Intercept Announces New Phase 2 Data Showing Significant Impact of OCA-Bezafibrate Combination on Normalization of Multiple Key Biomarkers of PBC-Induced Liver Damage at AASLD The Liver Meeting® 2023

Data from two Phase 2 studies in PBC show combination of OCA + bezafibrate achieved biochemical remission (normalization of ALP, total bilirubin, GGT, ALT and AST) in 40-44% of patients in the first 12 weeks

OCA 5 or 5-10 mg + bezafibrate 400 mg cohorts in both studies showed a >60% reduction from baseline in serum ALP (primary endpoint)

Treatment-emergent adverse events were generally balanced across all cohorts in both studies

Data support progression to Phase 3 trials of sustained release formulation of bezafibrate with low doses of OCA

Results featured in late-breaking poster presentation on Monday, November 13, during The Liver Meeting^® 2023

MORRISTOWN, N.J., Nov. 13, 2023 (GLOBE NEWSWIRE) — Intercept Pharmaceuticals, Inc., a biopharmaceutical company and wholly owned subsidiary of Alfasigma S.p.A. focused on the development and commercialization of novel therapeutics to treat rare and serious liver diseases, today announced new data from two Phase 2 studies, including a topline full data analysis (Study 747-213) and an interim analysis (Study 747-214), evaluating the effects of the investigational combination of farnesoid X receptor (FXR) agonist, obeticholic acid (OCA) and peroxisome proliferator-activated receptor (PPAR) agonist, bezafibrate, on multiple key serum biomarkers in primary biliary cholangitis (PBC) that have been shown to predict clinical outcomes. These data will be presented on Monday, November 13, 2023, at the American Association for the Study of Liver Diseases’ (AASLD) The Liver Meeting^® in Boston (poster #5019-C).

“The results of both Phase 2 studies reinforce our excitement for the combination of OCA-bezafibrate to build on the improved transplant-free survival seen in patients with PBC taking OCA across multiple real-world studies,” said M. Michelle Berrey, M.D., M.P.H., President of Research & Development and Chief Medical Officer of Intercept. “These data support progression to Phase 3 trials of the sustained release formulation of bezafibrate with low doses of OCA, an important step as we continue to prioritize Intercept’s investment in PBC.”

Patients with PBC in Study 747-213 were randomized 1:1:1:1 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 immediate release (B200 IR) (n=19)
• bezafibrate 400 mg sustained release (B400 SR) (n=19)
• bezafibrate 200 mg IR + OCA 5 mg titrated to 10 mg at week 4 (OCA5-10/B200 IR) (n=19)
• bezafibrate 400 mg SR + OCA 5 mg titrated to 10 mg at week 4 (OCA5-10/B400 SR) (n=18)

Patients with PBC in Study 747-214 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 100 mg IR (B100 IR) (n=11)
• bezafibrate 400 mg IR (B400 IR) (n=11)
• bezafibrate 100 mg IR + OCA 5 mg (OCA5/B100 IR) (n=9)
• bezafibrate 400 mg IR + OCA 5 mg (OCA5/B400 IR) (n=10)

The primary endpoint of both studies is change in alkaline phosphatase (ALP) from baseline to Week 12. The study also assessed percentage change and normalization rates of several 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 beyond ALP, including gamma-glutamyl transferase (GGT) and total bilirubin. Safety was assessed by monitoring of adverse events (AEs) and laboratory values.

Efficacy Results

Study 747-213

• OCA5-10/B400 SR showed a −60.6% change in ALP from baseline at week 12 (primary endpoint)
• At week 12, OCA5-10/B400 SR induced biochemical remission, defined as normalization of ALP, GGT, ALT, AST (all ≤ULN) and total bilirubin (≤0.6xULN), in 44.4% of patients compared to 31.6% in B400 SR, 31.6% in OCA5-10/B200 IR and 15.8% in B200 IR
• 66.7% of patients in the OCA5-10/B400 SR arm achieved normalization of ALP (≤ULN) and 100% achieved TB ≤0.6xULN at week 12
• Normalization rates of GGT, ALT and AST (≤ULN) for OCA5-10/B400 SR at week 12 were 58.86%, 94.1% and 82.4% respectively

Study 747-214

• OCA5/B400 IR showed a −65.4% change in ALP from baseline at week 12 (primary endpoint)
• At week 12, OCA5/B400 IR induced biochemical remission in 40.0% of patients compared to 18.2% in B400 IR, 11.1% in OCA5/B100 IR and 9.1% in B100 IR
• 70.0% of patients in the OCA5/B400 IR arm achieved normalization of ALP (≤ULN) and 90.0% achieved TB ≤0.6xULN at week 12
• Normalization rates of GGT, ALT and AST (≤ULN) for OCA/B400 IR at week 12 were 40.0%, 100%, and 90.0%, respectively

Safety Results

The frequency of treatment-emergent adverse events (TEAEs) reported was generally balanced across all arms in both studies. Two severe TEAEs (pruritus [OCA5-10/B400 SR] and hypertension [B200 IR]) occurred in Study 213; the severe TEAE of pruritus led to study discontinuation. One severe TEAE (pruritus, OCA5/B100 IR) occurred in Study 214; no TEAEs led to study discontinuation in Study 214.

The rate of new events of pruritus or worsening of baseline pruritus was very low in the OCA5-10/B400 SR arm of Study 747-213 (2/18 patients). Preliminary data from the OCA5/B400 IR arm of Study 747-214 showed a higher rate of new events of pruritus (7/10 patients), likely due to pharmacokinetic differences between the IR formulation of bezafibrate compared to the SR formulation used in Study 747-213.

“Results from these studies illustrate the OCA-bezafibrate combination’s potential to deliver biochemical responses across a range of biomarkers that predict improved clinical outcomes in PBC,” said Cynthia Levy, M.D., Hepatologist at the University of Miami Hospital and Professor of Medicine at the University of Miami. “These positive findings, including low rates of pruritus, are an important milestone for the PBC community.”

The company is continuing its two ongoing Phase 2 studies (747-213 / NCT04594694, 747-214 / NCT05239468) that are exploring a range of therapeutic doses and formulations for the combination of OCA and bezafibrate. The Company expects to have the necessary data from the OCA-bezafibrate combination program to submit a request in 2023 for an End-of-Phase 2 meeting with the FDA. These data include analyses from both Phase 2 studies, in addition to Phase 1 and preclinical data.

Poster Presentation
“Combined Effect of Obeticholic Acid and Bezafibrate in Patients with Primary Biliary Cholangitis and Inadequate Response to Or Intolerance of Ursodeoxycholic Acid: Results from Two Phase 2 Clinical Trials” Poster #5019-C
Monday, November 13, 1-2 PM ET
Cynthia Levy, Vaclav Hejda, Alexandre Louvet, Ziad Younes, Manuel Mendizabal, Alan Bonder, Heng Zou, Antonio Civitarese, Alejandra Villamil and Frederik Nevens

A full list of sessions at The Liver Meeting^® 2023 is available at https://www.aasld.org/the-liver-meeting.

About the Investigational OCA-Bezafibrate Fixed-Dose Combination
Intercept, a wholly owned subsidiary of Alfasigma S.p.A., 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 common and 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.

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.

About Intercept
Intercept is a biopharmaceutical company and a wholly owned subsidiary of Alfasigmna S.p.A. 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 LinkedIn, Threads, and X (formerly Twitter).

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