ICPT Intercept Pharmaceuticals Inc

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 sub-analysis of the landmark Phase 3 POISE trial evaluating the impact of obeticholic acid (OCA) on achievement of gamma-glutamyl transferase (GGT) <3.2×upper limit of normal (ULN) and alkaline phosphatase (ALP) <1.5×ULN for the treatment of primary biliary cholangitis (PBC). This analysis suggests OCA’s potential to reduce GGT, in addition to the well-known effects on ALP levels, below the biochemical thresholds that are prognostic for worsening 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.

“These new data demonstrate the potential of OCA to reduce GGT, in addition to the already established effect on ALP levels, which have been shown to be predictive of risk of liver transplantation or death in patients with PBC,” said M. Michelle Berrey, M.D., M.P.H., President of Research & Development and Chief Medical Officer of Intercept. “With the increasing evidence of improved event-free survival for patients treated with OCALIVA across different studies, it was important to improve our understanding of OCALIVA’s impact on different biochemical markers and how that correlates with improved outcomes. We are pleased to join clinicians, researchers and industry peers at The Liver Meeting® 2023 to share these data that reaffirm the need for comprehensive assessment of treatment response beyond ALP when managing patients with PBC.”

In the study, patients with PBC who were receiving a stable dose of ursodeoxycholic acid (UDCA) or who were unable to tolerate UDCA were randomized to receive placebo, OCA 5-10 mg (OCA titration), or OCA 10 mg daily. For the OCA 5-10 mg group, OCA 5 mg was titrated to 10 mg at 6 months based on tolerability and biochemical response. A 12-month double-blind (DB) period was followed by a 5-year optional open-label extension (OLE), in which all patients were initially treated with OCA 5 mg daily for the first 3 months; every 3 months thereafter, patients had the option to increase the dose up to 10 mg. Serum GGT and ALP levels were assessed at baseline and every 3 months through the 5-year follow-up.

Hepatocyte injury causes GGT to be released into the blood. Elevated GGT in the setting of elevated ALP and other liver enzyme abnormalities is a marker for hepatobiliary disorder. The goal of this sub-analysis was to evaluate the proportion of patients receiving OCA who achieved and sustained GGT <3.2×ULN and ALP <1.5×ULN. Results include:

• In the double-blind (DB) intent-to-treat population (N=203), the proportion of responders was significantly greater at each time point in both OCA cohorts compared with placebo, with the highest responder rates observed in the OCA 10 mg group.
• In the OCA titration group, 17% (11/66) were responders at DB Months 9 and 12. In the OCA 10 mg group, the highest responder rate was observed at DB Month 9 (31% [21/68]), followed by DB Month 12 (26% [18/68]).
• In the open-label extension (OLE) intent-to-treat population (N=119), the proportion of responders generally increased over time, ranging from 18% (22/119) at OLE Month 3 to 38% (35/91) at OLE Month 51. At OLE Month 60, 37% (17/46) were responders.

“A recent study from the Global PBC study group showed that GGT ≥3.2xULN and ALP≥1.5xULN increase the risk of liver transplantation or death in patients with PBC,” said Robert G. Gish, M.D. FAASLD, Professor at Loma Linda University Department of Medicine. “This new analysis shows that OCA can reduce and maintain GGT and ALP levels below these thresholds over a 6-year period, adding to an already substantial body of evidence supporting OCA’s potential to decrease the risk of progression to liver transplant or death in patients with PBC.”

Poster Presentation“Effect of Obeticholic Acid on Prognostic Thresholds of Gamma-Glutamyl Transferase and Alkaline Phosphatase Levels: Sub-analysis of the Phase 3 POISE Trial in Primary Biliary Cholangitis” Poster #4545-CMonday, November 13, 1-2 PM ETAlan Bonder, Darren Wheeler, Radhika Nair, Erik Ness, Elizabeth S. Malecha and Robert G. Gish

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

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 CholangitisPrimary 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 CirrhosisHepatic 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 PruritusSevere 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-CPatients 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 ReactionsThe 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 ResinsBile 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.

• WarfarinThe 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 IndexObeticholic 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 PumpAvoid 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 InterceptIntercept is 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, 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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