‘Not just science, but an art form’

Kinase inhibitor may prove useful in treating rare genetic disease

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DURHAM, N.C.—Scientists at BioCryst Pharmaceuticals have identified a potential treatment for fibrodysplasia ossificans progressiva (FOP), a glimmer of hope in the quest to find a treatment for the devastating genetic condition also known as stone man disease. This extremely rare disease immobilizes those affected, seeming to turn them to stone as it causes bone to form in muscles, tendons, ligaments and other connective tissues. Bridges of extra bone develop across joints, progressively restricting movement and forming a second skeleton that imprisons the body.
“I am encouraged by pharmaceutical company efforts directed at ALK2, the central target of FOP,” stated Dr. Frederick Kaplan, the Isaac & Rose Nassau Professor of Orthopedic Molecular Medicine and co-director of The Center for Research in FOP & Related Disorders at the Perelman School of Medicine of the University of Pennsylvania.
Kaplan and his colleagues at the University of Pennsylvania have clearly established that an activating mutation in the ALK2 (activin receptor-like kinase-2) enzyme is seen in all cases of FOP and is necessary for the disease to occur. When BioCryst—which specializes in structure-based, small-molecule drug design—targeted FOP, they looked at the ALK2 kinase and built a molecular scaffold that might block access to the mutation.
As its name suggest, FOP is progressive—flare-ups are episodic, but the progression and resulting immobility are cumulative and irreversible. There is no treatment, and no cure. In an article in The Atlantic published in 1998, Kaplan, the world’s leading authority on FOP at the time, explained the disease like this: “These people aren’t just forming little bones here and there. They are forming a whole extra skeleton. You never see the stomach turn into the small intestine. But here you see what seems to be perfectly normal muscle turn into perfectly normal bone. Normal bone. It looks normal on X-ray and under the microscope. It behaves like normal bone—if it bears weight, it gets denser, and if it doesn’t bear weight, it becomes osteoporotic. If you break it, it heals, just like a normal fracture. It even contains marrow. It’s normal in every way except one: it shouldn’t be there.”
But that may change thanks to the work of small-molecule researchers at BioCryst. They are exploring ALK2 inhibitors, with two potential lead candidates in nonclinical development. Preliminary results show promise for the possibility of the orally administered kinase inhibitor. The two lead candidate molecules dramatically reduced progressive formation of bone in soft tissues, also known as heterotopic ossification (HO) in laboratory rats, with up to 89-percent reduction in volume of HO compared to controls.
Tests indicate that the potential therapeutic is able to hit its target—it can be successfully absorbed into the blood and further absorbed into cells. The lead candidates for the inhibitor are currently being tested in accordance with regulatory requirements for proof of shape, potency, strength, exposure response and purity. Following testing on transgenic mice, the company expects to complete IND-enabling manufacturing and nonclinical safety studies to support Phase 1 trials beginning in 2019.
“We are thrilled that our drug discovery culture has succeeded in bringing forward attractive oral ALK2 inhibitors that have the potential to treat patients with FOP,” said Dr. William P. Sheridan, BioCryst’s senior vice president and chief medical officer. “At BioCryst, we constantly strive to create medicines that not only treat serious rare diseases, but do so in a way that retains the best quality of life possible for patients and, ultimately, their families and caregivers as well. We expect our core integrated drug discovery capabilities, refined over years of research and applied in new ways, to impact the BioCryst pipeline in an accelerating fashion in coming periods.”
BioCryst’s search for a successful drug to treat FOP has been underway for less than three years, and they are making speedy progress for structure-based drug design. Based on what Sheridan calls “not just science, but an art form,” the leading candidates are meeting industry assay standards and are ready for the next phase of clinical development. The hope is that the successful drug can be used to prevent the mutation that causes FOP, both as a daily prophylactic to prevent HO growth, and as a short course to be taken following traumas that can cause a flare-up.

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