Palovarotene

The pathogenesis of FOP is driven by a gain-of-function mutation in the ACVR1/ALK2 gene encoding activin A receptor type 1 (ACVR1)/activin-like kinase 2 (ALK2), a bone morphogenetic protein type 1 receptor (BMPR-I). BMP signalling begins with the complexation of BMPR-II and BMPR-I, which initiates an intracellular signalling pathway mediated by phosphorylated SMAD proteins. The sustained and aberrant signalling caused by the gain-of-function mutation in ACVR1/ALK2 results in overactivation of the downstream SMAD1/5/8 signalling pathway, which in turn is thought to trigger the formation of ectopic chondrogenesis, osteogenesis, and joint fusion characteristic of FOP.

Palovarotene is a selective agonist of retinoic acid receptor gamma (RARγ), a receptor expressed in chondrogenic cells and chondrocytes that acts as a transcriptional repressor. In binding to RARγ, palovarotene decreases BMP signalling and subsequently inhibits the SMAD1/5/8 signalling pathway. Palovarotene's interference with these pathways inhibits chondrogenesis and allows for normal muscle tissue repair to take place, ultimately reducing damage to muscle tissue.