Wednesday, February 20, 2019

Intercept - Phase 3 REGENERATE Study of Obeticholic Acid in Patients with Liver Fibrosis Due to NASH

Recommended Reading
February 19, 2019
The beginning of 2019 has already seen several significant advancements for the field of nonalcoholic steatohepatitis, from the inaugural NASH-TAG meeting to the recently announced positive results from the phase 3 study of Ocaliva.
Healio Gastroenterology and Liver Disease presents the following reports including trial results for Ocaliva (obeticholic acid, Intercept Pharma), a take-home report from NASH-TAG, and an update for this year’s International NASH Day.

February 5, 2019
Nonalcoholic steatohepatitis may soon supplant chronic hepatitis C as the leading cause of hepatocellular carcinoma among patients awaiting liver transplantation, according to the findings of a national longitudinal registry study

Press Release
Intercept Announces Positive Topline Results from Pivotal Phase 3 REGENERATE Study of Obeticholic Acid in Patients with Liver Fibrosis Due to NASH

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

The International Liver CongressTM
Every year in April, scientific and medical experts from a broad range of fields including hepatology, gastroenterology, internal medicine, cell biology, transplant surgery, infectious diseases, microbiology and virology, pharmacology, pathology and radiology and imaging come together from around the world to learn about the latest in liver research. Specialists share recent data, present studies and findings, and discuss the hottest topics on liver disease. The annual Congress attracts around 10,000 delegates and 250 media representatives from all over the world making this a truly international networking opportunity!

The International Liver CongressTM 2019 #ILC2019 will take place 10-14 April 2019 at the Reed Messe Wien Exhibition & Congress Center, Vienna, Austria.

Intercept Press Release
NEW YORK, Feb. 19, 2019 (GLOBE NEWSWIRE) -- 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. 

Click On Image To Enlarge

Fibrosis Improvement at Month 18

NASH Resolution at Month 18

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
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There are no approved treatments for NASH, or nonalcoholic steatohepatitis, a serious liver disease caused by fat accumulation in the liver that can result in chronic inflammation and scarring, or fibrosis. Eventually, the disease can lead to liver failure, cancer and death. 
Intercept’s treatment, obeticholic acid (OCA), is meant to treat patients with liver fibrosis due to NASH. The Phase 3 trial enrolled 931 patients with liver fibrosis who were randomly assigned to be treated with a placebo drug or one of two doses of OCA. 

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