INTEGRIS-PSC trial - J of Hepatology -Jan.26

The INTEGRIS-PSC trial, as described in the Journal of Hepatology on January 26, is a phase II clinical study investigating the safety, tolerability, and exploratory pharmacodynamics of bexotegrast (PLN-74809), an oral, once-daily dual selective inhibitor of αvβ6 and αvβ1 integrins, in participants with primary sclerosing cholangitis (PSC) and liver fibrosis. Below is a detailed breakdown of the problem statement, the investigational drug, and the conclusions:

What is Bexotegrast?

Bexotegrast (PLN-74809) is a novel, oral, once-daily medication that selectively inhibits αvβ6 and αvβ1 integrins. These integrins play a critical role in activating transforming growth factor-β (TGF-β) signaling pathways, which are implicated in the development and progression of liver fibrosis. By targeting these integrins, bexotegrast aims to reduce the activation of TGF-β, thereby potentially halting or reversing liver fibrosis in conditions like PSC.

Problem Statement

Primary sclerosing cholangitis (PSC) is a rare, chronic, and progressive cholestatic liver disease of unknown etiology. It is characterized by inflammation and fibrosis of the bile ducts, leading to liver damage and, ultimately, liver failure. Currently, there are no approved therapies to effectively halt or reverse the progression of PSC. This creates an urgent unmet medical need for safe and effective treatments that can address the fibrosis and other pathological processes associated with PSC.

Study Design

The INTEGRIS-PSC trial was a randomized, double-blind, dose-ranging phase II study that enrolled 117 participants with PSC and suspected liver fibrosis. Participants were randomized to receive bexotegrast (at doses of 40 mg, 80 mg, 160 mg, or 320 mg) or placebo for varying durations (12 to 40 weeks). The primary endpoint was the incidence of treatment-emergent adverse events (TEAEs), while exploratory pharmacodynamic endpoints included biomarkers of fibrosis (e.g., ELF score, PRO-C3), liver stiffness measurements, and imaging parameters.

Key Findings

1. Safety and Tolerability:

• Bexotegrast was well tolerated across all dose levels (up to 320 mg daily for 40 weeks).
• The incidence of treatment-emergent adverse events (TEAEs) was similar between the bexotegrast (72.7%) and placebo (70.0%) groups.
• TEAEs were mild to moderate, with no serious adverse events attributed to the study drug.

2. Pharmacodynamic Outcomes:

• Participants receiving bexotegrast showed numerically less progression in exploratory pharmacodynamic markers (e.g., ELF score, PRO-C3 levels, MRI-based liver assessments) compared to placebo at Week 12.
• Improvements in MRI parameters continued through Week 24, indicating potential ongoing benefits of the drug.

Conclusion

The INTEGRIS-PSC trial demonstrated that bexotegrast is safe and well tolerated in participants with PSC and liver fibrosis, with no serious drug-related adverse events reported. Additionally, the drug was associated with less progression in exploratory pharmacodynamic markers of fibrosis and liver health compared to placebo. These findings support the hypothesis that targeting integrin-mediated TGF-β activation could be a promising therapeutic strategy for PSC.

Impact and Implications

This study provides early evidence for the safety and potential efficacy of bexotegrast in PSC, addressing a critical unmet need for therapies capable of halting or reversing the progression of this debilitating disease. Future studies are warranted to further evaluate the long-term efficacy and clinical benefits of bexotegrast in PSC.