Intercept Presents New Sub-Analyses of Phase 3 POISE Data Showcasing the Effect of OCA on Key Liver Biomarkers in Patients with PBC at EASL Congress 2024

OCA significantly reduces ALT and AST, liver biomarkers associated with poor clinical outcomes, as early as Week 2 in both OCA treatment groups, and by Month 6, normalized ALT in >50% and AST in almost 33% of patients with elevated levels at baseline

MORRISTOWN, N.J., June 04, 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 sub-analyses from its Phase 3 POISE trial in primary biliary cholangitis (PBC) showing the effect of obeticholic acid (OCA) across a number of key biomarkers of liver health in people living with PBC will be presented at the European Association for the Study of the Liver (EASL) Congress 2024 being held June 5-8, 2024, in Milan, Italy. Additional analyses showing the impact of OCA on enhanced liver fibrosis (ELF) and transient elastography (TE), aminotransferase to platelet ratio index (APRI) score and fibrosis-4 (FIB-4) index, and normalization of inflammatory and immune biomarkers in patients from POISE will also be presented.

“These new analyses highlight the potential impact of OCA on multiple serum biochemical and inflammatory markers associated with better clinical outcomes,” said Robert G. Gish, M.D. FAASLD, Professor at Loma Linda University Department of Medicine. “Additionally, by leveraging noninvasive measurements like ELF, TE, FIB-4, and APRI, we see that OCA has the potential to stabilize fibrosis regardless of severity at baseline, suggesting that earlier treatment with OCA may benefit patients by preventing fibrosis progression. As a clinician, it is important that we understand the multifaceted aspects of this disease and tailor treatment for our patients accordingly.”

The landmark Phase 3 POISE study evaluated the safety and efficacy of once-daily treatment with OCA in PBC patients with an inadequate therapeutic response to, or who were unable to tolerate, ursodeoxycholic acid. Patients were randomized to one of three groups in the trial: placebo, OCA 5 mg with option to titrate to 10 mg after 6 months, or OCA 10 mg daily. The study included a 12-month double-blind phase, as well as a long-term safety extension phase up to five years. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were assessed at all visits.

This analysis showed that among the intention-to-treat (ITT) population, OCA significantly reduced ALT and AST in both OCA groups (p<0.001) as early as Week 2, and by Month 6, normalized ALT in > 50% and AST in almost 33% of patients with elevated levels at baseline.

• Among the 61% of patients with ALT >41 U/L at baseline,16% receiving placebo normalized at Month 6 compared to 55% on OCA titration and 53% on OCA 10 mg (p≤0.001 for both). As early as Week 2, three to four times more patients had normalized ALT in both OCA groups (both p<0.01 vs. placebo).
• Among the 71% of patients with AST >34 U/L at baseline, normalization rates at Month 6 were 12% in the placebo arm, 30% in the OCA titration arm, and 31% in the OCA 10 mg arm (p<0.05 for both).
• The proportions of patients normalizing ALT and AST on OCA were maintained through Month 12.

Additional post hoc analyses showed the impact of OCA on ELF and TE, APRI score, and FIB-4 index, and normalization of inflammatory and immune biomarkers in patients from POISE.

• In a post hoc analysis assessing the impact of OCA on ELF and TE, no worsening in noninvasive measures of fibrosis (ELF and TE liver stiffness) was observed throughout the OCA treatment suggesting that OCA stabilized fibrosis over time regardless of severity at baseline.
  • OCA stabilized ELF over 24 months in patients with evidence of moderate or severe fibrosis or cirrhosis at baseline.
  • OCA stabilized TE measures over 24 months in patients with a TE of <10 or ≥ 10 kPa at baseline.
• In a post hoc analysis evaluating the impact of OCA on APRI score and FIB-4 index, overall APRI and FIB-4 scores decreased with OCA treatment and increased in the placebo group in the 12-month double blind phase.
  • Among patients with higher FIB-4 at baseline, FIB-4 increased to a lesser extent in the OCA group compared with placebo while OCA treatment decreased APRI in both high and low APRI subgroups.
• A post hoc analysis assessing the impact of OCA on normalization of inflammatory and immune biomarkers showed OCA significantly increased the proportion of patients with PBC who achieved normalization of the inflammatory biomarkers, tumor necrosis factor alpha (TNFα), high-sensitivity C-reactive protein (hsCRP) or immunoglobulin M (IgM), the latter of which is associated with better clinical outcomes.

“Building on data presented at Digestive Disease Week, these data suggest that in addition to reductions in ALP, OCA significantly reduces ALT and AST, two important liver biomarkers used to assess clinical outcomes,” said Sangeeta Sawhney, Senior Vice President and Head of U.S. Research & Development at Intercept. “Additional analyses of the Phase 3 POISE trial continue to enhance our understanding of PBC treatment response, which may help minimize the risk of disease progression in people living with PBC. We look forward to sharing these findings with the scientific community at EASL.”

About the POISE Trial
The POISE trial studied the safety and efficacy of once-daily treatment with Ocaliva in PBC patients with an inadequate therapeutic response to, or who were unable to tolerate, ursodeoxycholic acid (UDCA). There were 217 patients randomized to one of three groups in the trial: placebo, OCA 10 mg, or OCA 5 mg for six months titrated to 10 mg based on clinical response. Seven subjects did not participate in the open-label extension and were not included in the current study. Patients completing the double-blind phase had the option to continue in an open-label extension (OLE) phase for a maximum of five additional years, during which all patients received treatment with OCA 5-10 mg once daily. Of the 198 patients who completed the double-blind phase, more than 95 percent continued in the long-term safety extension phase of the trial for up to 5 years. Additional information regarding the POISE trial can be found on the NIH clinical study listing website: http://clinicaltrials.gov/ct2/show/NCT01473524.

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.

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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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