Intercept Presents New Data on the Results of OCA-Bezafibrate Combination Therapy in PBC After Six Months of Treatment in Late-Breaking Poster Presentation at EASL Congress 2024

MORRISTOWN, N.J., June 05, 2024 (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 a planned six-month analysis of its ongoing Phase 2 study 747-213 evaluating the combination of obeticholic acid (OCA) and bezafibrate in patients with primary biliary cholangitis (PBC) at the European Association for the Study of the Liver (EASL) Congress 2024 being held June 5-8, 2024, in Milan, Italy. Results from the study show that six-month administration of OCA and bezafibrate has the potential to normalize multiple serum biomarkers associated with improved transplant-free and decompensation-free survival in PBC.

“These data add to a growing body of evidence showing that the combination of OCA and bezafibrate may provide additive clinical efficacy and tolerability benefits in the treatment of PBC,” said David Jones, Professor of Liver Immunology, Newcastle University. “This investigational, combination therapy is the first we’ve seen to induce biochemical remission – or normalization of multiple biomarkers – in the majority of patients, marking a potentially new standard for efficacy in PBC therapeutic development. With over two-thirds of patients experiencing this level of efficacy, these results surpass the benchmark normalization rates and underscore the potential of the OCA and bezafibrate combination to achieve meaningful clinical outcomes 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 (OCA/B200 IR) (n=19)
• bezafibrate 400 mg SR + OCA 5 mg titrated to 10 mg at Week 4 (OCA/B400 SR) (n=18)

Following the 12-week double-blind treatment period, OCA-bezafibrate dosage could be optimized in the long-term safety extension.

In this analysis, OCA/B400 SR showed the greatest impact on biochemical response. Key findings at Month 6 include:

• OCA/B400 SR demonstrated a 65.3% reduction in alkaline phosphatase (ALP) (p≤0.05 vs B400 SR) and 61.1% achieved ALP less than or equal to the upper limit of normal (ULN); 77.8% experienced ≥40% reduction in ALP from baseline
• OCA/B400 SR induced a 27.6% reduction in total bilirubin (TB) and 83.3% of patients in this treatment arm achieved TB ≤ 0.6 x ULN
• OCA/B400 SR also demonstrated the greatest percentage reductions in alanine aminotransferase (ALT; 41.9%), aspartate aminotransferase (AST; 16.1%), and gamma-glutamyl transferase (GGT; 81.6%)
• Normalization rates of ALT, AST, and GGT with OCA/B400 SR were 83.3%, 77.8%, and 72.2%, respectively
• 66.7% of patients in the OCA/B400 SR arm achieved biochemical remission, defined as normalization (≤ ULN) or ≥40% change in ALP; GGT, ALT, and AST ≤ ULN; and TB ≤ 0.6 x ULN

In addition, OCA/B400 SR induced the greatest change in GLOBE (-0.7) and UK-PBC (-1.1) scores, two prognostic tools used to assess the long-term outcomes of people living with PBC. Treatment-emergent adverse events were generally balanced across cohorts.

“These results show that OCA-bezafibrate combination therapy in PBC has the potential to normalize multiple serum biomarkers associated with improved transplant-free and decompensation-free survival,” said Sangeeta Sawhney, Senior Vice President and Head of U.S. Research & Development at Intercept. “We believe this combination has the potential to redefine benefit in PBC, and we look forward to progressing to Phase 3 as part of our ongoing clinical development program.”

Intercept is continuing its two ongoing Phase 2 studies (747-213 / NCT04594694, 747-214 / NCT05239468), which are exploring a range of therapeutic doses and formulations for the combination of OCA and bezafibrate.

About the Investigational OCA-bezafibrate Combination
Intercept is investigating a 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 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 Alfasigma 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). Intercept owns the commercial rights to Ocaliva in the U.S. market. For more information, please visit www.interceptpharma.com or connect with the Company on LinkedIn, Threads and X (formerly Twitter).

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