Pliant Therapeutics, Inc. announced positive data from INTEGRIS-PSC, a Phase 2a clinical trial of bexotegrast in patients with primary sclerosing cholangitis (PSC) and suspected moderate to severe liver fibrosis. The trial met its primary and secondary endpoints demonstrating that bexotegrast was well tolerated over a 12-week treatment period and its plasma concentrations increased with dose. The trial?s exploratory efficacy endpoints assessed changes in the liver fibrosis markers, Enhanced Liver Fibrosis (ELF) score and PRO-C3 levels, as well as liver biochemistry and magnetic resonance imaging (MRI) of the liver.

Results at the initial three doses tested showed bexotegrast reduced both ELF scores and PRO-C3 levels at Week 12 at all doses relative to placebo with statistically significant differences at the 160 mg dose relative to placebo at Week 12. Patients also showed stabilization of liver chemistry, including a dose-dependent trend in reduction of alkaline phosphatase (ALP) levels, relative to placebo at Week 12. In addition, preliminary MRI imaging results suggest improved hepatocyte function and bile flow with bexotegrast 160 mg.

Twelve-week interim data from the high-dose 320 mg cohort is expected in the first quarter of 2024. INTEGRIS-PSC is a multinational, randomized, dose-ranging, double-blind, placebo-controlled Phase 2a trial evaluating bexotegrast at once-daily doses of 40 mg, 80 mg, 160 mg or placebo for 12 weeks in 85 patients with PSC. 64 patients were enrolled in the active arms and 21 patients were enrolled in the placebo arm.

the company believe INTEGRIS-PSC to be the first randomized clinical trial to use an enrichment strategy to enroll patients with suspected moderate to severe liver fibrosis based on liver stiffness measure, ELF score or historical liver biopsy. Baseline characteristics of the trial population reflected this enrichment. The primary endpoint of the INTEGRIS-PSC trial is the evaluation of the safety and tolerability of bexotegrast.

The secondary endpoint is an assessment of its pharmacokinetics. Bexotegrast was well tolerated at all three doses tested. Of the 64 patients treated with bexotegrast, 60 (94%) completed 12 weeks of treatment with no deaths or drug-related severe or serious adverse events (SAE).

Most treatment emergent adverse events (TEAEs) were mild or moderate in severity and consistent with PSC disease symptoms. Patients in the trial who had concomitant inflammatory bowel disease (IBD) saw no change in their IBD symptoms as measured by partial Mayo Score while on treatment. Bexotegrast total and unbound plasma concentrations increased with dose. A treatment effect was observed on ELF score in all bexotegrast dose groups.

The ELF score is a well-established prognostic marker of liver disease severity and liver-related events in patients with advanced fibrosis. ELF is strongly associated with transplant-free survival in PSC and may be useful as a surrogate marker in clinical trials. Bexotegrast reduced ELF scores relative to placebo at all doses, with a statistical significance achieved at the 160 mg dose.

The bexotegrast 160 mg dose group demonstrated an 84% reduction of the change in ELF score relative to placebo at Week 12. Importantly, at the 160 mg dose group, statistically significant reductions were observed across all three components of the ELF score (tissue inhibitor of metalloproteinase 1 (TIMP-1), procollagen III N-terminal propeptide (PIIINP) and hyaluronic acid (HA)). Similarly, the bexotegrast 160 mg dose showed a statistically significant reduction in PRO-C3 level relative to placebo at Week 12.

PRO-C3 is a biomarker of active fibrogenesis with higher levels associated with greater disease activity. Patients with PSC tend to have elevated or fluctuating liver biochemistry levels. Patients treated with bexotegrast showed stabilization of liver chemistry levels, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST), as well as total and direct bilirubin, at all doses versus increases in placebo at Week 12.

Additionally, bexotegrast-treated patients with elevated baseline ALP levels (ie, > upper limit of normal) showed a dose-dependent trend in reduction in ALP relative to placebo at Week 12. Preliminary MRI imaging of the liver using gadoxedate contrast showed small increases in MRI relative enhancement from baseline across all dose groups, compared to a decrease observed in the placebo group to Week 12. MRI relative enhancement using gadoxedate contrast is a measure of hepatocyte function, with increased enhancement suggesting improved hepatocyte function.

Similarly, the change in time of arrival of gadoxedate in the common bile duct from baseline to Week 12 was shorter in the bexotegrast arms compared to the placebo group. Time to arrival is a measure of bile flow with shorter times suggestive of improved bile flow. Patients with PSC often experience pruritus, or itch, as part of their disease.

Treatment with bexotegrast demonstrated dose dependent reductions in the Itch Numerical Rating Scale relative to placebo with statistical significance achieved at the 160 mg dose at Week 12.