Intercept Makes No Changes To Ocaliva NASH Study Despite PBC Safety Issues

Attempting to stem a significant downturn in its share price, Intercept Pharmaceuticals Inc. told an investor call Sept. 25 that its Phase III REGENERATE study of Ocaliva in non-alcoholic steatohepatitis will continue unaltered despite recent safety concerns about the drug in its already approved indication of primary biliary cholangitis (PBC).

Over a two-day period last week, Intercept’s stock price decreased 38% from $98.59 to $61.59 as US FDA issued a safety communication outlining 19 patient deaths and 11 serious liver injuries in patients receiving Ocaliva (obeticholic acid) for PBC. (Also see "FDA Warning On Ocaliva Puts Intercept's NASH Opportunity In Jeopardy" - Scrip, 22 Sep, 2017.) On the conference call, Intercept CEO Mark Pruzanski said the data monitoring safety board for the pivotal REGENERATE trial recommended that the study continue unchanged – apparently providing some relief to investors, as the firm’s stock finished trading Sept. 25 down less than 1% to $61.23.

Pruzanski told the call that Intercept is working with FDA on labeling changes for Ocaliva, possibly to include a boxed warning, to stress the importance of proper dosing. Seven of the 19 reported deaths were determined to be related to significantly higher dosing than recommended by the drug’s labeling for PBC patients with advanced disease. In the meantime, Intercept is investigating whether serious liver injuries reported in five patients with less-advanced PBC are drug-related.

The executive sought to assure analysts and investors that Ocaliva remains on track to produce interim Phase III data in NASH in early 2019, an important milestone as Ocaliva is considered ahead of the pack of four drugs that have begun pivotal studies for the unmet medical need. (Also see "Intercept's Revised NASH Trial Improves Prospects" - Pink Sheet, 13 Feb, 2017.) Genfit SA, Gilead Sciences Inc. and Allergan PLC also are conducting Phase III studies in NASH, whose projected annual market could reach $30bn, according to Morningstar research.

“We reiterate our previous guidance,” Pruzanski said. “We plan to initiate our NASH cirrhosis trial this half and details are forthcoming. In our flagship REGENERATE trial, we currently have more than 1,300 patients enrolled, and we continue to guide the data from interim analysis in the first half of 2019.”

Asked how often the data safety monitoring board reviews the REGENERATE trial, he declined to offer much in the way of specifics. “As is true in any such clinical trial, the DSMC has a regular meeting schedule, also meets as needed at and I can't comment beyond that,” Pruzanski told the call. “In a trial like REGENERATE, and again this is true of any clinical trial, there are various stopping rules based on adverse events that emerge.”

Since adverse event reports began emerging related to Ocaliva, many analysts have stated that the risks of liver damage in sicker PBC patients were well understood and asserted that issues in that disease presented little or no read-through to development in NASH. Some have pointed out, however, that many of the safety issues seen in PBC are related to over-dosing, and NASH uses higher dosing. The PBC label guides to a maximum of 10 mg twice-weekly for advanced PBC patients, while in REGENERATE Intercept is testing 10 mg and 25 mg daily doses of the drug.

Analyst Alethia Young of Credit Suisse noted that PBC is a disease featuring impaired bile flow (cholestasis), which means high dosing of Ocaliva can result in increased liver enzymes, while most NASH patients are non-cholestatic. Saying that NASH and PBC are “different diseases fundamentally,” the analyst said Sept. 25 that “we think that any risk might be centralized around patients with cholestasis, which is a small group; we think that hepatic safety should be considered separately for the two diseases.”

Somewhat more concerned, however, was Joseph Schwartz of Leerink Partners. In his Sept. 25 note, he lowered the probability of regulatory success for Ocaliva in NASH, suggesting that FDA might await final data from REGENERATE rather than considering approval based on interim data expected in early 2019. Such a decision by FDA potentially could delay Ocaliva approval by several years, giving the three other candidates in Phase III (and possibly others) a chance to jump the line. (Also see "Genfit Says Safety/Tolerability Will Give Elafibranor An Edge In NASH" - Scrip, 15 Dec, 2016.)

Kelsey Tsai of Morningstar wrote Sept. 25 that Intercept currently is ahead of Genfit by an estimated six months, while Gilead and Allergan are expected to struggle with enrolling their Phase III trials because of patient/clinician hesitancy to participate in studies requiring one or more liver biopsies. (Also see "Genfit's Enrollment Delay In NASH May Aid Intercept's First-To-Market Goal" - Scrip, 25 Apr, 2017.) Apparently, Tsai does not expect the PBC safety issues to diminish Intercept’s clinical development lead, as he wrote “we do not believe there is enough evidence to justify a read-through of Ocaliva’s PBC issues to the NASH program.”