——Ocaliva（obeticholic acid）被美国FDA加快批准治疗原发性胆汁性肝硬化
2016年5月31日,美国食品和药品监管局(FDA)授权加快批准Ocaliva(obeticholic acid)与熊去氧胆酸(UDCA)组合为原发性胆管炎(PBC)在成年有对UDCA反应不佳，或在成年中作为单独治疗不能耐受UDCA。
PBC是一种慢性，或长持续，疾病致在肝中小胆管成为炎症，受损和最终地被破坏。这个致胆汁在肝脏中，它随时间损伤肝细胞，和导致肝硬化，肝脏瘢痕形成。当肝硬化进展，和肝中瘢痕组织量增加，肝脏丧失其功能。
FDA的药品评价和研究中心中药品评价III室副主任Amy Egan，M.D.，M.P.H.说： “患者任其不治疗，或患者对UDCA不反应，是处于肝脏衰竭和death,” “Ocaliva的今天批准为有原发性胆管炎PBC生活，对UDCA唯一的被批准其他治疗患者提供一个重要的治疗选择。”
Ocaliva，口服给药，结合至法尼醇X受体(FXR)，在肝和小肠中细胞的核中发现的一种受体。FXR的胆汁酸代谢通路的关键调节剂。Ocaliva增加来自肝脏的胆汁流和抑制在肝中胆汁酸产生，因此减低肝对胆汁酸毒性水平的暴露。
FDA的批准是根据生物标志物碱性磷酸酶(ALP)水平中的一个减低，作为替代性终点它，基于证据的多水平(机制性，临床试验，流行病学)，可被合理地被可靠可能预测临床获益，包括无移植生存中改善。在一项有216例参加者对照临床试验中显示Ocaliva的安全性和疗效。在12个月后，实现ALP水平中减低的参加者比例，Ocaliva-治疗参加者与安慰剂参加者比较中是较高。
Ocaliva的最常见副作用是皮肤的严重瘙痒，疲乏，腹痛和不适，关节痛，喉中部疼痛(口咽)，眩晕和便秘。在有完全胆道梗阻患者中不应使用Ocaliva。
对原发性胆管炎PBC有一个被批准的其他治疗，即熊去氧胆酸UDCA，它在1997年被FDA批准。UDCA在再超过50%患者中有效，但用UDCA高达40%患者没有实现血液化学中适当减低(如，ALP和/或总胆红素)，而5-10%不能耐受UDCA。
FDA授权Ocaliva快速通道指定，一种被设计加速意向治疗严重情况和显示解决一个满足医疗需求的药物发展，和加快审评的过程。FDA还授权Ocaliva一个孤儿药物指定。一个孤儿药物指定提供奖励例如税收减免，用户费用减免和对孤儿药物专有权资格以帮助和鼓励对罕见疾病药物的开发。
Ocaliva是在监管局的加快批准程序下被批准，该程序允许根据临床数据显示药物有一种对替代性终点的影响合理地可能预测对患者的临床获益，而批准一个药物治疗严重或危及生命疾病。该程序提供患者较早得到鼓舞人有前途新药，而公司进行验证性试验。
正在用Ocaliva 治疗的患者尚未曽被确定在生存，进展至肝硬化，或其他疾病相关症状改善，尽管正在进行一项验证性试验。
Ocaliva是由总部在纽约的Intercept Pharmaceuticals，有限公司制造。

Ocaliva, obeticholic acid (DSP-1747) (formerly 6ECDCA, INT-747, OCA)
U.S. Food and Drug Administration (FDA) has granted accelerated approval to Ocaliva (obeticholic acid) for the treatment of primary biliary cholangitis, previously known as primary biliary cirrhosis (PBC), in combination with ursodeoxycholic (UDCA) in adults with an inadequate response to UDCA or as monotherapy in adults unable to tolerate UDCA. Ocaliva is an agonist of the farnesoid X receptor (FXR), a nuclear receptor expressed in the liver and intestine and a key regulator of bile acid, inflammatory, fibrotic and metabolic pathways.
About the Phase 3 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 are unable to tolerate, UDCA. The POISE data showed that Ocaliva, at both a 10 mg dose and a 5 mg dose titrated to 10 mg, met the trial's primary endpoint of achieving a reduction in serum ALP to below a threshold of 1.67 times the upper limit of normal, with a minimum of 15% reduction in ALP level from baseline, and a normal bilirubin level after 12 months of therapy. Pruritus was the most frequently reported adverse event associated with Ocaliva treatment. In a group of patients who initiated Ocaliva at a 5 mg once-daily dose and titrated up to 10 mg once daily, only one patient (1%) discontinued from the study due to pruritus as compared to seven patients (10%) in the 10 mg dose group and after 12 months of treatment, efficacy was essentially equivalent to those patients who started the study at the 10 mg dose. Based on these results, a 5 mg to 10 mg titration regimen is recommended for Ocaliva dosing in PBC. Decreases in HDL-C were observed during treatment.
About Ocaliva™ (obeticholic acid)
Ocaliva is indicated in the United States 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.
The 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.
A marketing authorization application for Ocaliva for the treatment of PBC was accepted by the European Medicines Authority (EMA) in June 2015 and is currently under review. The brand name Ocaliva has been provisionally approved by the EMA.
IMPORTANT SAFETY INFORMATION
Contraindications
Ocaliva is contraindicated in patients with complete biliary obstruction.
Warnings and Precautions
Liver-Related Adverse Reactions
In two 3-month, placebo-controlled clinical trials a dose-response relationship was observed for the occurrence of liver-related adverse reactions including jaundice, 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 a pooled analysis of three placebo-controlled trials in patients with PBC, the exposure-adjusted incidence rates for all serious and otherwise clinically significant liver-related adverse reactions, and isolated elevations in liver biochemical tests, per 100 patient exposure years (PEY) were:  5.2 in the Ocaliva 10 mg group (highest recommended dosage), 19.8 in the Ocaliva 25 mg group (2.5 times the highest recommended dosage) and 54.5 in the Ocaliva 50 mg group (5 times the highest recommended dosage) compared to 2.4 in the placebo group.
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 clinically significant 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 the POISE trial, a 12-month double-blind randomized controlled 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.  In the subgroup of patients in the Ocaliva titration arm who increased their dosage from 5 mg once daily to 10 mg once daily after 6 months of treatment (n=33), the incidence of severe pruritus was 0% from months 0 to 6 and 15% from months 6 to 12. The median time to onset of severe pruritus was 11, 158 and 75 days for patients in the Ocaliva 10 mg, Ocaliva titration and placebo arms, respectively.
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). In the POISE trial, 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. At month 12, the reduction from baseline in mean HDL-C level was 19% in the Ocaliva 10 mg arm, 12% in the Ocaliva titration arm and 2% in the placebo arm. Nine patients in the Ocaliva 10 mg arm and six patients in the Ocaliva titration arm, versus three patients in the placebo arm had reductions in HDL-C to less than 40 mg/dL.
Monitor patients for changes in serum lipid levels during treatment. For patients who do not respond to Ocaliva after one 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 from subjects taking Ocaliva (≥5%) were pruritus, fatigue, abdominal pain and discomfort, rash, oropharyngeal pain, dizziness, constipation, arthralgia thyroid function abnormality and eczema.
Drug Interaction
Bile Acid Binding Resins
Bile acid binding resins such as cholestyramine, colestipol or colesevelam absorb and reduce bile acid absorption and may reduce the absorption, systemic exposure and efficacy of Ocaliva. If taking bile acid binding resins, take Ocaliva at least 4 hours before or 4 hours after (or at as great an interval as possible) taking a bile acid binding resin.
Please see Full Prescribing Information for Ocaliva (obeticholic acid) 5 mg and 10 mg tablets.
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm503964.htm