bone formation around the rib cage, suffocating them. According to the company, about 400 people in the US have the disease, and about 900 people globally.

The FDA was originally skeptical about palovarotene. In December of last year, the regulator rejected the application, asking for more data from existing studies. Ipsen resubmitted the application with more analyses from the clinical trials, including data from the first Phase III study.

Even with additional analyses, the FDA wasn’t convinced about palovarotene’s efficacy and safety, including apparent increased flare-ups of the disease while patients were taking the medication, premature closure of growth plates in pediatric patients that led to a partial clinical hold in 2019, and whether post-hoc analyses conducted by the company were reliable after the drug appeared to miss the primary endpoint in an initial analysis in a Phase III trial.

The Paris-based company also said it appeared to miss the primary endpoint because of the trial’s initial statistical methods.

Ipsen acknowledged those issues and has said the drug should come with a boxed warning about premature growth plate closure after there were 13 adverse events in pediatric patients in trials.

Michelle Davis

Michelle Davis, executive director of the International Fibrodysplasia Ossificans Progressiva Association, told Endpoints News that the risks should be discussed between the patient, family and doctor.

“A mom described it to me as, ‘Would I rather my child be short and have their mobility or be fully grown but be riddled with bone and not able to move on their own?’” she said. “This will be a tough decision for some families, but families deserve the right to make that decision. They shouldn’t have someone deciding for them that that’s an unacceptable side effect.”

Palovarotene comes with serious side effects: During the Phase III trial, 9% of the target patient group discontinued the drug due to an adverse event, and more than one-third of patients had adverse events that led to a dose modification. In addition, 65% of patients had one or more flare-ups compared to 54% in the untreated patients in a natural history study.

Patients “know it’s not a cure, but it’s something to slow it down,” Davis said. “They want the ability to slow it down so that they can enjoy the life that they have.”

In June, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee largely voted in support of the drug’s efficacy and risk-benefit profile. The panel of outside advisors voted 10-4 that evidence from a Phase III study showed the drug was effective and 11-3 that the benefits of the drug outweighed its risks.

Jefferies analysts said then that the committee’s recommendation de-risked the approval, and they predict €80 million in peak sales of the drug.

In early 2022, the drug won approval in Canada, where it is marketed as Sohonos, while the EMA’s Committee for Medicinal Products for Human Use has twice offered a negative opinion on palovarotene.

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