肝病重磅新药OCALIVA(obeticholic acid)—20年来首个获批治疗原发性胆汁性胆管炎

2016年12月16日，美国生物制药公司Intercept开发的一款肝病新药Ocaliva（obeticholic acid，OCA，一种鹅脱氧胆酸衍生物）近日在欧盟监管方面传来喜讯。
欧盟委员会（EC）有条件批准Ocaliva：（1）联合熊去氧胆酸（ursodeoxycholic acid，UDCA）用于对UDCA反应不足的原发性胆汁性胆管炎（以前被称为原发性胆汁性肝硬化，PBC）成人患者；（2）作为单药疗法用于对UDCA不耐受的原发性胆汁性胆管炎（PBC）成人患者。
在美国，Ocaliva于今年5月底获得美国食品和药物管理局（FDA）加速批准。
在此之前，熊去氧胆酸（UDCA）是唯一获批治疗原发性胆汁性胆管炎（PBC）的药物。此次批准，使Ocaliva成为近20年来获批治疗PBC的首个新药。
Ocaliva的获批是基于一项III期临床研究的数据，该研究入组了216例原发性胆汁性胆管炎（PBC）患者。
数据显示，经过12个月治疗后，与安慰剂组相比，Ocaliva治疗组有显著更高比例的患者碱性磷酸酶（alkaline phosphatase，病情进展的一个重要指标）水平实现降低（47% vs 10%）。
Ocaliva（obeticholic acid，OCA）是Intercept开发的一款创新药物法尼酯X受体（FXR）激动剂，这是一种人类胆汁酸模拟物，目前正开发用于多种慢性肝脏疾病的治疗，包括原发性胆汁性胆管炎（PBC）、非酒精性脂肪性肝炎（NASH）、原发性硬化性胆管炎（PSC）、胆道闭锁。此前，FDA已授予OCA治疗伴有肝纤维化的NASH的突破性药物资格、治疗PBC的快车道地位、治疗PBC和PSC的孤儿药地位。Intercept拥有OCA在日本、中国、韩国以外地区的全球权力；在日中韩地区，Intercept已将OCA授权给了日本住友制药。
FXR是表达于肝脏和小肠中的一种核受体，是胆汁酸、炎症、纤维化、代谢通路中的关键调节因子。目前，其他处于临床开发的FXR还包括诺华的LJN 452和吉利德的GS 9674，这2个药物均处于II期临床开发，治疗原发性胆汁性胆管炎（PBC）和非酒精性脂肪性肝炎（NASH）。另外，艾尔健和Arkana的一款药物AKN-083也处于早期开发阶段。
原发性胆汁性胆管炎是一种罕见的肝脏疾病，主要是因胆管（功能为将胆汁运出肝脏）遭到自身免疫性破坏，导致胆汁淤积。该病主要是一种女性疾病，在40岁以上女性群体中的发病率约为千分之一。在美国，原发性胆汁性胆管炎是导致女性肝脏移植的首要病因。在欧洲，该病约占胆汁郁积性疾病所致肝移植病例的一半左右，约占所有肝移植病例的6%。（生物谷Bioon.com）

OCALIVA® (obeticholic acid)
INDICATION AND IMPORTANT SAFETY INFORMATION
OCALIVA® (obeticholic acid) is indicated for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as monotherapy in adults 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.
Contraindications: OCALIVA is contraindicated in patients with complete biliary obstruction.
Warnings and Precautions
Liver-Related Adverse Reactions
Dose-related, liver-related adverse reactions including jaundice, worsening ascites and primary biliary cholangitis flare have been observed in clinical trials, as early as one month after starting treatment with OCALIVA 10 mg once daily up to 50 mg once daily (up to 5-times the highest recommended dosage). Monitor patients during treatment with OCALIVA for elevations in liver biochemical tests and for the development of liver-related adverse reactions. Weigh the potential risks against the benefits of continuing treatment with OCALIVA in patients who have experienced serious liver-related adverse reactions. The maximum recommended dosage of OCALIVA is 10 mg once daily. Adjust the dosage for patients with moderate or severe hepatic impairment. Discontinue OCALIVA in patients who develop complete biliary obstruction.
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 trial that consisted of 216 patients. Severe pruritus consists of intense or widespread itching, interfering with activities of daily living, or causing severe sleep disturbance, or intolerable discomfort, and typically requiring medical interventions. Management strategies include the addition of bile acid 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 tolerable, recommended dosage (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 from subjects taking OCALIVA (≥5%) were 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) is decreased following co-administration 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, the active ingredient in OCALIVA, 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.
Please see Full Prescribing Information for OCALIVA (obeticholic acid) 5 mg and 10 mg tablets.
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.