- Conatus Pharmaceuticals' lead candidate has failed a trial testing it in the highly competitive area of non-alcoholic steatohepatitis, or NASH, sending shares in the company down almost 50% Thursday morning.
- The Phase 2b ENCORE-PH study enrolled patients with NASH cirrhosis and severe portal hypertension. Treatment with Conatus' drug, called emricasan, led to what the company called a "clinically meaningful" improvement in mean hepatic venous pressure gradient (HVPG), which measures pressure in the vein system that directs blood to and from the liver. The effect, however, fell short of meeting the study's primary endpoint.
- HVPG is quantified in mmHG, or the pressure exerted by a one millimeter vertical column of mercury. Patients with severe portal hypertension have HVPG of 12 mmHG or more. On a Thursday investor call, Conatus leaders said they're still confident in emricasan's prospects given that many of the patients with compensated NASH cirrhosis (which comprised about 75% of the trial's participants) experienced statistically significant HVPG improvements from baseline to Week 24.
Drugmakers are on a mad dash to be first to the NASH market and its millions of estimated patients. Novartis, for one, is trying to catch up to leaders in the space through research collaborations with fellow big pharmas Allergan and Pfizer. In late 2016, the Swiss company also agreed to pay $50 million upfront for an exclusive option to emricasan — though continued setbacks have dimmed the outlook on that deal.
Earlier this year, emricasan failed a Phase 2b study that, while not part of the Novartis deal, didn't help the drug's profile.
The study evaluated emricasan's effects on fibrosis in liver transplant patients with fibrosis or cirrhosis. Though it didn't meet statistical significance in the overall study population, Conatus said the data supported further investigation in patients with advanced fibrosis and early cirrhosis, a subgroup "where the histology endpoint is most relevant," the company argued.
The small pharma pulled a similar move in announcing ENCORE-PH Thursday, highlighting how patients with compensated NASH cirrhosis, meaning they show few to no symptoms, appeared to experience significant benefits from emricasan treatment.
"If we were going to look at this trial again, I think all we would need to do is increase the number of patients in the compensated patient population, and then I think we would see across the board at 12 millimeters of mercury or above improvements that would lead to further studies," Conatus CEO Steven Mento said on the Dec. 6 investor call.
Still, the greatest improvements were seen in patients with baseline HVPG of 16 mmHg or higher — causing some analysts to question why the drug's mechanism of action appears most effective in patients with more severe disease, as well as how these results may affect the ongoing ENCORE-LF study evaluating liver function of patients with decompensated NASH cirrhosis.
"A lot of what we're seeing in the patient populations that have higher baselines at higher numbers is strictly mathematics. It's just simpler to see a percentage difference in patients that have a higher value to start with," Mento said.
"So, for example, with statins it's much easier to see that initial response," he added, "but once you get around the normal level or just above the normal level it really takes you a sledge hammer to get you down a bit more."
Shareholders seem to view the mathematics a bit differently. Shares of Conatus have declined more than 50% year to date.