First and largest successful pivotal Phase 3 study in patients with liver fibrosis due to NASH
OCA achieves primary endpoint demonstrating statistically significant improvement in liver fibrosis without worsening of NASH at 18 months (p=0.0002)
Intercept intends to file for regulatory approval in the U.S. and Europe in the second half of 2019
Results to be presented at European Association for the Study of the Liver 2019 International Liver Congress
NEW YORK, NY, USA I February 19, 2019 I Intercept Pharmaceuticals, Inc. (Nasdaq:ICPT), a biopharmaceutical company focused on the development and commercialization of novel therapeutics to treat progressive non-viral liver diseases, today announced positive results from its pivotal Phase 3 REGENERATE study of obeticholic acid (OCA) in patients with liver fibrosis due to nonalcoholic steatohepatitis (NASH). In the primary efficacy analysis, once-daily OCA 25 mg met the primary endpoint of fibrosis improvement (≥1 stage) with no worsening of NASH at the planned 18-month interim analysis (p=0.0002 vs. placebo). In the primary efficacy analysis, a numerically greater proportion of patients in both OCA treatment arms compared to placebo achieved the primary endpoint of NASH resolution with no worsening of liver fibrosis, but this did not reach statistical significance. As agreed with the U.S. Food and Drug Administration (FDA), in order for the primary objective to be met, the study was required to achieve one of the two primary endpoints.
“We are thrilled to report the first positive registrational Phase 3 study results in patients with NASH, a devastating disease that is on track to become a leading cause of liver transplant in coming years,” said Mark Pruzanski, M.D., President and Chief Executive Officer of Intercept. “The topline REGENERATE data we are reporting today support our belief that OCA will become the first approved medicine for those living with liver fibrosis due to NASH. We are deeply grateful to the patients, investigators and study staff whose ongoing participation in REGENERATE has brought us one step closer to delivering a much-needed therapeutic option to address the enormous unmet medical need in this population.”
Based on these results, Intercept intends to file for approval in the U.S. and Europe in the second half of 2019. OCA remains the only investigational drug to have received Breakthrough Therapy designation from the FDA for NASH with fibrosis. REGENERATE results will be presented at the European Association for the Study of the Liver (EASL): The International Liver CongressTM 2019.
“Patients with significant fibrosis due to NASH are at the greatest risk of progression to severe liver-related complications, such as liver failure and death, and fibrosis is considered the strongest predictor of liver-related mortality in this population,” said Zobair M. Younossi, M.D., Professor and Chairman of the Department of Medicine at Inova Fairfax Medical Campus, Professor of Medicine at Virginia Commonwealth University, Inova Campus and the Chair of the REGENERATE Steering Committee. “I am very encouraged by these results that demonstrate OCA’s ability to significantly improve fibrosis in patients with advanced disease. As the first successful pivotal trial in NASH, REGENERATE is an important advancement for the liver community.”
Efficacy Results
The primary efficacy analysis (Intent-to-Treat or ITT) assessed efficacy at 18 months in 931 patients with stage 2 or 3 liver fibrosis due to NASH. Overall study discontinuations in the primary efficacy analysis population were balanced across treatment arms: 16% in placebo, 17% in OCA 10 mg and 15% in OCA 25 mg.
An additional pre-specified full efficacy analysis at 18 months added an exploratory cohort of 287 NASH patients with stage 1 liver fibrosis and additional risk factors who were at increased risk of progression to cirrhosis (N=1,218).
Patients with biopsy proven NASH with fibrosis were randomized 1:1:1 to receive placebo, OCA 10 mg or OCA 25 mg once daily. A repeat biopsy was conducted after 18 months for histologic endpoint assessment. Patients without a repeat biopsy due to study discontinuation or other reason were treated as non-responders in the primary and full efficacy analyses.
Fibrosis Improvement at Month 18
| Primary Efficacy Analysis (ITT population: NASH with stage 2 and 3 liver fibrosis) |
Placebo n=311 |
OCA 10 mg n=312 |
OCA 25 mg n=308 |
| Fibrosis improvement (≥1 stage) with no worsening of NASH* | 11.9% | 17.6% p=0.0446 |
23.1% p=0.0002** |
| Additional Full Efficacy Analysis (ITT population plus stage 1 liver fibrosis patients) | Placebo n=407 |
OCA 10 mg n=407 |
OCA 25 mg n=404 |
| Fibrosis improvement (≥1 stage) with no worsening of NASH* | 10.6% | 15.7% p=0.0286 |
21.0% p<0.0001 |
| *Defined as no worsening of hepatocellular ballooning, no worsening of lobular inflammation and no worsening of steatosis
**Statistically significant in accordance with the statistical analysis plan agreed with the FDA |
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NASH Resolution at Month 18
| Primary Efficacy Analysis (ITT population: NASH with stage 2 and 3 liver fibrosis) |
Placebo n=311 |
OCA 10 mg n=312 |
OCA 25 mg n=308 |
| NASH resolution‡ with no worsening of liver fibrosis stage | 8.0% | 11.2% p=0.1814 |
11.7% p=0.1268 |
| Additional Full Efficacy Analysis (ITT population plus stage 1 liver fibrosis patients) | Placebo n=407 |
OCA 10 mg n=407 |
OCA 25 mg n=404 |
| NASH resolution‡ with no worsening of liver fibrosis stage | 7.9% | 11.3% p=0.0903 |
14.9% p=0.0013 |
| ‡Defined as the overall histopathologic interpretation of (i) no fatty liver disease or (ii) fatty liver disease (simple or isolated steatosis) without steatohepatitis AND a nonalcoholic fatty liver disease (NAFLD) activity score of 0 for ballooning and 0-1 for inflammation | |||
Safety and Tolerability
The safety population in this planned 18-month analysis of REGENERATE included 1,968 randomized patients who received at least one dose of investigational product (OCA or placebo).
Adverse events were generally mild to moderate in severity and the most common were consistent with the known profile of OCA. The frequency of serious adverse events was similar across treatment arms (11% in placebo, 11% in OCA 10 mg and 14% in OCA 25 mg) and no serious adverse event occurred in >1% of patients in any treatment arm. There were 3 deaths in the study (2 in placebo: bone cancer and cardiac arrest, 1 in OCA 25 mg: glioblastoma) and none were considered related to treatment.
The most common adverse event reported was dose-related pruritus (19% in placebo, 28% in OCA 10 mg and 51% in OCA 25 mg). The large majority of pruritus events were mild to moderate, with severe pruritus occurring in a small number of patients (<1% in placebo, <1% in OCA 10 mg and 5% in OCA 25 mg). A higher incidence of pruritus associated treatment discontinuation was observed for OCA 25 mg (<1% in placebo, <1% in OCA 10 mg and 9% in OCA 25 mg). According to the clinical study protocol, investigator assessed severe pruritus mandated treatment discontinuation.
Consistent with observations from previous NASH studies, OCA treatment was associated with an increase in LDL cholesterol, with a peak increase of 22.6 mg/dL at 4 weeks and subsequently reversing and approaching baseline at month 18 (4.0 mg/dL increase from baseline). Triglycerides rapidly and continually decreased in the OCA treatment arms through month 18. There were few and varied serious cardiovascular events and incidence was balanced across the three treatment arms (2% in placebo, 1% in OCA 10 mg and 2% in OCA 25 mg).
With respect to hepatobiliary events, more patients (3%) on OCA 25 mg experienced gallstones or cholecystitis compared to <1% on placebo and 1% on OCA 10 mg. While numerically higher in the OCA 25 mg treatment arm, serious hepatic adverse events were uncommon with <1% incidence in each of the three treatment arms.
About Liver Fibrosis due to NASH
Nonalcoholic steatohepatitis (NASH) is a serious progressive liver disease caused by excessive fat accumulation in the liver that induces chronic inflammation, resulting in progressive fibrosis (scarring) that can lead to cirrhosis, eventual liver failure, cancer and death. Advanced fibrosis is associated with a substantially higher risk of liver-related morbidity and mortality in patients with NASH, and as early as 2020, the disease is projected to become the leading cause of liver transplants in the United States. There are currently no medications approved for the treatment of NASH.
About the REGENERATE Study
The Phase 3 REGENERATE study is a randomized, double-blind, placebo-controlled, multicenter study assessing the safety and efficacy of obeticholic acid (OCA) on liver-related clinical outcomes in patents with liver fibrosis due to NASH. An 18-month analysis was conducted to assess the effect of OCA in liver histology comparing month 18 biopsy with baseline. REGENERATE is targeted to enroll more than 2,000 adult NASH patients with stage 2 and 3 fibrosis across 339 qualified centers worldwide. A smaller exploratory cohort of 287 patients with high-risk early fibrosis (defined as stage 1 fibrosis and metabolic syndrome) were also enrolled in REGENERATE, but were not included in the primary efficacy analysis. These patients were included in the full efficacy analysis and safety analysis. REGENERATE is planned to continue through clinical outcomes in order to confirm clinical benefit. The end-of-study analysis will evaluate the effect of OCA on mortality and liver-related clinical outcomes, as well as its long-term safety.
About the REVERSE Study
The Phase 3 REVERSE study is a randomized, double-blind, placebo-controlled, multicenter trial evaluating the safety and efficacy of OCA in histological improvement in fibrosis with no worsening of NASH in NASH patients with compensated cirrhosis.
Conference Call at 8:00 a.m. ET
Intercept will hold a conference call to discuss the topline results of the Phase 3 REGENERATE study in patients with liver fibrosis due to NASH today at 8:00 a.m. ET. The live event will be available on the investor page of Intercept’s website at http://ir.interceptpharma.com or by calling (855) 232-3919 (toll-free domestic) or (315) 625-6894 (international) five minutes prior to the start time (no passcode is required). A replay of the call will be available on Intercept’s website approximately two hours after the completion of the call and will be archived for two weeks.
About Intercept
Intercept is a biopharmaceutical company focused on the development and commercialization of novel therapeutics to treat progressive non-viral liver diseases, including primary biliary cholangitis (PBC) and nonalcoholic steatohepatitis (NASH). Founded in 2002 in New York, Intercept has operations in the United States, Europe and Canada. For more information, please visit www.interceptpharma.com or connect with the company on Twitter and LinkedIn.
SOURCE: Intercept
