Breakthrough Work Leads to Rare Bone Disease Trial

As rare pediatric diseases go, Fibrodysplasia Ossificans Progressiva (FOP) is about as rare and debilitating as rare diseases come. Affecting approximately one in two million people around the world, FOP is a condition in which ectopic (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 FOP 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 in 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.

All of which 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 in ALK2. HO “can happen to any of us,” Dr. Pacifici pointed out, because the condition can be brought on by any number of causes, such as 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, creating major difficulties for the soldiers’ physical recovery and return to service as studies by U.S. Department of Defense (DoD) investigators showed.

Palovarotene: From Emphysema to FOP

Supported in large part by DoD funding, Dr. Pacifici and colleagues have been looking at ways to arrest HO (and by extension, FOP) for several years. They have also been collaborating with researchers from the military — particularly the Navy’s Jonathan Forsberg, MD, of the Walter Reed National Military Medical Center — who was the lead author of papers describing the incidence and clinical consequences of HO in wounded soldiers.

In 2011, the CHOP researchers’ investigations led to a paper in Nature Medicine showing that 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. The team had previously shown, in a 2010 Journal of Orthopedic Research study on ectopic bone formation and HO, that RARs “are major modulators and regulators of skeletal development and function.”

In their Nature Medicine study, using mouse models of HO and FOP, the team — led by Drs. Iwamoto and Pacifici — 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-γ 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 effective reported so far, for this condition and related ectopic ossification conditions.”

Moreover, the drugs all “seem to have minimal side effects,” the authors noted.

In an editorial that accompanied the Nature Medicine study, the University of Pennsylvania’s FOP Research Center’s Frederick S. Kaplan, MD, and Eileen M. Shore, PhD, said the CHOP group’s “tantalizing findings … suggest that successful, long-term inhibition of [HO] may be possible even a week or more after the inflammatory inductions events have occurred, an achievement that has not yet been realized by any other class of medications.”

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 FOP. When the trial was announced, Clementia’s Chief Executive Officer, Clarissa Desjardins, PhD, said, “We could not have arrived at this point without the support and collaboration of countless members of the FOP community including scientists, physicians, and most importantly patients and their families, who inspire our work everyday.”

“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 about the basic and translational research work by the CHOP Orthopaedics’ investigators, use the following link to their CHOP Research Institute website.

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