As rare pediatric diseases go, fibrodysplasia ossificans progressiva (FOP) is about as rare and debilitating as they come. Affecting roughly 1 in 2 million people around the world, FOP—a congenital mutation in a gene called ALK2—is a condition in which extraskeletal bone is formed when muscle tissue and connective tissue such as tendons and ligaments are gradually replaced by bone.
Over time, this ectopic bone — also known as heterotopic ossification (HO) — becomes pervasive and widespread, eventually restricts FOP patients’ ability to move, speak, and feed themselves, and can lead to near-total paralysis and early death. In addition, a nongenetic form of HO that is not as severe as FOP can occur in individuals of any age.
There are roughly 300 cases of FOP in the United States. Like so many rare diseases, there are few treatment options for FOP because it has been studied by fewer research groups and has attracted less research money than more common conditions.
“Fibrodysplasia ossificans progressiva is an extremely serious disease,” says Maurizio Pacifici, PhD, director of orthopedic research at The Children’s Hospital of Philadelphia (CHOP) and holder of the Bong Lee Endowed Chair in Pediatric Orthopedics. Families come to CHOP often desperate to find a treatment for the condition.
Pacifici is among a group of Orthopedics’ investigators at the Hospital—including Masahiro Iwamoto, DDS, PhD, and Motomi Enomoto-Iwamoto, DDS, PhD—who have been working to better understand, and ultimately treat, FOP. Their many years of work may soon pay off, because a drug they identified as a possible FOP treatment is now being tested in a phase II clinical trial.
FOP is marked by flare-ups—localized swelling and inflammation —that signal the development of ossification in the affected area. Currently, the only approved treatment is to give patients steroids when they experience flare-ups. The steroids reduce inflammation and swelling, but are not able to prevent ossification and can also have considerable side effects. Because FOP patients are prone to getting multiple flare-ups, at times with little respite between episodes, the side effects of steroid treatments can be compounded.
This has spurred the search for a safer, more effective treatment for FOP and HO. Unlike FOP, HO is not confined to a small community of patients with a genetic mutation, and can happen to any of us, notes Pacifici. The condition can be brought on by any number of causes, including trauma, invasive surgeries, and burns, as well as prolonged immobilization. Because severe trauma is such a strong inducer of HO, the condition was seen in some 65 percent of seriously wounded soldiers during the peak of recent wars.
Supported in large part by Department of Defense funding, Pacifici and colleagues have been looking at ways to arrest HO (and by extension, FOP) for several years. In 2011, their investigations led to a paper in Nature Medicine showing that drugs called retinoic acid receptor (RAR) agonists inhibited chondrogenesis—or the development of cartilage —which is the first step in the formation of ectopic bone during HO and FOP.
Using mouse models of HO and FOP, the study team found that several retinoid agonists were potent inhibitors of trauma-induced intramuscular and subcutaneous HO and a genetic form of FOP. In particular, they focused on RAR-g agonists, finding that they have the biological properties needed to interfere with the specific processes and mechanisms that are needed for the initiation and progression of heterotopic ossification and might therefore represent effective remedies, probably the most reported so far, for HO and related ectopic ossification conditions. Moreover, the study found that the drugs all seemed to have minimal side effects.
One of the drugs the CHOP researchers identified was Palovarotene. Originally developed by the pharmaceutical company Roche to treat emphysema, Palovarotene was shelved when trials showed the drug was effective but not as effective as expected. Following the publication of the Nature Medicine paper, the Montreal-based startup Clementia Pharmaceuticals acquired the rights to develop Palovarotene to treat FOP in close collaboration with the CHOP investigators. Clementia recently launched a phase II trial using Palovarotene to treat FOP.
“It is rare to go from basic science to a clinical trial, and it took us a long time to do,” says Pacifici. “Our hope now is that Palovarotene will turn out to be an effective treatment for FOP in the pediatric and young adult population, as well as HO in wounded soldiers and other affected individuals.”