Possible FOP therapy shines in preclinical study

BLU-782 offers hope for patients with difficult-to-target genetic disease that turns muscle to bone

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CAMBRIDGE, Mass.—Blueprint Medicines presented promising preclinical proof-of-concept data for its investigational therapy designed to target mutant activin-like kinase 2 (ALK2)—the underlying cause of fibrodysplasia ossificans progressiva (FOP)—at the 2018 American Society for Bone and Mineral Research (ASBMR) Annual Meeting in Quebec, Canada, on Sept. 30. The investigational compound, BLU-782, showed in preclinical studies in a genetically accurate FOP model to prevent injury- and surgery-induced heterotopic ossification, reduce edema and restore healthy tissue response to muscle injury.
Blueprint Medicines, which specializes in the development of targeted kinase medicines for patients with genomically defined diseases, is developing BLU-782 as an oral precision therapy for patients with FOP, a rare genetic disease that causes the abnormal transformation of skeletal muscle, ligaments and tendons into bone. There is currently no approved therapy for the disease.
“Although the FOP gene was discovered more than a decade ago, efforts to develop a selective ALK2 inhibitor faltered due to technical challenges,” says Dr. Marion Dorsch, Blueprint Medicine’s chief scientific officer. “Specifically, it proved difficult to selectively target ALK2 without inhibiting other members of the ALK family, including ALK1, ALK3 and ALK6, which have the potential to drive off-target toxicity.”
In the preclinical studies, BLU-782 demonstrated exquisite selectivity for R206H mutant ALK2 in cellular assays while, importantly, sparing closely related anti-targets ALK1, ALK3 and ALK6. Additionally, BLU-782 potently inhibited mutant ALK2 in vitro, regardless of the activating ligand, including activin A, activin B and BMP6. In-vivo studies in a conditional knock-in ALK2R206H transgenic mouse model showed BLU-782 prevented the formation of injury-induced heterotopic ossification and edema, restored a healthy response to tissue injury—including skeletal myofiber regeneration—and prevented the formation of surgery-induced heterotopic ossification following fibular osteotomy surgery.
The company sees the promising preclinical results as a credit to its scientific platform, including the proprietary compound library that serves as its centerpiece, from which BLU-782 was derived.
“The library includes novel chemical matter developed by Blueprint Medicines that has been fully annotated against the human kinome,” says Dorsch. “With the library, we are able to take a kinase disease target—such as ALK2—and identify selective starting points. With these starting points, we then optimize drug candidates with structure-based medicinal chemistry. With this approach, we aim to rapidly and reproducibly develop highly selective drug candidates. BLU-782 is the embodiment of our approach.”
According to Dorsch, Blueprint Medicines' portfolio strategy focuses on using their scientific platform to develop targeted and potent kinase medicines in three areas: genomically defined cancers, rare diseases and cancer immunotherapy.
“BLU-782 is a cornerstone program within our rare disease focus area,” she remarks. “Importantly, BLU-782 also highlights the power of our scientific platform, and our unique ability to design highly selective therapeutic candidates for difficult-to-drug disease targets.”
FOP is a devastating rare genetic disease caused by mutations in the ACVR1 gene, which encodes the protein kinase ALK2. Mutant ALK2 causes damaged soft tissue—such as skeletal muscle, ligaments and tendons—to regrow as bone. Beginning in childhood, disease manifestations include painful flare-ups in the form of tumor-like swellings, abnormal bone formation and locking of joints, progressive loss of mobility, and respiratory dysfunction. Premature death typically occurs in middle age due to cardiorespiratory complications. There are no approved therapies for FOP, and the current standard of care—typically corticosteroids and pain medications—generally focuses on the alleviation of symptoms associated with disease flare-ups.
“We currently estimate a prevalence of about 1,100 patients in major geographies, including the United States, EU5 countries and Japan,” notes Dorsch. “In addition, we continue to evaluate emerging data characterizing FOP epidemiology. For example, recently published independent data from a French registry estimated a prevalence of 1.36 per million inhabitants.” (Baujat, et al. Orphanet Journal of Rare Diseases, 2017.)
Blueprint Medicines owns worldwide development and commercialization rights for BLU-782. The company plans to submit an Investigational New Drug application for the compound to the U.S. Food and Drug Administration by the end of 2018. If approved, Blueprint Medicines is prepared to proceed with a Phase 1 trial.
“We plan to initiate a Phase 1 clinical trial of BLU-782 in healthy volunteers in the first quarter of 2019,” says Dorsch. “Our goal is to advance BLU-782 into a Phase 2 clinical trial in patients with FOP, though we have not yet guided to when this trial may be initiated.”

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