This proposal, in response to PAR-17-465 (UG3/UH3), describes a repositioning program for AZD0530, a multi-kinase inhibitor originally developed to target SRC family kinases for the treatment of solid tumors. We found that AZD0530 is an equally potent, nanomolar inhibitor of the BMP type I receptor kinase ACVR1. Dysregulated signaling of ACVR1 via highly conserved gain-of-function mutations of the regulatory domain is known to cause fibrodysplasia ossificans progressiva (FOP), a congenital syndrome in which soft tissues are gradually infiltrated with ectopic bone to cause profound immobility, premature mortality, and severely decreased quality of life. There are no currently approved therapies to prevent heterotopic ossification (HO) of soft tissues in FOP, and thus affected individuals are frequently immobilized by early adulthood. Attempts at surgical treatment to remove bone lesions to restore mobility is almost universally met with recurrence of HO, resulting in rapid loss of any recovered mobility, and often worsened function. We have shown that AZD0530 inhibits the formation of HO in an authentic animal model of FOP, and importantly, inhibits the recurrence of heterotopic bone following surgical excision of bone in this model that would otherwise occur in 100% of animals undergoing surgery. To enable an IND application using AZD0530 as an adjuvant therapy to permit surgical intervention in FOP disease, a preclinical (UG3) Aim 1A of this proposal will determine optimal dosing and duration of treatment for prophylaxis of recurrent HO following surgical excision in the ACVR1R206H knock-in mouse model, and a pre-clinical Aim 1B will test the tolerability of AZD0530 in surgical transdermal and intramuscular wound healing in a mini-pig model. If compatible with surgical wound healing and effective in surgical prophylaxis at doses equivalent to those tolerated in human studies, Aim 2A (UH3) proposes to generate quantitative radiographic data on recurrent HO following surgery in FOP patients in a retrospective study, permitting clinical trial design activities in Aim 2B to design a clinical protocol for a Phase 2 study using AZD0530 to permit surgical treatment and recovery of function in patients severely affected by FOP.
Fibrodysplasia ossificans progressiva (FOP) is a disabling genetic condition that results in the replacement of soft tissues with bone, causing profound immobility, impaired quality of life, and reduced life expectancy. Attempts to remove abnormal bone in FOP to improve mobility are almost always met with the return of bone formation, and often worsening of immobility. Based on promising animal model results, this proposal tests whether an existing experimental drug, AZD0530, that has already been tested for safety in hundreds of human patients, could be effective and safe in suppressing bone formation following surgical removal of bone in patients with FOP, thereby providing a strategy for restoring quality of life and function for a condition that currently has no effective therapies.