Intercept Presents New Data Showing Significant Impact of OCA-bezafibrate Combination on Normalization of Multiple Biomarkers of PBC-Induced Liver Damage

Intercept Presents New Data Showing Significant Impact of OCA-bezafibrate Combination on Normalization of Multiple Biomarkers of PBC-Induced Liver Damage

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Planned interim analysis from the first of two Phase 2 studies shows combination of OCA 5-10 mg + bezafibrate 400 mg normalized a range of biomarkers of PBC (ALP, total bilirubin, GGT, ALT and AST) in 58% of patients at 12 weeksALP normalized in 75% of patients in the OCA 5-10 mg + bezafibrate 400 mg arm at 12 weeks

Combination well-tolerated with lowest rates of pruritus observed in OCA 5-10 mg + bezafibrate 400 mg treatment arm

Results featured in podium presentation today at EASL Congress 2023

MORRISTOWN, N.J., June 23, 2023 (GLOBE NEWSWIRE) -- Intercept Pharmaceuticals, Inc. (Nasdaq: ICPT), a biopharmaceutical company focused on the development and commercialization of novel therapeutics to treat rare and serious liver diseases, today announced new results from a planned interim analysis of its ongoing Phase 2 study 747-213 assessing improvements in serum biomarkers of hepatic function, cholestasis and inflammation in patients with primary biliary cholangitis (PBC) after treatment with an investigational combination of obeticholic acid (OCA) and bezafibrate. Results from the full interim data set, shared in a podium presentation today at the European Association for the Study of the Liver (EASL) Congress 2023 in Vienna, Austria, showed that the combination of OCA 5-10 mg and bezafibrate 400 mg was effective in normalizing multiple biochemical markers associated with PBC-induced liver damage.

“The results of this interim analysis, specifically the normalization of key biochemistries in nearly 60 percent of patients in the OCA 5-10 mg and bezafibrate 400 mg combination arm, demonstrate the potential for synergy between the mechanisms of FXR and PPAR agonists,” said M. Michelle Berrey, M.D., M.P.H., President of Research & Development and Chief Medical Officer of Intercept. “We have an opportunity to build on the improved transplant-free survival seen in patients with PBC taking OCA across multiple real-world studies. We are encouraged by the best-in-class potential of our novel combination with rapid biochemical responses that have predicted improved clinical outcomes and believe that a fixed-dose combination of OCA and bezafibrate could reframe the parameters for efficacy in PBC.”

“Results of this planned interim analysis of the combination of OCA and bezafibrate represent a milestone for the PBC community,” said Frederik Nevens, M.D., Ph.D., Professor at University Hospitals KU Leuven, Belgium. “The potential of this therapy to deliver such broad biochemical responses in a large percentage of patients across serum markers associated with outcomes in PBC suggests that this combination can provide a new level of clinical benefit.”

In this planned interim analysis from the first of two Phase 2 studies, 62 patients with PBC were randomized to receive 12 weeks of once-daily oral therapy in addition to ongoing ursodeoxycholic acid (UDCA) treatment (if any) in one of four treatment arms:

· bezafibrate 200 mg (B200) (n=16)
· OCA 5 mg titrated to 10 mg at week 4 + bezafibrate 200 mg (OCA5-10/B200) (n=16)
· bezafibrate 400 mg (B400) (n=15)
· OCA 5 mg titrated to 10 mg at week 4 + bezafibrate 400 mg (OCA5-10/B400) (n=15)

The goal of this interim analysis was to assess improvements in serum biomarkers of PBC-induced liver damage including alanine transaminase (ALT) and aspartate aminotransferase (AST) as well as markers shown to predict transplant-free survival including alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT) and total bilirubin. Safety was assessed by monitoring of adverse events (AEs) and laboratory values. The primary efficacy endpoint of Study 747-213 is change in ALP from baseline to week 12. Preliminary data from the abstract accepted by EASL were previously reported on June 7.

*Efficacy*
Biochemical remission, defined as normalization of ALP, GGT, ALT, AST (all ≤ULN) and total bilirubin (≤0.6xULN), was induced in 58% of patients on OCA5-10/B400 at 12 weeks vs 7% (B200), 27% (B400) and 31% (OCA5-10/B200) in the other treatment arms. Further, patients in the OCA5-10/B400 arm experienced consistently high levels of normalization of individual biomarkers ALP (75% normalized), GGT (75% normalized), total bilirubin (≤0.6xULN, 100% normalized), ALT (100% normalized) and AST (92% normalized). The lower target for total bilirubin was selected as it is associated with the lowest risk for liver transplant or death.

Patients in the OCA5-10/B400 arm demonstrated the highest rates of reduction from baseline in ALP, ALT, total bilirubin and GGT with a clear dose response seen in total bilirubin and GGT.

*Safety*
Treatment-emergent adverse events (TEAEs) were generally balanced across all arms (8 in B200, 11 in OCA5-10/B200, 12 in B400, 9 in OCA5-10/B400) with the majority being mild and not related to study drug. No deaths occurred in the study.

Pruritus events were low across all study arms with the lowest rate in the OCA5-10/B400 arm (2 events, 13.3%). Observed pruritus in the other arms were 4 events (25%) in B200; 4 events (25%) in OCA5-10/B200; and 3 events (20%) in B400. One serious treatment-related pruritus TEAE leading to discontinuation was reported in the OCA5-10/B400 arm.

There was a reduction from baseline in mean cholesterol levels at 4 weeks in the combination arms and relative to the active control, bezafibrate. Patients in the two OCA-bezafibrate treatment arms demonstrated the largest reductions in cholesterol at 12 weeks with a clear dose response.

Intercept has two ongoing Phase 2 studies (747-213 / NCT04594694, 747-214 / NCT05239468) that are exploring a range of therapeutic doses for the fixed-dose 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.

*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 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 Intercept*
Intercept is a biopharmaceutical company focused on the development and commercialization of novel therapeutics to treat rare and serious liver diseases, including primary biliary cholangitis (PBC) 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.**Contraindications*

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*
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.

*Adverse Reactions*
The most common adverse reactions (≥5%) are: pruritus, fatigue, abdominal pain and discomfort, rash, oropharyngeal pain, dizziness, constipation, arthralgia, thyroid function abnormality, and eczema.

*Drug Interactions*

· 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.

*Contact*
For more information about Intercept, please contact:

For investors:
Nareg Sagherian, Executive Director, Global Investor Relations
investors@interceptpharma.com

For media:
Karen Preble, Executive Director, Global Corporate Communications
media@interceptpharma.com

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