Efficacy and Safety of Bezafibrate 400 mg and Bezafibrate 200 mg as Adjunctive Treatments in Patients With Primary Biliary Cholangitis and Non-optimal Biochemical Response to Ursodeoxycholic Acid Therapy: a 12-month, Double-blind, Randomized, Placebo-controlled Trial With a 12-month, Double-blind, Placebo-free Extension Phase.

Primary biliary cholangitis (PBC) is a rare chronic, progressive, cholestatic liver disease that leads to cirrhosis and its life-threatening complications if undertreated. Ursodeoxycholic acid (UDCA) is the standard-of-care therapy for PBC. However, patients with an inadequate biochemical response to UDCA according to the Paris-2 criteria are still at high-risk of poor clinical outcome. In this situation of biochemical resistance to UDCA, bezafibrate 400 mg/d given in association with UDCA has been shown to improve the symptoms, biochemical response (BEZURSO study), histologic features, and possibly long-term clinical outcome. However, it has been shown that even patients with an adequate response to UDCA but persistent elevation in biochemical markers of cholestasis or liver inflammation, including alkaline phosphatases (ALP), gamma-glutamyl transpeptidase (GGT), transaminases, or total bilirubin (i.e., non-optimal biochemical response) have still an increased risk of death or liver transplantation in the long term, thus defining the complete normalization of these markers as the new clinically-relevant target for PBC treatment. In parallel to these findings, bezafibrate 400 mg/d as a second-line therapy for PBC could be associated with potentially dose-related, muscle, kidney, or liver toxic effects, and whether bezafibrate 200 mg/d could have a better benefit/risk ratio in this disease-setting remains to be determined. Therefore, our aim is to evaluate the efficacy and safety of bezafibrate 400 mg and bezafibrate 200 mg as adjunctive treatments in PBC patients with non-optimal biochemical response to UDCA.

Start Date01 Sep 2024

Sponsor / Collaborator

Assistance Publique des Hôpitaux de Paris SA

NCT05239468 / Active, not recruitingPhase 2

A Phase 2a, Double-Blind, Randomized, Active Controlled, Parallel Group Study Evaluating the Efficacy, Safety, and Tolerability of Bezafibrate Administered in Combination With Obeticholic Acid in Subjects With Primary Biliary Cholangitis

Study to determine the effect of the investigational drug bezafibrate (BZF) alone and in combination with the investigational drug obeticholic acid (OCA) in participants with Primary Biliary Cholangitis (PBC).

Start Date21 Mar 2022

Sponsor / Collaborator

Intercept Pharmaceuticals, Inc.

JPRN-jRCTs031210066 / RecruitingPhase 2

Prospective study of bezafibrate for post operated bilirary atresia

Start Date06 May 2021

Sponsor / Collaborator-

100 Clinical Results associated with Bezafibrate

100 Translational Medicine associated with Bezafibrate

100 Patents (Medical) associated with Bezafibrate

1,781

Literatures (Medical) associated with Bezafibrate

01 Feb 2024·Toxicology and applied pharmacology

Inhibition of tumor migration and invasion by fenofibrate via suppressing epithelial-mesenchymal transition in breast cancers

Article

Author: Chen, Yen-Chang ; Chang, Pei-Chun ; Chen, Jia-Hong ; Tsai, Cheng-Fang ; Wu, Chen-Teng ; Yeh, Wei-Lan

The recurrence and metastasis in breast cancer within 3 years after the chemotherapies or surgery leads to poor prognosis with approximately 1-year overall survival. Large-scale scanning research studies have shown that taking lipid-lowering drugs may assist to reduce the risk of death from many cancers, since cholesterol in lipid rafts are essential for maintain integral membrane structure and functional signaling regulation. In this study, we examined five lipid-lowering drugs: swertiamarin, gemfibrozil, clofibrate, bezafibrate, and fenofibrate in triple-negative breast cancer, which is the most migration-prone subtype. Using human and murine triple-negative breast cancer cell lines (Hs 578 t and 4 T1), we found that fenofibrate displays the highest potential in inhibiting the colony formation, wound healing, and transwell migration. We further discovered that fenofibrate reduces the activity of pro-metastatic enzymes, matrix metalloproteinases (MMP)-9 and MMP-2. In addition, epithelial markers including E-cadherin and Zonula occludens-1 are increased, whereas mesenchymal markers including Snail, Twist and α-smooth muscle actin are attenuated. Furthermore, we found that fenofibrate downregulates ubiquitin-dependent GDF-15 degradation, which leads to enhanced GDF-15 expression that inhibits cell migration. Besides, nuclear translocation of FOXO1 is also upregulated by fenofibrate, which may responsible for GDF-15 expression. In summary, fenofibrate with anti-cancer ability hinders TNBC from migration and invasion, and may be beneficial to repurposing use of fenofibrate.

01 Feb 2024·Journal of hazardous materials

Correlations between China’s socioeconomic status, disease burdens, and pharmaceuticals and personal care product levels in wastewater

Article

Author: Mu, Hongxin ; Ren, Hongqiang ; Chen, Ling ; Wu, Bing ; He, Ruonan

The presence of pharmaceutical and personal care products (PPCPs) in domestic wastewater can potentially indicate socioeconomic status and disease burdens. However, current knowledge is limited to the correlation between specific pharmaceuticals and diseases. This study aims to explore the associations between socioeconomic status, disease burdens, and PPCP levels in domestic wastewater at a national level. Samples from 171 wastewater influents across China were used to measure PPCPs, and the per capita consumption of PPCPs was calculated. Results showed that the 31 targeted PPCPs were widely present in wastewater with varying occurrence characteristics. The mean consumption levels of different PPCPs varied greatly, ranging from 0.03 to 110723.15 µg/d/capita. While there were no significant regional differences in the overall pattern of PPCP consumption, 22 PPCPs showed regional variations between Northern China and Southern China. PPCPs with similar usage purposes exhibited similar distribution patterns. Disease burden (70.1%) was the main factor affecting most PPCP consumption compared to socioeconomic factors (26.4%). Through correlation analyses, specific types of PPCPs were identified that were highly associated with socioeconomic status and disease burdens, such as hypertension-bezafibrate, brucellosis-quinolones, sulfonamides, hepatitis-triclosan, triclocarban, socioeconomic development-fluoxetine, and people's living standards-gemfibrozil. Despite some uncertainties, this study provides valuable insights into the relationship between PPCPs in domestic wastewater and socioeconomic status and human health.

01 Jan 2024·Journal of environmental sciences (China)

Factors hindering the degradation of pharmaceuticals from human urine in an iron-activated persulfate system

Article

Author: Guan, Dao ; Chen, Guanghao ; Luo, Yu ; Deng, Yangfan ; Sato, Yugo ; Xie, Yiruiwen

This study investigated the degradation of clofibric acid (CFA), bezafibrate (BZF), and sulfamethoxazole (SMX) in synthetic human urine using a novel mesoporous iron powder-activated persulfate system (mFe-PS system), and identified the factors limiting their degradation in synthetic human urine. A kinetic model was established to expose the radical production in various reaction conditions, and experiments were conducted to verify the modeling results. In the phosphate-containing mFe-PS system, the 120 min removal efficiency of CFA decreased from 95.1% to 76.6% as the phosphate concentration increased from 0.32 to 6.45 mmol/L, but recovered to 90.5% when phosphate concentration increased to 16.10 mmol/L. Meanwhile, the increased concentration of phosphate from 0.32 to 16.10 mmol/L reduced the BZF degradation efficacy from 91.5% to 79.0%, whereas SMX removal improved from 37.3% to 62.9%. The mFe-PS system containing (bi)carbonate, from 4.20 to 166.70 mmol/L, reduced CFA and BZF removal efficiencies from 100% to 76.8% and 80.4%, respectively, and SMX from 83.5% to 56.7% within a 120-min reaction time. In addition, alkaline conditions (pH ≥ 8.0) inhibited CFA and BZF degradations, while nonacidic pH (pH ≥ 7.0) remarkably inhibited SMX degradation. Results of the kinetic model indicated the formation of phosphate (H₂PO₄^·/HPO₄^·-) and/or carbonate radicals (CO₃^·-) could limit pharmaceutical removal. The transformation products (TPs) of the pharmaceuticals revealed more incompletely oxidized TPs occurred in the phosphate- and (bi)carbonate-containing mFe-PS systems, and indicated that H₂PO₄^·/HPO₄^·- mainly degraded pharmaceuticals via a benzene ring-opening reaction while CO₃^·- preferentially oxidized pharmaceuticals via a hydroxylation reaction.

News (Medical) associated with Bezafibrate

05 Jun 2024

·www.biospace.com

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  . 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 or connect with the Company on LinkedIn, Threads and X (formerly Twitter). Contact For more information about Intercept, please contact: For media: media@interceptpharma.com

Clinical ResultPhase 2Accelerated Approval

29 May 2024

·www.globenewswire.com

Intercept Announces New Data to be Presented at the European Association for the Study of the Liver (EASL) Congress 2024

Abstracts include late breaker featuring new six-month data from ongoing Phase 2 study evaluating the combination of obeticholic acid and bezafibrate in PBCMORRISTOWN, N.J., May 29, 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 nine abstracts related to primary biliary cholangitis (PBC) and alcohol-related liver disease will be presented at EASL Congress 2024. The congress will be held from June 5-8 in Milan, Italy. “We are thrilled to present our latest research in PBC at this year’s EASL Congress,” said Sangeeta Sawhney, Senior Vice President and Head of U.S. Research & Development at Intercept. “The promising six-month results from one of our ongoing Phase 2 studies evaluating the combination of obeticholic acid and bezafibrate as well as new analyses from our landmark Phase 3 POISE trial underscore our commitment to advancing treatment options for people living with PBC. We look forward to sharing our findings with the global liver health community.” Presentations by Intercept at EASL Congress 2024 include:Late Breaker Poster Presentation“Combined effect of obeticholic acid and bezafibrate in patients with primary biliary cholangitis and inadequate response or intolerance to ursodeoxycholic acid: 6-month results from a Phase 2 trial” (Abstract #LB136; Poster ID LBP-027)Wednesday, June 5, 8:30 CEST David Jones, Alexandre Louvet, Christophe Corpechot, Vaclav Hejda, Heng Zou, Antonio Civitarese, Alejandra Villamil, Frederick Nevens PBC Poster Presentations“Time to initiation of the second-line therapy obeticholic acid in patients with primary biliary cholangitis” (Abstract #1278; Poster ID THU-110) Thursday, June 6, 8:30 CEST Sonal Kumar, Joanna P. MacEwan, Alina Levine, Leona Bessonova, Radhika Nair, Darren Wheeler, Jing Li, Robert S. Brown, Jr. “Obeticholic acid normalizes inflammatory biomarkers in patients with primary biliary cholangitis” (Abstract #3230; Poster ID THU-132) Thursday, June 6, 8:30 CEST David E. Jones, Christopher L. Bowlus, Arash Thranian, Mary Erickson, Jing Li, Christopher Gasink, Robert G. Gish “Effect of obeticholic acid on reduction and normalization of alanine aminotransferase and aspartate aminotransferase in the Phase 3 POISE trial in primary biliary cholangitis” (Abstract #1322; Poster ID FRI-023) Friday, June 7, 8:30 CEST Robert G. Gish, Darren Wheeler, Jing Li, Christopher Gasink, David W. Victor III “Evaluation of aspartate aminotransferase to platelet ratio index and fibrosis-4 index stabilization in the Phase 3 POISE trial of obeticholic acid for the treatment of primary biliary cholangitis” (Abstract #1315; Poster ID FRI-030) Friday, June 7, 8:30 CEST Alan Bonder, Darren Wheeler, Jing Li, Christopher Gasink, Robert G. Gish “Stabilization of enhanced liver fibrosis and liver stiffness measures in the open-label extension of the Phase 3 POISE trial of obeticholic acid for the treatment of primary biliary cholangitis” (Abstract #1293; Poster ID FRI-015) Friday, June 7, 8:30 CEST Robert G. Gish, Darren Wheeler, Jing Li, Christopher Gasink, Alan Bonder “Association of elevated liver biochemistries and clinical outcomes within strata of alkaline phosphatase levels in patients with primary biliary cholangitis” (Abstract #1301; Poster ID FRI-008) Friday, June 7, 8:30 CEST David W. Victor III, Joanna P. MacEwan, Jennifer Hernandez, Radhika Nair, Mustafa Kamal, Darren Wheeler, Jing Li, Leona Bessonova, Christopher Gasink, Kris V. Kowdley Alcohol-related Liver Disease Poster Presentations“Farnesoid X receptor agonist INT-787 exhibits high intestinal localization” (Abstract #1313; Poster ID THU-316) Thursday, June 6, 8:30 CEST Jennifer Burkey, Sanjay Kansra, Antonio Macchiarulo, Kenneth Brouwer, Luciano Adorini, Mary Erickson, Roberto Pellicciari “Farnesoid X receptor agonist INT-787 protects human liver organoids from alcohol-induced injury” (Abstract #1320; Poster ID TOP-313) Thursday, June 6, 8:30 CEST Francesca De Franco, Daniela Passeri, Sanjay Kansra, Luciano Adorini, Mary Erickson, Roberto Pellicciari More information about these abstracts will be made available after the respective embargoes, as set by the EASL organizers, are lifted for each presentation. A full list of sessions at EASL Congress 2024 is available at www.easlcongress.eu. About the Investigational OCA-bezafibrate CombinationIntercept has two ongoing Phase 2 studies (747-213 / NCT04594694, 747-214 / NCT05239468) that are exploring a range of therapeutic doses for the 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 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 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 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 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 InterceptIntercept 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). ContactFor more information about Intercept, please contact: For media:media@interceptpharma.com

Phase 2Clinical ResultAccelerated ApprovalPhase 3

20 May 2024

·www.globenewswire.com

Intercept Presents New Data Demonstrating the Impact of OCA-Bezafibrate Combination Therapy on ALP and Metabolic Outcomes After Six Months of Treatment at Digestive Disease Week® 2024

Results from a Phase 2 study show combination of OCA 5-10mg and bezafibrate 400mg induced the greatest percent change from baseline in ALP at Month 6 OCA and bezafibrate combination therapy has acceptable metabolic profile Results featured in podium presentation today at DDW 2024 May 18, 2024 -- 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 new data from a planned six-month analysis of its ongoing Phase 2 study 747-213 evaluating a fixed-dose combination of obeticholic acid (OCA) and bezafibrate in patients with primary biliary cholangitis (PBC) at Digestive Disease Week® (DDW) 2024 in Washington, D.C. Results from the study show that six-month administration of OCA and bezafibrate has the potential to normalize alkaline phosphatase (ALP), a serum biomarker of PBC-related liver damage that has been correlated with improved transplant-free and decompensation-free survival. “I am encouraged by the findings from this six-month analysis of the fixed-dose combination of OCA and bezafibrate,” said Alan Bonder, MD, Medical Director of Liver Transplant, BIDMC, and Associate Professor of Medicine, Harvard Medical School. “As a clinician, normalizing ALP is a key component of pharmacological therapy in PBC, and the impact of this combination on ALP, coupled with its ability to normalize total and LDL cholesterol, gives me confidence in this investigational therapy.” 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 (OCA5-10/B200 IR) (n=19) bezafibrate 400 mg SR + OCA 5 mg titrated to 10 mg at week 4 (OCA5-10/B400 SR) (n=18) Following the 12-week double-blind treatment period, OCA-bezafibrate dosage could be optimized in the long-term safety extension. The objectives of this study were to evaluate change in ALP from baseline to Month 6, as well as changes in lipid panel over the same time period. Six-Month Results on ALP Reduction OCA/B400 SR induced the greatest percent change from baseline of ALP, resulting in a -65.3% reduction (p B400 resulted in a -49.0% change from baseline OCA/B200 IR induced a -42.4% reduction from baseline B200 IR induced a -39.3% change from baseline Six-Month Results on Metabolic Outcomes Mean total cholesterol was reduced to less than 200 mg/dl in the OCA/B400 SR arm along with 19% mean reduction in LDL cholesterol. HDL levels remained within normal range. Total Cholesterol Only the OCA/B400 SR arm resulted in normalization of total mean cholesterol levels at Month 6 to less than 200 mg/dL OCA/B400 SR induced a -19.6% reduction from baseline (p=0.004 vs. B400 SR, which induced a -6.8% reduction from baseline) OCA/B200 IR resulted in a -14.5% reduction from baseline (p LDL Cholesterol OCA/B400 SR induced a -18.7% change from baseline OCA/B200 IR resulted in a -9.6% reduction from baseline B400 SR and B200 IR induced a -11.1% and -9.5% reduction from baseline, respectively HDL Cholesterol OCA/B400 SR and OCA/B200 IR both induced reductions in HDL cholesterol; however, levels remained within a normal range as defined by the U.S. National Library of Medicine. OCA/B400 SR induced a -17.9% reduction from baseline (p OCA/B200 IR resulted in a -14.9% reduction from baseline (p “The results from this analysis provide important insights on the potential benefits of OCA-bezafibrate combination therapy in PBC,” said Sangeeta Sawhney, Senior Vice President and Head of U.S. Research & Development. “We have conducted multiple studies demonstrating the value of OCA – namely, transplant-free survival – and we are eager to continue innovating on behalf of people living with PBC by studying OCA’s apparent synergy with bezafibrate to further improve clinical outcomes. We look forward to presenting these data in further depth at DDW 2024.” The company 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 Fixed-Dose Combination Intercept is investigating a fixed-dose 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. 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. 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. 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). The content above comes from the network. if any infringement, please contact us to modify.

Clinical ResultAccelerated Approval

100 Deals associated with Bezafibrate

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KEGG	Wiki	ATC	Drug Bank
D01366	Bezafibrate	C10AB02	DB01393

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Hyperlipidemias	JP	Kissei Pharmaceutical Co., Ltd.	15 Mar 1991
Hypercholesterolemia	JP	Nipro Corp.	01 Jan 1978
Hyperlipidemia, Familial Combined	JP	Nipro Corp.	01 Jan 1978
Hypertriglyceridemia	JP	Nipro Corp.	01 Jan 1978

Developing

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Indication	Highest Phase	Country/Location	Organization	Date
Primary Biliary Cholangitis	Phase 3	FR	Assistance Publique des Hôpitaux de Paris SA	01 Sep 2024
Cholangitis, Sclerosing	Phase 3	FR	Assistance Publique des Hôpitaux de Paris SA	06 Apr 2021
Carnitine Palmitoyl Transferase 2 Deficiency	Phase 3	FR	Assistance Publique des Hôpitaux de Paris SA	01 Jun 2006

Clinical Result

Indication

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Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04594694 (747-213, GlobeNewswire) Manual	Phase 2	Primary Biliary Cholangitis	75	bezafibrate 400 mg SR + OCA 5 mg titrated to 10 mg at week 4	bfjyrbmaxz(ysnbalrfze) = gwpirnpcgp eevswdqwfc (eoiiaztmzy ) View more	Positive	18 May 2024
				bezafibrate 200 mg IR + OCA 5 mg titrated to 10 mg at week 4	bfjyrbmaxz(ysnbalrfze) = ygmfdlxgkq eevswdqwfc (eoiiaztmzy ) View more
NCT02548832 (CTgov)	Phase 3	Hyperlipidemia, Familial Combined	36	Berberine (Berberine)	eouiclddvs(nwtkxknzfc) = wdwnlaflqg zraadpngns (nkmfeckktm, dzdclsooyb - flcbygbxvl) View more	-	24 Feb 2023
				Bezafibrate (Bezafibrate)	eouiclddvs(nwtkxknzfc) = grcdhhpnju zraadpngns (nkmfeckktm, nngyvsnsew - cvwhoybmtq) View more
Japan PBC Study Group (EASL2022)	Not Applicable	albumin \| bilirubin	889	Bezafibrate and Ursodeoxycholic Acid	xtocfdzjxs(momddxxpyv) = nrwpowrzoa nxotkaijkh (bgblymukjb )	Negative	23 Jun 2022
WCLC2021	Not Applicable	Non-Small Cell Lung Cancer	-	Fibrates	hifmvztgze(qceiqfaogf): HR = 0.86 (95% CI, 0.75 - 0.99), P-Value = 0.042	-	08 Sep 2021
				No Fibrates
EASD2020	Not Applicable	Glucose Intolerance	-	Bezafibrate 400 mg/die	kmfjhlvjzj(vbdpderaad) = egwccdfwup jwbonvqviq (jixbpsxuqt ) View more	-	22 Sep 2020
NCT02984982 (ODYSSEY J-IVUS, CTgov)	Phase 4	Acute Coronary Syndrome \| Coronary Artery Disease \| Hypercholesterolemia	206	Antiplatelets+Atorvastatin+Rosuvastatin+Bezafibrate+Ezetimibe+Anticoagulants (Standard of Care)	lybusemnez(nrhsblwhxa) = tjgqlvobzs tfjzenvixc (frftchoopq, aduvohauew - pvjwyrsavb) View more	-	09 Sep 2019
				Antiplatelets+Atorvastatin+Rosuvastatin+Alirocumab SAR236553+Bezafibrate+Ezetimibe+Anticoagulants (Alirocumab)	lybusemnez(nrhsblwhxa) = keyytnkwzd tfjzenvixc (frftchoopq, hyvdbobmke - hqnurovitl) View more
NCT01654731 (Pubmed \| Br Dent J) Manual	Phase 3	Primary Biliary Cholangitis	100	Bezafibrate	yxirvtplxi(bicfkojhsq) = qodjdpkwtu maikoduftd (nabsyaalps ) View more	Positive	07 Jun 2018
				Placebo	yxirvtplxi(bicfkojhsq) = bjmjtyzhbm maikoduftd (nabsyaalps ) View more
ISRCTN34303497 (Pubmed \| Br J Haematol)	Phase 2	Burkitt Lymphoma	95	Bezafibrate	amnxmoxrmq(urdnquvvbr) = doqznjcrap jbjcmennxo (qsefeiunvh )	-	01 Mar 2014
				Medroxyprogesterone acetate	amnxmoxrmq(urdnquvvbr) = lrffiszxta jbjcmennxo (qsefeiunvh )
NCT02937012 (Pubmed)	Phase 3	Primary Biliary Cholangitis	151	Bezafibrate	vkbjbzekho(cgceowomiy) = fnvyqyifen thahptncot (keeufuqkmw ) View more	-	18 Jan 2012
IAS2002	Not Applicable	-	-	Fibrates	bkafoyegxq(wdgytszuww) = nsvfulfoet cszoagsldu (zhctthdadl ) View more	-	01 Jan 2002
				Statins	bkafoyegxq(wdgytszuww) = auxsprgnpr cszoagsldu (zhctthdadl ) View more

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