First Ever Drug Treatment for Aggressive Pediatric Bone Disease Nears FDA Approval

The Food and Drug Administration (FDA) has accepted a new drug application (NDA) for palovarotene, a drug identified by researchers at Children’s Hospital of Philadelphia (CHOP) to treat fibrodysplasia ossificans progressiva (FOP). The drug, currently in a phase 3 clinical trial run by Ipsen, targets the pathological process that leads to formation and accumulation of bone where it does not belong, the hallmark pathology of FOP. It would be the first-ever approved treatment targeting this condition.

The disease involves a process called heterotopic ossification (HO) which starts with formation of cartilage that turns into bone. Although a milder form of HO can occur in otherwise healthy individuals following traumatic injury, deep burns or severe war wounds, HO is far more severe, aggressive, and unrelenting in FOP and is caused by a genetic mutation. Starting around the age of 2 or 3, patients with FOP begin to form cartilage and bone at diverse sites outside the skeleton spontaneously or after local inflammation, first through the upper body and later, over several years, down the trunk and along the limbs.

The HO bone forms at the expense of muscle and neighboring tissues, damaging and blocking joints and other structures so that eventually it becomes difficult – if not impossible – for FOP patients to perform basic life functions, like opening the mouth or using the legs to walk. By the time patients reach their 30s or 40s, very little mobility is usually left. While HO does not occur within internal organs such as the heart or liver, it can cause constriction of the chest wall, impeding normal respiration and circulation. Most patients die prematurely, often from lung and heart complications.

More than 20 years ago, Maurizio Pacifici, PhD, Director of Orthopaedic Research at CHOP, began to explore the possibility of using the retinoic pathway to treat FOP, as this mechanism had been shown by his and other labs to regulate cartilage and bone formation. Pacifici and his team hypothesized that if they could identify a clinically suitable pharmacologic compound that would turn this pathway on, they could use it to turn off the development of unwanted cartilage and bone in FOP patients.

In 2011, Pacifici and his collaborators published a study in Nature Medicine showing that one such retinoid agonist drug known as R667, or palovarotene, was able to inhibit HO formation in an animal model of FOP, with tolerable side effects. In subsequent studies with colleagues at Penn Medicine, the team demonstrated that palovarotene also blocked HO in animals carrying the exact human disease-causing mutation for FOP.  

“The dream of every biomedical researcher is to go from the lab to the bedside and discover a treatment that improves the lives of patients,” Pacifici said. “We are very excited that the FDA will review this drug for final approval, as the patients currently lack an effective treatment that will slow down or block their debilitating disease.”

The FDA is scheduled to vote on approving palovarotene on November 30, 2021. Learn more about the NDA for palovarotene here.