The stellar top-line data unveiled in January from Intercept Pharmaceuticals Inc.'s phase IIb obeticholic acid (OCA) trial known as FLINT in nonalcoholic steatohepatitis (NASH) helped the shares to a near 300 percent gain and whetted investor appetite for the full results, but it looks like they'll have to wait longer than next month's annual meeting of the American Academy for the Study of Liver Diseases (AASLD).

New York-based Intercept's oral farnesoid X receptor agonist wowed Wall Street at the start of the year, when a data safety monitoring board found OCA provided a highly statistically significant improvement (p = 0.0024 on an intention-to-treat basis) in the primary histological endpoint: a decrease in the nonalcoholic fatty liver disease activity score of at least two points with no worsening of fibrosis, as compared to placebo. (See BioWorld Today, Jan. 10, 2014.)

Some investors may have been hoping for full outcomes from the study, proposed and designed by the National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK), to turn up at the AASLD meeting, but Intercept said in a press release that the NIDDK is finalizing the manuscript detailing the FLINT results for publication instead. Intercept does plan to provide abstracts from the phase III effort with OCA for primary biliary cirrhosis at the meeting.

A spokesperson for Intercept said the company was unavailable. Leerink Partners analyst Joseph Schwartz predicted the news about FLINT would "likely cause some weakness in the stock today, given that it removes a near-term opportunity for full disclosure on a study that has been extremely high profile and controversial in some respects (e.g., cardiovascular safety)." He predicted that "some investors will now question whether or not the pivotal OCA NASH program can still start in the first half of 2015, as previously expected." Intercept, though, said the phase III effort remains on track.

The company's shares (NASDAQ:ICPT) closed Wednesday at $221.12, down $1.50. On the day of the top-line FLINT data unveiling, shares closed at $275.87. RBC Capital Markets analyst Michael Yee noted the "large pullback since the announcement of 'landmark' NASH data," and wrote in a research report that "the stock already reflects a lot of negative/bearish sentiment and questions." Still, he said, "feedback from key opinion leaders is that the top-line FLINT data look very positive and OCA would be an important and exciting potential treatment for these NASH patients for a multibillion-dollar market opportunity."

NASH is a serious chronic buildup of fat in the liver that can lead to cirrhosis and death. Estimates suggest 2 percent to 5 percent of the U.S. population is afflicted with the severest forms, with 10 percent to 20 percent more having the mostly harmless "fatty liver." If the patient's blood test raises suspicion, a biopsy is done to determine which of those is the case. More than 10 percent of the U.S. population may have some form of NASH, and the worst-off population could make up 6 million patients, more than the market for chronic hepatitis C virus or alcoholic liver disease. The condition is projected to become the leading indication for liver transplant.

Leerink's Schwartz pointed out that investors might see the Intercept picture differently from key opinion leaders, at least for the moment. "While it's encouraging on the surface that Intercept reiterated its phase III timing guidance, we believe some investors may be a bit skeptical given that the top-line results were announced in January 2014 and [the company] still does not have all of the full data," he wrote in his report.

'UNCERTAINTIES, SKEPTICISM'

Intercept "has continuously struggled with the NASH Clinical Research Network [sponsored by the NIDDK] to get access to the full data and subsequently agree upon what it can make public," Schwartz said. But a lot of FLINT data showed up in Intercept's 10-Q filing with the SEC in August, so there may not be much more to learn from the journal publication.

The trial, a double-blind, placebo-controlled experiment, tested once-daily dosing of 25 mg of OCA or placebo given for 72 weeks in 283 patients with biopsy-proven NASH. NIDDK provided to Intercept histological data from the primary intention-to-treat population, composed of the 219 patients who were eligible for a repeat biopsy after completing the 72-week treatment phase of the trial, and nonhistological secondary endpoints from all patients who went on to complete the post-treatment follow-up visit, which took place 24 weeks after the conclusion of the treatment phase.

The proportion of patients meeting the FLINT primary histological endpoint, defined as a decrease in the NAFLD Activity Score (NAS) of at least two points with no worsening of fibrosis, was 46 percent in the OCA treatment group and 21 percent in the placebo treatment group (p < 0.001, n = 219). Subgroup analyses showed a numerically higher response rate in OCA-treated patients with more advanced NASH, as assessed by NAS, fibrosis staging or co-morbid type 2 diabetes, Intercept said. The mean pre-treatment baseline NAS for patients in the OCA treatment group was 5.3 of a total possible score of 8 (comprising hepatocellular ballooning 0 – 2, lobular inflammation 0 – 3 and steatosis 0 – 3).

Intercept acknowledged in the SEC filing that the "NIDDK's decision to stop the FLINT treatment phase early was based primarily on OCA having met the efficacy criterion, while also being informed by the risks involved in continuing to perform liver biopsies in the remaining patients and the available safety data from the trial with respect to disproportionate lipid abnormalities and the occurrence of cardiovascular [CV] events in the OCA treatment arm." Two shareholder lawsuits, which have been consolidated, were disclosed in the filing. They claimed Intercept's January data disclosure was misleading because it did not contain anything about the lipid findings.

In the view of analyst Schwartz, "formal publication of the [FLINT] results in a top-tier, peer-reviewed journal would likely help the stock, as it could resolve some of the uncertainties and skepticism surrounding the protocol and safety data; in particular some wonder how and why CV events (which first showed an 'imbalance' in the OCA group) were later re-adjudicated to find no imbalance between the arms." Getting the results into a peer-reviewed journal could take a while, and is "generally unpredictable," he noted.

Intercept did not comment specifically on how the talks are going with the FDA regarding the pivotal program with OCA in NASH, but Schwartz "look[s] to the start of phase III as an event that can set up a more positive agenda for investors to focus on."