Experts' Research Leads to Rare Disease Clinical Trial

As rare pediatric diseases go, Fibrodysplasia Ossificans Progressiva (FOP) is about as rare and debilitating as they come. Affecting roughly one in two million people around the world, FOP 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,” according to the NIH’s Genetics Home Reference page. FOP is caused by a congenital mutation in a gene called ALK2.

Over time, this ectopic bone — also known as heterotopic ossification (HO) — becomes pervasive and widespread and eventually restricts FOP patients’ ability to move, speak, and feed themselves, and can lead to near-total paralysis and early death. In addition, there is a non-genetic form of HO that is not as severe as FOP and can occur in individuals of any age.

Like so many rare diseases, there are few treatment options for fibrodysplasia ossificans progressiva because its rarity means it has been studied by fewer research groups and has attracted less research money than more common conditions. In the U.S., a disease is considered rare if it affects fewer than 200,000 people, so FOP — of which there are roughly 300 cases in the U.S. — is one of the very rarest rare diseases.

Fibrodysplasia Ossificans Progressiva “is an extremely serious disease,” said CHOP’s Maurizio Pacifici, PhD, who often hears from families desperate to find a treatment for FOP.

Dr. Pacifici is among a group of CHOP Orthopaedics’ Investigators — 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 into a phase II clinical trial to treat FOP.

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 for FOP 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, their steroid treatments’ side effects can be compounded, Dr. Pacifici pointed out.

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,” Dr. Pacifici pointed out. The condition can be brought on by any number of causes — trauma, invasive surgeries, and burns, as well as prolonged immobilization. Because severe trauma is such a strong inducer of HO, it 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, Dr. 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 agonists inhibited chondrogenesis, or the development of cartilage, which is the first step in the formation of ectopic bone during HO and FOP. Moreover, the drugs all “seem to have minimal side effects,” the authors noted.

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. Fast forward to today: in July, Clementia launched a phase II trial Palovarotene to treat fibrodysplasia ossificans progressiva.

“It is rare to go from basic science, and we really started with completely basic science, to a clinical trial, …it took us a long, long time to do it,” Dr. Pacifici noted. Palovarotene may turn 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.

To read more of this remarkable story of how research was taken from a lab at CHOP to a clinical trial, see this month’s issue of Bench to Bedside.