Rho kinase (ROCK) signal transduction pathways are implicated in the development of fibrosis. Inhibition of the ROCK isoforms, ROCK1 and ROCK2, has shown promise in fibrosis; however, ROCK1 inhibition has been associated with inducing hypotension. Recent scientific work using specific genetic or pharmacological inhibition of ROCK2 indicates ROCK2 inhibition alone can result in anti-fibrotic activity without causing hypotension. These findings informed our strategy to develop ROCK2-specific inhibitors as a potential treatment of fibrosis.
Dual ROCK1/2 inhibitors have been shown to have problematic side effects including hypotension and vascular permeability. However, in vivo studies demonstrate our lead compound has more than five hundred-fold selectivity for ROCK2 versus ROCK1. We believe high selectivity for ROCK2 could translate into a product candidate with enhanced tolerability that may support long-term systemic use.
The initial focus for our ROCK2 program is expected to be on fibrotic indications such as chronic kidney disease, IPF and nonalcoholic steatohepatitis (NASH). Given the heterogeneity of these diseases, we believe development of this program will benefit from our precision medicine approach and use of established clinical biomarkers.