Intercept Announces New Data to be Presented at The European Association for the Study of the Liver (EASL) Congress 2023 and Provides Update on OCA-bezafibrate Fixed-Dose Combination (FDC) Development Program
Seven abstracts in primary biliary cholangitis (PBC) and nonalcoholic steatohepatitis (NASH) accepted at EASL 2023
Accepted abstracts include podium presentation of new data from the planned interim analysis of a Phase 2 study of investigational combination of obeticholic acid (OCA) and bezafibrate in PBC
Company expects to complete planned interim analyses from two ongoing Phase 2 studies of OCA-bezafibrate in 2023 in preparation for end-of-phase 2 meeting with the
One of the accepted abstracts includes new data from a planned interim analysis of an ongoing Phase 2 study evaluating the effects of the investigational combination of the FXR agonist OCA and bezafibrate, a peroxisome proliferator-activated receptor (PPAR) agonist, on serum biomarkers in PBC that have been shown to predict clinical outcomes.
“We look forward to the opportunity to share new data in PBC and NASH at EASL 2023, including a podium presentation of new Phase 2 interim data from our clinical development program investigating the combination of obeticholic acid and bezafibrate,” said
Intercept has completed a Phase 1 clinical study in healthy adult subjects that assessed multiple dose combinations of OCA and bezafibrate. The company also has two ongoing Phase 2 studies (747-213 / NCT04594694, 747-214 / NCT05239468) that are exploring a range of therapeutic doses for the combination of OCA and bezafibrate. Intercept expects to complete planned interim analyses from both ongoing Phase 2 studies this year, with the first data being presented at EASL 2023. The planned interim analyses from these Phase 2 studies, in addition to Phase 1 and preclinical data, will serve as the basis of an end-of-phase 2 meeting with the FDA.
Available information about the Intercept abstracts accepted for presentation at EASL 2023 is listed below. More information about these abstracts will be made available after the respective embargoes, as set by the EASL organizers, are lifted for each presentation. A full list of sessions at EASL 2023 is available at www.easlcongress.eu.
PBC Podium Presentation
“Results from a Planned Interim Analysis of a Randomized, Double-Blind, Active-Controlled Trial Evaluating the Effects of Obeticholic Acid and Bezafibrate on Serum Biomarkers in Primary Biliary Cholangitis” Abstract #2495
“Modulation of Alkaline Phosphatase Levels by Obeticholic Acid in Clinical Trials and Cultured Human Hepatocytes” Abstract #1505
“Risk Of Death, Liver Transplant, or Hepatic Decompensation in Primary Biliary Cholangitis Increases with Increased Duration and Degree Beyond Established Clinical Thresholds for Hepatic Biomarkers and Fibrosis Scores” Abstract #1522
“Fibrosis-4 Score Less Than 2.67 and Normal Gamma-Glutamyl Transferase Levels are Associated with High Negative Predictive Value for High-Risk of Liver Stiffness in Patients with Primary Biliary Cholangitis” Abstract #1518
“Incidence and Median Times to Onset and Resolution of Pruritus Adverse Events in a Phase 3 Study of Obeticholic Acid in Patients with Nonalcoholic Steatohepatitis” Abstract #2349
“Incidence and Risk of Dyslipidemia and Hyperglycemia in a Phase 3 Study of Obeticholic Acid for the Treatment of Nonalcoholic Steatohepatitis” Abstract #2321
“Significant Dose-Dependent Reduction in Liver Stiffness Using Transient Elastography in a Phase 3 Randomized Placebo-Controlled Trial of Obeticholic Acid Over 48 Months in Patients with Pre-Cirrhotic Fibrosis due to Nonalcoholic Steatohepatitis” Abstract #2443
The use of OCA for fibrosis due to NASH is investigational and has not been approved by FDA or any other health authority.
About the Investigational OCA-Bezafibrate Fixed-Dose Combination
Intercept is investigating a fixed-dose combination of OCA and bezafibrate for the potential treatment of individuals with PBC. OCA, a farnesoid X receptor (FXR) agonist, is marketed by Intercept as Ocaliva in
FXR and PPAR are distinct pathways that each play a role in PBC. Simultaneously targeting both pathways may offer the greatest potential to impact bile acid synthesis, metabolism, and clearance that underly cholestatic liver diseases. Published studies establish a clinical proof-of-concept that suggests that the combination of OCA and bezafibrate may provide additive clinical efficacy and tolerability benefits in the treatment of PBC. OCA-bezafibrate combination therapy is investigational; safety and efficacy have not been established.
About Primary Biliary Cholangitis
Primary biliary cholangitis (PBC) is a rare, progressive, and chronic autoimmune disease that affects the bile ducts in the liver and is most prevalent (approximately 1 in 10,000) in women over the age of 40. PBC causes bile acid to build up in the liver, resulting in inflammation and scarring (fibrosis), which, if left untreated, can lead to cirrhosis, a liver transplant, or death.
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. As patients progress, their risk of serious liver-related consequences increases, and those with advanced fibrosis are at a substantially higher risk of liver-related morbidity and mortality. There are currently no medications approved for the treatment of NASH.
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), nonalcoholic steatohepatitis (NASH) and severe alcohol-associated hepatitis (sAH). For more information, please visit www.interceptpharma.com or connect with the Company on Twitter and LinkedIn.
About Ocaliva® (obeticholic acid)
OCALIVA, a farnesoid X receptor (FXR) agonist, is indicated for the treatment of adult patients with primary biliary cholangitis (PBC)
- without cirrhosis or
- with compensated cirrhosis who do not have evidence of portal hypertension, either in combination with ursodeoxycholic acid (UDCA) with an inadequate response to UDCA or as monotherapy in patients unable to tolerate UDCA.
This indication is approved under accelerated approval based on a reduction in alkaline phosphatase (ALP). An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
IMPORTANT SAFETY INFORMATION
WARNING: HEPATIC DECOMPENSATION AND FAILURE IN PRIMARY BILIARY CHOLANGITIS PATIENTS WITH CIRRHOSIS
- Hepatic decompensation and failure, sometimes fatal or resulting in liver transplant, have been reported with OCALIVA treatment in primary biliary cholangitis (PBC) patients with either compensated or decompensated cirrhosis.
- OCALIVA is contraindicated in PBC patients with decompensated cirrhosis, a prior decompensation event, or with compensated cirrhosis who have evidence of portal hypertension.
- Permanently discontinue OCALIVA in patients who develop laboratory or clinical evidence of hepatic decompensation; have compensated cirrhosis and develop evidence of portal hypertension, or experience clinically significant hepatic adverse reactions while on treatment.
OCALIVA is contraindicated in patients with:
- decompensated cirrhosis (e.g., Child-Pugh Class B or C) or a prior decompensation event
- compensated cirrhosis who have evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia)
- complete biliary obstruction
Warnings and Precautions
Hepatic Decompensation and Failure in PBC Patients with Cirrhosis
Hepatic decompensation and failure, sometimes fatal or resulting in liver transplant, have been reported with OCALIVA treatment in PBC patients with cirrhosis, either compensated or decompensated. Among post-marketing cases reporting it, median time to hepatic decompensation (e.g., new onset ascites) was 4 months for patients with compensated cirrhosis; median time to a new decompensation event (e.g., hepatic encephalopathy) was 2.5 months for patients with decompensated cirrhosis.
Some of these cases occurred in patients with decompensated cirrhosis when they were treated with higher than the recommended dosage for that patient population; however, cases of hepatic decompensation and failure have continued to be reported in patients with decompensated cirrhosis even when they received the recommended dosage.
Hepatotoxicity was observed in the OCALIVA clinical trials. A dose-response relationship was observed for the occurrence of hepatic adverse reactions including jaundice, worsening ascites, and primary biliary cholangitis flare with dosages of OCALIVA of 10 mg once daily to 50 mg once daily (up to 5-times the highest recommended dosage), as early as one month after starting treatment with OCALIVA in two 3-month, placebo-controlled clinical trials in patients with primarily early stage PBC.
Routinely monitor patients for progression of PBC, including hepatic adverse reactions, with laboratory and clinical assessments to determine whether drug discontinuation is needed. Closely monitor patients with compensated cirrhosis, concomitant hepatic disease (e.g., autoimmune hepatitis, alcoholic liver disease), and/or with severe intercurrent illness for new evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia), or increases above the upper limit of normal in total bilirubin, direct bilirubin, or prothrombin time to determine whether drug discontinuation is needed. Permanently discontinue OCALIVA in patients who develop laboratory or clinical evidence of hepatic decompensation (e.g., ascites, jaundice, variceal bleeding, hepatic encephalopathy), have compensated cirrhosis and develop evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia), experience clinically significant hepatic adverse reactions, or develop complete biliary obstruction. If severe intercurrent illness occurs, interrupt treatment with OCALIVA and monitor the patient’s liver function. After resolution of the intercurrent illness, consider the potential risks and benefits of restarting OCALIVA treatment.
Severe pruritus was reported in 23% of patients in the OCALIVA 10 mg arm, 19% of patients in the OCALIVA titration arm, and 7% of patients in the placebo arm in a 12-month double-blind randomized controlled clinical trial of 216 patients. Severe pruritus was defined as intense or widespread itching, interfering with activities of daily living, or causing severe sleep disturbance, or intolerable discomfort, and typically requiring medical interventions. Consider clinical evaluation of patients with new onset or worsening severe pruritus. Management strategies include the addition of bile acid binding resins or antihistamines, OCALIVA dosage reduction, and/or temporary interruption of OCALIVA dosing.
Reduction in HDL-C
Patients with PBC generally exhibit hyperlipidemia characterized by a significant elevation in total cholesterol primarily due to increased levels of high-density lipoprotein-cholesterol (HDL-C). Dose-dependent reductions from baseline in mean HDL-C levels were observed at 2 weeks in OCALIVA-treated patients, 20% and 9% in the 10 mg and titration arms, respectively, compared to 2% in the placebo arm. Monitor patients for changes in serum lipid levels during treatment. For patients who do not respond to OCALIVA after 1 year at the highest recommended dosage that can be tolerated (maximum of 10 mg once daily), and who experience a reduction in HDL-C, weigh the potential risks against the benefits of continuing treatment.
The most common adverse reactions (≥5%) are: pruritus, fatigue, abdominal pain and discomfort, rash, oropharyngeal pain, dizziness, constipation, arthralgia, thyroid function abnormality, and eczema.
- Bile Acid Binding Resins
Bile acid binding resins such as cholestyramine, colestipol, or colesevelam adsorb and reduce bile acid absorption and may reduce the absorption, systemic exposure, and efficacy of OCALIVA. If taking a bile acid binding resin, take OCALIVA at least 4 hours before or 4 hours after taking the bile acid binding resin, or at as great an interval as possible.
The International Normalized Ratio (INR) decreased following coadministration of warfarin and OCALIVA. Monitor INR and adjust the dose of warfarin, as needed, to maintain the target INR range when co-administering OCALIVA and warfarin.
- CYP1A2 Substrates with Narrow Therapeutic Index
Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates. Therapeutic monitoring of CYP1A2 substrates with a narrow therapeutic index (e.g., theophylline and tizanidine) is recommended when co-administered with OCALIVA.
- Inhibitors of Bile Salt Efflux Pump
Avoid concomitant use of inhibitors of the bile salt efflux pump (BSEP) such as cyclosporine. Concomitant medications that inhibit canalicular membrane bile acid transporters such as the BSEP may exacerbate accumulation of conjugated bile salts including taurine conjugate of obeticholic acid in the liver and result in clinical symptoms. If concomitant use is deemed necessary, monitor serum transaminases and bilirubin.
Please click here for Full Prescribing Information, including Boxed WARNING.
To report SUSPECTED ADVERSE REACTIONS, contact Intercept Pharmaceuticals, Inc. at 1-844-782-ICPT or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Forward Looking Statements
This press release contains forward-looking statements (“FLS”), including regarding:
- the progress, timing and results of our clinical trials;
- the safety and efficacy of our approved product, Ocaliva (obeticholic acid or “OCA”) for primary biliary cholangitis (“PBC”), and our product candidates, including OCA for liver fibrosis due to NASH, and the OCA-bezafibrate FDC for PBC; and
- the timing and acceptance of our regulatory filings.
Important factors could cause actual results to differ materially from the FLS. For example:
- any future determination that the regulatory applications and subsequent information we submit for our product candidates, including OCA for liver fibrosis due to NASH and the OCA-bezafibrate FDC for PBC, do not contain adequate clinical or other data or meet applicable regulatory requirements for approval;
- any potential side effects associated with Ocaliva for PBC, OCA for liver fibrosis due to NASH or our other product candidates that could delay or prevent approval, require that an approved product be taken off the market, require the inclusion of safety warnings or precautions, or otherwise limit the sale of such product or product candidate;
- the initiation, timing, cost, conduct, progress and results of our research and development activities, preclinical studies and clinical trials, including any issues, delays or failures in identifying patients, enrolling patients, treating patients, retaining patients, meeting specific endpoints, or completing and timely reporting the results of our NASH or PBC clinical trials;
- the outcomes of interactions with regulators including the FDA regarding our clinical trials;
- our ability to identify, develop and successfully commercialize our products and product candidates; and
- our ability to obtain and maintain intellectual property protection for our products and product candidates, including our ability to cost-effectively file, prosecute, defend and enforce any patent claims or other intellectual property rights.
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Source: Intercept Pharmaceuticals, Inc.