Little Conatus’ Novartis-partnered liver drug is one step closer to the scrap heap, with its third mid-stage failure.
The Swiss drugmaker handed the San Diego-based biotech $50 million upfront and an injection of confidence in late 2016 to license the drug, emricasan. Since then, it has flopped in a trifecta of studies. Another Phase II study is expected to readout later this year.
The 318-patient trial, dubbed ENCORE-NF, was testing two doses (5 mg, 50 mg) of the drug against a placebo in biopsy-confirmed NASH and liver fibrosis patients. Emricasan missed the primary endpoint of improving fibrosis by ≥1 on the validated Clinical Research Network (CRN) stage system, with no worsening of steatohepatitis compared to placebo at week 72, the company said late Thursday.
In a separate filing, Conatus provided a little more trial detail. The response rates in the 5 mg emricasan, 50 mg emricasan and placebo treatment groups were 11.2%, 12.3% and 19.0%, respectively. Statistically significant reductions were observed in ALT (elevated levels of this enzyme indicates a liver in distress) and Caspase 3/7 (enzymes that play essential roles in programmed cell death) in the 5 mg and 50 mg emricasan treatment groups.
The company’s shares $CNAT more than halved pre-market on Friday to $1.43.
Akin to the previous failures, Conatus’ CEO played it cool, suggesting the drug could still work in patients with NASH, which is typically associated with obesity and diabetes and is set to eclipse hepatitis C as the leading reason for liver transplants by 2020.
“Although emricasan did not have the desired effect in these earlier-stage NASH fibrosis patients, we believe its demonstrated biomarker activity across a broad spectrum of liver disease warrants continued evaluation in more advanced-stage NASH cirrhosis patients,” chief Steven Mento said in a statement, adding that the company would await additional data readouts later this year before determining the next steps for the emricasan program with Novartis.
Stifel’s Stephen Willey did not buy what Conatus was selling. “The failure…further limits our ability to generate any lingering enthusiasm for remaining full year 2019 milestones.”
“The limited efficacy details provided by management actually suggested a directional detriment in emricasan-treated patients…the lack of any clinical consequences associated with these benefits is consistent with every other emricasan study reported to date.”
Last April, emricasan failed its first Phase II trial, involving liver transplant patients with fibrosis or cirrhosis. In December, the drug failed to impress in a second study (dubbed ENCORE-PH), involving NASH cirrhosis patients — whose livers were coping with the damage and still able to perform important functions, but were at high risk for decompensation.
Willey predicted the Phase IIb ENCORE-LF trial, slated for readout in mid-2019 and involving decompensated NASH patients, is also doomed to fail, given that the 5/25mg emricasan doses given in ENCORE-PH actually resulted in worsening of symptoms in patients with baseline decompensated cirrhosis.
“(T)he only emricasan dose within ENCORE-PH to suggest an incremental benefit in decompensated patients was the 50mg dose – which isn’t even being evaluated in ENCORE-LF. We also believe ENCORE-LF-eligible patients represent a very difficult-to-treat population of patients in whom the nature and rate of events are often both difficult to predict and uncorrelated to supportive care therapy – making the achievement of a statistical win in this setting an even more-challenging endeavor.”
NASH — 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 — is a high risk-reward disease that has attracted a plethora of drugmakers big and small, and researchers expect it will take a cocktail of new drugs to truly defeat the disease.
Intercept $ICPT in February reported that a pivotal late-stage study testing its OCA treatment hit a highly statistically significant score on an improvement in liver fibrosis without any worsening of NASH, but missed the endpoint for NASH resolution without worsening of fibrosis. Gilead $GILD, meanwhile, experienced a major setback after its NASH drug selonsertib failed its Phase III. France’s Genfit is expected to offer its key NASH readout later this year.
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