ORF08-02 - Inhibition of Activin A Stops the Regrowth of Surgically Resected Heterotopic Bone in a Mouse Model of Fibrodysplasia Ossificans Progressiva

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by episodic yet cumulative heterotopic ossification (HO) of skeletal muscle, tendons, ligaments, and fascia. The resulting heterotopic bone develops connections to the normal skeleton, resulting in progressive (and irreversible) immobility. The heterotopic bone lesions cannot be resected because surgery is invariably followed by regrowth of the resected lesions and even induction of additional HO. FOP is caused by gain-of-function missense mutations in ACVR1, with the most common variant being ACVR1[R206H]. We have demonstrated that unlike wild type ACVR1, ACVR1[R206H] perceives Activin A as an agonistic ligand. Importantly, inhibition of Activin A using a neutralizing Activin A antibody (garetosmab) blocks the formation of new HO lesions and cause stasis and even regression of pre-existing nascent HO lesions with great efficacy (Hatsell, Idone et al, PMID 26333933; and Upadyhay et al, PMID 28782882). The relevance of these findings for FOP patients was demonstrated in a Phase II clinical trial where garetosmab, blocked the formation of new heterotopic bone lesions with ~90% efficacy (Di Rocco et al; PMID 37770652). However, given that most FOP patients already present with ongoing or existing HO at the time of diagnosis (and given the number of patients with established heterotopic bone lesions that are already connected to the skeleton), there is an interest in developing strategies for effective removal of the heterotopic bone. Hence, we explored whether garetosmab can block the recurrence of HO after surgical excision of pre-existing lesions. Using FOP mice, we demonstrate that whereas surgical excision of heterotopic bone lesions (in the absence of garetosmab) induces explosive growth of the resected lesions as well as nearby lesions, this effect is completely inhibited by garetosmab. Our results not only demonstrate that Activin A remains a key HO-inducing factor even after initiation of HO but also indicate that inhibition of Activin A may enable surgical excision of pre-existing HO lesions while minimizing the chances of recurrence.