Enanta's NASH drug barely meets main goal in mid-stage study
A platoon of drug developers big and small has long been working on combating NASH, a fatty liver disease that has ravaged the developed world. On Wednesday, Enanta Pharmaceuticals unveiled data from a short mid-stage study which suggested its liver drug had — by a minuscule margin — met the main goal in NASH patients.
The drug, EDP-305, is a Farnesoid X Receptor (FXR) agonist, akin to Intercept’s $ICPT obeticholic acid, which produced mixed data in a landmark phase III study. FXR is a nuclear receptor and a crucial regulator of bile acid levels in the liver and small intestine.
In the 12-week ARGON-1 trial, EDP-305 was tested against a placebo. The main goal was to assess the change in ALT levels (when the liver is damaged, ALT levels are elevated) as well as safety and tolerability.
EDP-305 conferred a statistically significant reduction of 28 units per liter (U/L) in ALT levels, versus 15 U/L for the placebo arm at week 12. However, the p-value just about made the cut at 0.049.
Key secondary goals, including a change in liver fat content and lipids, were also met, the company said.
Despite the barely-there main goal win, Enanta’s lead study investigator offered his vote of confidence on the experimental drug.
“Based on data from ARGON-1, EDP-305 clearly displays enhanced efficacy over other second-generation FXR agonists currently in development,” said Vlad Ratziu, the principal investigator of the study, in a statement.
But Baird’s Brian Skorney wasn’t impressed. “Although there are some numerical differences across the major parameters used as a basis of comparison, the modest differences are likely to be just noise,” he said.
“Further development of EDP-305 has questionable value, in our view, as the likely outcome is that it winds up having a clinical profile that mirrors OCA in NASH, which is almost a decade ahead.”
Shares of the Watertown, Massachusetts-based Enanta $ENTA slipped more than 10% to $64 in Thursday premarket trading.
As for EDP-305’s safety profile, pruritus (severe itching) emerged as the primary issue in the Phase II trial — the side-effect also caused pause in Intercept’s trials.
The majority of adverse events seen in the EDP-305 arm were pruritus, GI-related symptoms as well as headaches and dizziness. The incidence of pruritus appeared dose-related, with 51% of the subjects in the 2.5 mg arm compared to less than 10% in the 1 mg arm — which contributed to discontinuations of 20.8% in the higher dose arm, and 1.8% in the lower dose.
“This is the data point that gives us the greatest concern as we believe it is OCA’s biggest commercial liability,” Skorney added.
“However, EDP-305 appeared to cause pruritus at a higher rate than OCA. OCA had a pruritis rate of 23% in FLINT vs. 47% of patients in the high dose of ARGON1. REGENERATE had a 51% rate of pruritis for OCA but the placebo rate was 19% vs. 4% and 6% for ARGON1 and FLINT, respectively,” he said.
The company is now planning on initiating a 72-week Phase IIb study — ARGON-2 — in the first half of 2020, Enanta chief Jay Luly said.
Non-alcoholic steatohepatitis, or NASH, is characterized by a buildup of excess fat in the liver that induces chronic inflammation and eventually culminates in scarring that can lead to cirrhosis, liver failure, cancer and death. Dubbed the silent disease, it is hard to diagnose in the early stages, making it difficult to estimate its prevalence, but studies show that it afflicts up to 12% of the adult population in developed countries. Although there are no approved drugs for the disease, the size of the NASH market is expected to cross $20 billion by 2025.
While other major NASH contenders — Gilead $GILD (fail in Phase III) and Intercept $ICPT (mixed win in Phase III) — have disclosed the top-line numbers of their late-stage trials, Genfit $GNFT is expected to come out with its Phase III interim results by early 2020.
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