Garetosmab

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of episodic, progressive heterotropic ossification. Approximately 97% of FOP patients share the same c.617G > A; R206H mutation in the ACVR1 gene encoding a type I TGFβ/BMP family ligand-receptor that binds BMPs to signal through Smad1/5/8. This mutation is predicted to destabilize the intracellular glycine-serine (GS) activation domain. Activin A signals typically through a complex of the type I receptor ACVR1B and one of the type II receptors ACVR2A, ACVR2B, or BMPR2 that interfaces with Smad2/3. However, Activin A can also form a non-signalling complex (NSC) together with ACVR1 that sequesters both the ligand and cognate receptors resulting in an apparent inhibition of ACVR1-mediated BMP signalling.

Surprisingly, the R206H ACVR1 mutation confers signalling sensitivity to the Activin A-ACVR1-type II receptor NSC, causing aberrant activation of Smad1/5/8 pathways and ossification of FOP lesions. At the same time, the mutant ACVR1 receptor retains its ability to signal through BMPs. Garetosmab is a human IgG4κ antibody specific for Activin A. By inhibiting Activin A signalling through the mutant R206H receptor, garetosmab will likely improve the course of heterotropic ossification in FOP while not interfering with normal TGFβ/BMP family functions.