- Shares in Conatus Pharmaceuticals Inc. slid more than 30% Thursday after the California biotech announced the failure of a Phase 2b proof-of-concept study testing its experimental drug emricasan in liver transplant patients with fibrosis or cirrhosis.
- Overall, nearly the same number of patients who received emricasan responded over two years as those given placebo, missing the study's primary endpoint.
- Conatus, however, pointed to an apparent benefit to treatment in a subgroup of patients with advanced fibrosis. The company also said the experience using biopsy-based testing of fibrosis stabilization in the study would help in other development of emricasan as a treatment for non-alcoholic steatohepatitis (NASH).
Progressive liver fibrosis remains a major problem for patients with recurrent hepatitis C (HCV) after liver transplantation, as the livers of these patients are in a perpetual state of wound-healing. The abnormal reparative response leads to chronic inflammation and replacement of functional liver tissue with scar tissue. Even if HCV infection is eliminated (thanks to many of the improved antiviral medications on the market), the fibrosis or cirrhosis can remain in transplanted livers — and this damage can continue to progress over time.
This continuous damage served as a rationale for a Phase 2b trial of Conatus' lead compound emricasan, a pan-caspase inhibitor, according to a presentation from the company.
The experimental drug is being tested for its ability to resolve this type of liver damage and for its disease-modifying potential. Conatus' rationale is that emricasan could potentially reduce the enzymes that mediate inflammation and apoptosis, thereby reducing the effects of residual fibrosis.
Results from the POLT-HCV-SVR study included data from 51 patients who had developed HCV post-transplant, and still showed evidence of fibrosis or incomplete cirrhosis upon liver biopsy despite antiviral treatment. Conatus compared the change from patients' baseline Ishak Fibrosis scores after two years of treatment with either emricasan or placebo.
Across all patients randomized, 77% of those on emricasan responded to treatment compared to 75% who experienced a response on placebo.
While the study failed, the company highlighted what it sees as a silver lining worthy of further evaluation. Emricasan showed evidence of an anti-fibrotic effect in patients with advanced fibrosis or early cirrhosis, with 19 of 20 patients in the treatment arm achieving responses after two years compared with seven of 12 on placebo.
"With two-year dosing in an immunosuppressed patient population, this trial also significantly expands our safety database, basically doubling our total patient years of drug exposure," CEO Steve Mento said in a March 7 fourth-quarter earnings call
Though looking at patient tissue post-treatment could be an informative indicator of efficacy in subsequent trials, biopsies are quite invasive, which the company acknowledged in its statement.
Investors weren't impressed with the results, however, pushing shares in Conatus down sharply.
Three other studies of emricasan in NASH, conducted in partnership with Novartis AG, are considered more important for the company. Conatus expects readouts of those trials within the next two years, which could support advancement of those candidate to Phase 3 trials.