Blueprint Medicines Corporation, a leader in discovering and developing targeted kinase medicines for patients with genomically defined diseases, today announced preclinical proof-of-concept data for BLU-782, an investigational oral precision therapy specifically designed to target mutant activin-like kinase 2, the underlying cause of fibrodysplasia ossificans progressiva. Preclinical studies in a well-characterized, genetically accurate FOP model showed BLU-782 prevented injury- and surgery-induced heterotopic ossification, reduced edema and restored healthy tissue response to muscle injury. The data were presented on September 30 in a plenary oral session at the 2018 American Society for Bone and Mineral Research Annual Meeting in Quebec, Canada.
“We are excited to report preclinical proof-of-concept data for BLU-782, a highly selective oral inhibitor of mutant ALK2, the underlying cause of FOP,” said Marion Dorsch, Ph.D., Chief Scientific Officer of Blueprint Medicines. “Despite the discovery of the FOP gene more than a decade ago, prior efforts to develop a selective ALK2 inhibitor faltered due to persistent technical challenges. By leveraging our proprietary compound library and expertise in structure-guided medicinal chemistry, we overcame these challenges and successfully designed BLU-782 to selectively target mutant ALK2. The new preclinical data reported at the ASBMR Annual Meeting showed BLU-782 prevented abnormal bone growth in a well-characterized FOP model, validating selective ALK2 inhibition as an important potential therapeutic strategy.”
FOP is a rare genetic disorder characterized by the abnormal transformation of skeletal muscle, ligaments and tendons into bone, either spontaneously or as the result of physical trauma. FOP is caused by a mutation in the gene for ALK2, which is known as ACVR1, that causes hypersensitivity to certain bone morphogenetic proteins (BMP) and a neomorphic response to activins.
In the preclinical data presented at the ASBMR meeting, BLU-782 demonstrated exquisite selectivity for R206H mutant ALK2 in cellular assays, while sparing closely related anti-targets including 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 HO and edema, as measured by micro computed tomography and magnetic resonance imaging. Immunohistochemistry analyses also showed restoration of a healthy response to tissue injury in ALK2R206H mice, including skeletal myofiber regeneration. In addition, BLU-782 prevented the formation of surgery-induced HO following fibular osteotomy surgery in ALK2R206H mice.
“Given the disabling and destructive nature of this disease, people living with FOP have a desperate need for a safe and effective treatment,” said Adam Sherman, Research Development and Partnerships Director at the International Fibrodysplasia Ossificans Progressiva Association. “We are immensely grateful to have companies like Blueprint Medicines developing new treatments for those living with FOP. We look forward to seeing BLU-782 advance through the development pathway and hope a therapeutic option will one day change the course of this disease.”
Blueprint Medicines expects to submit an investigational new drug (IND) application for BLU-782 by the end of 2018, and subject to approval of the IND application by the U.S. Food and Drug Administration, plans to initiate a Phase 1 clinical trial in healthy volunteers in the first quarter of 2019. In addition, Blueprint Medicines plans to continue working with clinical experts and the patient community to design a potential Phase 2 clinical trial of BLU-782 in patients with FOP.
Source: Blueprint Medicines