OCA normalizes levels of ALT and AST, liver biomarkers associated with poor clinical outcomes in a significantly higher proportion of patients after 12 months of treatment compared to placebo; reductions demonstrated as early as two weeks
OCA significantly reduces APRI scores, a non-invasive test that can predict liver fibrosis progression, compared to placebo after 12 months of treatment
Results featured in two podium presentations at DDW 2024
MORRISTOWN, N.J., May 20, 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, is presenting two new sub-analyses from its Phase 3 POISE study in primary biliary cholangitis (PBC), at Digestive Disease Week® (DDW) 2024 in Washington, D.C. One analysis evaluated the effect of obeticholic acid (OCA) on alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, liver biomarkers associated with poor clinical outcomes; the other evaluated the effect of OCA on aminotransferase to platelet ratio index (APRI) score, a non-invasive test that can predict liver fibrosis progression.
“Beyond the established effect of OCA on alkaline phosphatase (ALP) levels, these new analyses demonstrate the impact of OCA on other important indicators of poor clinical outcomes in PBC,” said Robert G. Gish, M.D. FAASLD, Professor at Loma Linda University Department of Medicine. “When treating PBC, it’s imperative to assess other biomarkers beyond ALP, such as ALT and AST, as well as potential liver fibrosis, which can be done via non-invasive measures like APRI. Together, these assessments can better equip clinicians to make informed decisions about their patients’ care.”
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 10 mg, or OCA 5 mg for six months, titrated to 10 mg based on clinical response. The study included a 12-month double-blind phase, as well as a long-term safety extension phase up to five years. The primary endpoint of the 12-month double-blind portion of the trial is the achievement of both an ALP level <1.67x ULN with a ≥15% reduction from baseline and a normal bilirubin level, as compared to placebo.
OCA Impact on ALT and AST
A retrospective analysis was conducted to evaluate the impact of OCA on serum ALT and AST levels, including the proportion of patients who achieved normalization. Specifically, this analysis assessed time course of ALT/AST reductions in treatment and placebo arms, as well as normalization of AST/ALT levels in the overall POISE trial population and in patients who achieved or did not achieve the POISE primary endpoint at Month 12.
Ultimately, both OCA treatment groups significantly reduced ALT and AST levels as early as Week 2 and normalized ALT and AST levels in a significantly higher proportion of patients after 12 months of treatment compared to placebo. Specific findings include:
ALT
- OCA 10 mg and OCA 5-10 mg resulted in -25 U/L and -21 U/L least squares (LS) mean change from baseline in ALT, respectively; the placebo arm resulted in -5 U/L during the 12-month time period (p<0.001 for both OCA arms vs placebo at all time periods).
- Overall, OCA 10 mg and OCA 5-10 mg normalized ALT levels in 33% and 29% of patients, respectively, as compared to 10% of patients in the placebo group (p<0.05).
- Among patients who achieved the POISE primary endpoint at Month 12, 44% (p<0.05 vs. placebo) and 34% achieved normalization of ALT levels in the OCA 10 mg and OCA 5-10 mg groups, respectively. None of the patients who achieved the primary endpoint at Month 12 in the placebo group achieved normal ALT levels.
- Even among patients who did not achieve the POISE primary endpoint at Month 12, 23% (p<0.05 vs. placebo) and 24% of patients achieved normalization of ALT levels in the OCA 10 mg and OCA 5-10 mg groups, respectively. This compares to 11% of patients in the placebo group.
AST
- By Month 12, OCA 10 mg and OCA 5-10 mg resulted in -15 U/L and -13 U/L LS mean change from baseline in AST, respectively; the placebo group induced a +1 U/L over the same time period (p<0.001 for both OCA arms vs. placebo at all time periods).
- Overall, OCA 10 mg and OCA 5-10 mg normalized AST levels in 30% and 23% of patients, respectively, as compared to 10% of patients in the placebo group (p<0.05).
- Among patients who achieved the POISE primary endpoint at Month 12, 47% (p<0.05 vs. placebo) and 31% achieved normalization of ALT levels in the OCA 10 mg and OCA 5-10 mg groups, respectively. None of the patients who achieved the primary endpoint at Month 12 in the placebo group achieved normal ALT levels.
- Among patients who did not achieve the POISE primary endpoint at Month 12, 15% (p<0.05 vs. placebo) and 16% of patients achieved normalization of ALT levels in the OCA 10 mg and OCA 5-10 mg groups, respectively. This compares to 11% of patients in the placebo group.
Results on APRI Reduction
A post hoc analysis was conducted to determine the impact of OCA on APRI in patients with PBC from the Phase 3 POISE trial. A subset of patients with higher liver stiffness as measured by transient elastography (TE) at baseline and FIB-4 at Month 3 (to account for rapid OCA reductions in ALT/AST), (i.e., TE >8 kPa at baseline or FIB-4 >1.3 at month 3), suggesting a higher risk of advanced fibrosis, was also analyzed.
Overall, treatment with OCA significantly reduced APRI when compared to the placebo group (p=0.0004), including among those at higher risk for fibrosis.
“The Phase 3 POISE study has been instrumental in furthering our collective understanding of the effects of OCA in PBC treatment,” said Sangeeta Sawhney, Senior Vice President and Head of U.S. Research & Development. “At a time when the field is rapidly evolving, we are pleased to share new analyses from this study that demonstrate the benefits of OCA and build on our eight years of real-world experience on the market.”
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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