FOP is a rare, severely disabling and ultimately life-shortening disease characterized by progressive replacement of skeletal muscle and connective tissue by heterotopic bone. FOP is caused by gain-of-function mutations in ACVR1, which encodes activin receptor-like kinase 2 (ALK2). The most common ALK2 mutation identified in FOP is R206H, but other ALK2 activating mutations exist in FOP, and all impart hypersensitivity to bone morphogenetic protein ligands and a neomorphic response to activins.
BLU-782 is a potent and selective ALK2 inhibitor that has been shown to prevent injury-induced heterotopic ossification (HO) in an ALK2R206H transgenic mouse model of FOP. Here, we describe preclinical data supporting the development of a prophylactic, once-daily dosing scheme for BLU-782 in FOP patients, including those with other activating ALK2 mutations.
To identify the optimal BLU-782 dosing scheme in FOP, we further evaluated the ALK2R206H transgenic mouse model. FOP manifests in this model with a progression from acute muscle degeneration on the day of the injury to a fibroproliferative response by day 4 post-injury, chondrocyte proliferation and cartilage deposition by day 7, a mix of cartilage and bone by day 10 and, lastly, mature bone formation by day 14. By delaying the initiation of BLU-782 dosing for increasing times post-injury, we found that ALK2 inhibition is necessary as early as day 2 post-injury and needs to be maintained up to 12 days post-injury to fully prevent HO formation in this in vivo mouse model. This observation suggests that ALK2R206H is activated shortly after muscle injury, before any detectable signs of a flare, and its activity persists until HO formation matures. Therefore, we recommend the dosing scheme for BLU-782 in the clinic to be once-daily and chronic, such that target coverage (i.e. >IC70 at Cmin) is maintained.
Results of the ongoing Phase 1 safety, tolerability, pharmacokinetics, and food effect trial in healthy adults will be discussed. One of the objectives of this randomized, double-blind, placebo-controlled, single and multiple ascending dose and food effect study is the recommendation of a Phase 2 dose. Blueprint Medicines plans to initiate a single-arm, open-label Phase 2 clinical trial in the fourth quarter of 2019 to evaluate the safety and tolerability of BLU-782 when administered chronically to FOP patients.