Drug candidate halts crippling excess bone growth in animal model of a rare bone disease

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New research in laboratory animals suggests that the drug palovarotene may prevent multiple skeletal problems caused by a rare but extremely disabling genetic bone disease, and may even be a candidate for use in newborn babies with the condition. Scientists at The Children's Hospital of Philadelphia, who previously repurposed the drug to prevent excess bone formation in animal models of fibrodysplasia ossificans progressiva (FOP), have extended that research in animals carrying the exact human disease-causing mutation.

In humans with FOP, an activating mutation in the ACVR1 gene triggers extraskeletal cartilage and bone formation and accumulation starting in early childhood. The extraskeletal bone occurs in muscles and other tissues where it does not belong. This pathological process, collectively called heterotopic ossification (HO), causes progressive loss of skeletal motion and hampers breathing and swallowing.

Currently untreatable and painful, FOP often causes death early in adulthood.

"This work represents a big step toward therapy," said co-study leader, Maurizio Pacifici, Ph.D., a developmental biologist and director of Orthopedic Research in the Division of Orthopedic Surgery at The Children's Hospital of Philadelphia (CHOP). "The mice used in this study were engineered to carry the human mutation that causes FOP, and the drug showed powerful and comprehensive benefits for skeletal growth and function in addition to inhibiting HO. If these results translate to humans, we may be able to treat children with FOP early in life, before the disease progresses."

The research appeared online March 12 in the Journal of Bone and Mineral Research.

"This is the first study to show in the mouse model of FOP that the drug palovarotene inhibits and abates multiple musculoskeletal problems associated with FOP," said co-study leader Eileen M. Shore, Ph.D., a professor in Genetics and Orthopaedics at the Center for Research in FOP and Related Disorders in the Perelman School of Medicine at the University of Pennsylvania. Another co-author from Penn Medicine, Frederick S. Kaplan, M.D., is a world expert in FOP.

Masahiro Iwamoto, D.D.S., Ph.D., also of CHOP, and a co-study leader with Pacifici and Shore, said, "This study has generated an unexpected and exciting finding, in that palovarotene appears to be better tolerated by mutant mice than control mice. If this finding translates to patients, the drug could be even safer for children with FOP than we previously realized."

Palovarotene was originally tested in adults with emphysema. Although the drug was not then developed beyond phase 2 trials for that indication, it showed few side effects. As a retinoic acid receptor-γ RAR-γ) agonist, palovarotene is a class of drug that selectively targets a regulatory pathway involved in cartilage formation. The extra bone that occurs in FOP appears first as cartilage before becoming fully mature bone cells. Iwamoto and Pacifici showed in 2011 that palovarotene inhibited HO in mouse models of genetic HO and injury-induced HO. The Department of Defense supported this research, given that injury-induced HO is prevalent in severely wounded soldiers.

The current study extended that research by using palovarotene in a novel mouse model carrying the human mutation, ACVR1 R206H, that causes most cases of FOP. The drug had potent effects–it prevented HO, and also preserved limb motion and normal bone growth in young mutant mice. The benefits for growth were a welcome surprise, said Pacifici, because palovarotene and similar retinoid agonists can impair skeletal growth–a side effect seen in control mice.

When the scientists gave palovarotene to nursing female mice, they passed along the drug's benefit to their offspring with the mutation. If the drug's benefits translate to humans, said Iwamoto, it could mean that newborn babies diagnosed with FOP could benefit from early treatment. "This is especially important, because once the extraskeletal bone forms in patients, it is permanent."

A major complication of FOP it that surgeons cannot remove the excess bone tissue, because tissue damage and injury from surgery trigger even more bone formation and growth. In this study, palovarotene not only inhibited spontaneous HO, but also prevented HO when mice were experimentally injured. This is another indicator of the drug's potential benefits for humans–possibly allowing the safe removal of previously formed HO in FOP patients and preventing HO in the general population experiencing trauma or surgery.

Clementia Pharmaceuticals is currently conducting phase 2 clinical trials in individuals with FOP, based on the 2011 preclinical results published by Iwamoto and Pacifici. That international study is being done at four sites, including the FOP Center at Penn Medicine, and is testing whether palovarotene is safe and effective in children and adults experiencing disease flare-ups.

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Editor's Note: Pacifici and Iwamoto are consultants to Clementia Pharmaceuticals. Kaplan is the global principal investigator for Clementia's phase 2 study.

The first authors of this study, with equal contributions, were Kenta Uchibe of CHOP and Salin A. Chakkalakal of Penn Medicine. Other co-authors, besides those already mentioned, were Michael R. Convente and Deyu Zhang of Penn Medicine; and Aris N. Economides, of Regeneron Pharmaceuticals.

Funds from the National Institutes of Health (grants AR056837 and AR41916), the U.S. Department of the Army (contract W81XWH-07-1-0212), the International Fibrodysplasia Ossificans Progressiva Association, the Penn Center for Musculoskeletal Diseases, the Ian Cali Endowment for FOP Research, the Whitney Weldon Endowment for FOP Research, and the Penn Center for Research in FOP and Related Disorders supported this research.

"Palovarotene Inhibits Heterotopic Ossification and Maintains Limb Mobility and Growth in Mice with the Human ACVR1r206H Fibrodysplasia Ossificans Progressiva (FOP) Mutation," Journal of Bone and Mineral Research, published online March 12, 2016, ahead of print. http://doi.org/10.1002/jbmr.2820

About The Children's Hospital of Philadelphia: The Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. In addition, its unique family-centered care and public service programs have brought the 535-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu.

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