Cilofexor Fails to Slow Fibrosis Progression in PRIMIS

Key Takeaways

• Cilofexor and placebo showed similar observed rates of week 96 histologic fibrosis progression.
• The randomized phase 3 trial compared cilofexor with placebo in adults with non-cirrhotic large-duct PSC.
• Pruritus was more frequent with cilofexor, while serious adverse events were similar and no treatment-related deaths occurred.

In the phase 3 PRIMIS trial, fibrosis progression at week 96 occurred in 31% of adults with non-cirrhotic large-duct primary sclerosing cholangitis receiving cilofexor and 33% receiving placebo. The prespecified primary endpoint was histologic fibrosis progression on liver biopsy in adults with non-cirrhotic large-duct disease. No separation between groups was seen at the week 96 assessment, and the trial was later stopped early after a planned futility analysis.

PRIMIS was a multicentre phase 3, double-blind, placebo-controlled trial that enrolled adults aged 18 to 75 years with non-cirrhotic, F0 to F3, large-duct PSC. Across 205 sites in 16 countries, participants were randomly assigned 2:1 to cilofexor 100 mg once daily or matching placebo for 96 weeks. Randomisation was stratified by ursodeoxycholic acid use and bridging fibrosis, and participants, study personnel, and outcome assessors remained masked to treatment assignment. A total of 419 participants were randomly assigned, and 416 entered the full and harms analysis sets. The primary endpoint was histologic progression of liver fibrosis, defined as at least a one-stage Ludwig increase at week 96 on liver biopsy.

In the final analysis of the histologic fibrosis endpoint, fibrosis progression occurred in 41 of 133 participants given cilofexor and 21 of 64 given placebo. These rates were 31% and 33%, respectively, for a treatment difference of -1.4 percentage points with a 95% CI of -15.2 to 12.3. The p value was 0.42, and a planned interim futility analysis estimated a 6.8% probability of detecting a significant difference after 160 patients reached week 96. The amended primary analysis used participants in the harms set who had baseline and week 96 biopsy data available. Investigators did not find a statistically significant reduction in histologic fibrosis progression with cilofexor.

Pruritus was the most common adverse event, affecting 136 of 277 participants receiving cilofexor and 50 of 139 receiving placebo. Grade 3 or higher pruritus occurred in 11 participants given cilofexor and one given placebo. COVID-19 was reported in 65 of 277 participants with cilofexor and 26 of 139 with placebo, and upper abdominal pain occurred in 40 and 20. Serious adverse events occurred in 53 of 277 participants with cilofexor and 26 of 139 with placebo, and no treatment-related deaths were reported. Overall, cilofexor was not associated with a significant reduction in histologic fibrosis progression versus placebo during the 96-week trial period in non-cirrhotic large-duct PSC.