“Patients with liver disease at any stage often experience disruptive cognitive problems, such as difficulty concentrating and short-term memory loss, which can greatly impact quality of life,” said co-lead investigators Fiona Oakley, PhD, and David E.J. Jones, MD, PhD, Newcastle University. “We conducted this research to better understand the mechanisms behind these cognitive symptoms and to equip us with information to find effective treatment options to improve patients’ lives.” The study assessed mice that were made cholestatic by bile duct ligation (BDL) with cognitive impairment of the type seen in human cholestatic patients and typically associated with significant brain changes including loss of blood brain barrier integrity, abnormalities in hippocampal function and senescence (deterioration usually associated with aging) of neurons. UDCA, bezafibrate and OCA, three therapies that are commonly used in the clinical setting for patients with primary biliary cholangitis (PBC), were initiated in these cognitively impaired mice. Only treatment with OCA – a potent farnesoid X receptor (FXR) agonist and approved second-line therapy for PBC – significantly reduced short-term memory abnormalities. These effects of OCA on cognition were confirmed in a separate validation cohort of mice, conducted by a different observer. In pathological evaluations, researchers found that FXR expression, the receptor targeted by OCA, was significantly lower in BDL mice vs. controls but returned to near normal levels with OCA therapy. Further, OCA metabolites were found in the bile, serum and brain of OCA-treated BDL mice, leading researchers to hypothesize that OCA could directly act on cell populations within the brain. OCA therapy also ameliorated cholestasis-induced hepatocyte senescence, which is commonly seen in cholestatic livers in animal models as well as PBC patients, and is considered a predictor of disease progression. An additional analysis of a human neural stem cell (hNSC) culture model, undertaken to explore translation into the human disease setting, showed that cholestatic serum induced senescence in human neurons and that the effect was again reversed by OCA but not by UDCA or bezafibrate. "We are encouraged by these positive findings, which show that OCA may improve cognitive impairment and neuronal senescence in animal and in vitro models of human disease," said M. Michelle Berrey, MD, MPH, President, Research & Development and Chief Medical Officer of Intercept. “We are excited about the potential of OCA to alleviate neurocognitive symptoms and to improve quality of life in patients living with PBC.” 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. 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. 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. OCALIVA is contraindicated in patients with: decompensated cirrhosis (e.g., Child-Pugh Class B or C) or a prior decompensation event
complete biliary obstruction
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 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. 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. 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. 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 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. Forward-Looking Statements
This press release contains forward-looking statements (“FLS”), including regarding our product pipeline, our clinical studies, and our research and development (“R&D”) plans. Important factors could cause actual results to differ materially from the FLS. For example, our clinical studies could be delayed, not reach enrollment targets, have methodological problems, or indicate that a studied drug is not effective, safe, or tolerable. As a result, our pipeline, studies, and R&D initiatives could be unsuccessful.
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