PLN-1474 is an oral, small-molecule selective inhibitor of αvβ1; in development for treatment of stage F3/F4 liver fibrosis associated with nonalcoholic steatohepatitis, or NASH.
NASH is a more severe form of non-alcoholic fatty liver disease, or NAFLD. NASH is highly prevalent, affecting approximately 16.5 million adults in the United States, including approximately 3.3 million with stage F3/F4 fibrosis. The stage of fibrosis is the strongest predictor of liver-related morbidity and all-cause mortality in NASH. Patients with F3 and F4 fibrosis carry liver-related mortality risk that is 17 times and 42 times greater, respectively, than NASH patients without fibrosis. Therefore, we believe that treating F3/F4 liver fibrosis will have an impact on liver-related morbidity and all-cause mortality in NASH.
Integrin αvβ1 serves as an activator of TGF-ß and its expression has been shown to be upregulated in activated hepatic stellate cells and correlated with severity of liver fibrosis. By inhibiting αvβ1, we believe PLN-1474 could have a potent direct antifibrotic effect in advanced liver fibrosis.
- Proven mechanism in NASH/liver fibrosis
- In a Phase 1 study, PLN-1474 was rapidly absorbed and well tolerated with no dose- or treatment-limiting toxicities or severe/serious adverse events observed
- Preclinical activity in animal models of NASH-fibrosis (CCl4 – CDA-HFD)
- Potent antifibrotic effect observed in live human NASH liver tissue
- Favorable drug properties and pharmacokinetics
- Orally bioavailable with preclinical PK suggesting BID or better oral dosing
- Highly potent and highly selective: >100-fold αvβ1 selectivity vs. other integrins
- PLN-1474 is a Phase-2 ready program
- In March 2021, Pliant announced the successful completion of a Phase 1 healthy volunteer trial
- In February 2023, Novartis, as part of a global reorganization, returned the rights to PLN-1474 to Pliant