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Interim analysis of ongoing Phase 2 study shows combination of OCA 5-10 mg + bezafibrate 400 mg improved levels of multiple biochemical markers associated with clinical outcomes in PBC including ALP, total bilirubin, ALT, and GGT at 12 weeks
OCA 5-10 mg + bezafibrate 400 mg also showed rapid biochemical response of mean ALP to within normal range at 4 weeks
Combination was well tolerated with low rates of pruritus
MORRISTOWN, N.J., June 07, 2023 (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 initial results from a planned interim analysis of its ongoing Phase 2 study 747-213, an active comparator trial demonstrating the therapeutic potential of the combination of obeticholic acid (OCA) and bezafibrate vs. bezafibrate monotherapy on serum biomarkers in primary biliary cholangitis (PBC). These data are part of a larger analysis that will be presented at 08:45 CEST on Friday, June 23 at the European Association for the Study of the Liver (EASL) Congress 2023 in Vienna, Austria.
Data will be presented from the planned interim analysis of patients with PBC who were randomized 1:1:1:1 to receive 12 weeks of once-daily oral therapy in addition to ongoing UDCA treatment (if any) in one of four treatment arms:
bezafibrate 200 mg (B200)bezafibrate 400 mg (B400)bezafibrate 200 mg + OCA 5 mg titrated to 10 mg at week 4 (OCA5-10/B200)bezafibrate 400 mg + OCA 5 mg titrated to 10 mg at week 4 (OCA5-10/B400)
Endpoints included serum biomarkers of PBC-induced liver damage such as alanine transaminase (ALT) and aspartate aminotransferase (AST) as well as markers shown to predict transplant-free survival such as alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT) and total bilirubin. Safety was assessed by monitoring of adverse events (AEs) and laboratory values.
As reflected in the abstract published today and available on the EASL website, data from the first 45 patients enrolled in Study 213 showed that over half of those receiving OCA5-10/B400 rapidly achieved normal range ALP at 4 weeks with continued improvement through week 12. In addition, patients randomized to OCA5-10/B400 exhibited the highest rates of biomarker normalization at week 12: ALP (60% normalized), total bilirubin (100% normalized), ALT (100% normalized), and GGT (70% normalized).
Low rates of AEs were observed, with a majority considered mild and not related to study drug. Rates of pruritus were 25% or less in any treatment arm. Four patients in the study experienced severe or serious treatment-emergent AEs (TEAEs), all deemed not study-drug related.
“This interim analysis provides important insights on the apparent synergistic mechanisms of action of the OCA-bezafibrate combination which we believe has the potential to normalize multiple biochemical surrogate markers beyond the criteria widely utilized for registrational trials in PBC,” said M. Michelle Berrey, M.D., M.P.H., President of Research & Development and Chief Medical Officer of Intercept. “Multiple real-world studies have demonstrated improved transplant-free survival of OCALIVA (obeticholic acid) following improvements in a specific combination of biomarkers. We are encouraged by the best-in-class potential of our novel combination to build on this evidence with rapid biochemical responses that have predicted improved clinical outcomes. We look forward to sharing the findings of the complete interim dataset at EASL 2023.”
Intercept 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. 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 FDA.
“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
Friday June 23, 08:45 – 09:00 CEST
Room: Strauss 2-3
Vaclav Hejda, Alexandre Louvet, Antonio Civitarese, Lynda Szczech, Heng Zou and Frederik Nevens
A full list of sessions at EASL 2023 is available at www.easlcongress.eu.
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 the United States for the treatment of PBC (see below for full indication and Important Safety Information). Bezafibrate, a pan-peroxisome proliferator-activated receptor (pan-PPAR) agonist, is not approved in the United States for any indication.
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 which suggests that the combination of OCA and bezafibrate may provide additive clinical efficacy and tolerability benefits that are unmatched 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.
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 orwith 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 eventcompensated 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.Warfarin
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; drug efficacy, safety, and tolerability; and the timing and subject matter of our meetings and other interactions with regulators. Important factors could cause actual results to differ materially from the FLS. For example, there could be efficacy, safety, or tolerability concerns about our product candidates; or we could have problems with our research and development activities and clinical trials, including their initiation, timing, cost, conduct, progress, and results, due to delays or failures in identifying, enrolling, treating, and retaining patients, meeting specific endpoints, or completing and reporting results.
For more information about Intercept, please contact:
Nareg Sagherian, Executive Director, Global Investor Relations
Karen Preble, Executive Director, Global Corporate Communications