英文药名：OCALIVA（obeticholic acid filmcoated tablets）

中文药名：奥贝胆酸薄膜片

生产厂家：Intercept Pharma UK
药品简介
奥贝胆酸obeticholic acid（商品名：OCALIVA）获欧盟批准用于罕见型原发性胆汁性胆管炎
2016年12月6日，欧盟委员会批准Intercept生产的的奥贝胆酸obeticholic acid（商品名：Ocaliva）用于原发性胆汁性胆管炎治疗，这也使得患者近20年来可以潜在获取到用于该疾病治疗的首个新的疗法。
原发性胆汁性胆管炎是一种罕见的自体免疫性胆汁淤积性肝病，其主要影响妇女。与普通人群相比，这种疾病如果不进行治疗，患者的生存期会严重恶化。
奥贝胆酸是一种高选择性法尼酯X受体拮抗剂，法尼酯X受体是表达在肝脏与调节胆汁酸、炎症、纤维化及代谢途径的肠脏上的一种核受体。
在一项3期临床试验中，以奥贝胆酸与熊去氧胆酸合并治疗的滴定组大约有一半的患者（46%）达到主要终点，即血清碱性磷酸酶获得明显下降，相比之下，对照组只有10%的患者达到这一结果，同时合并用药治疗组有77%的患者在治疗12个月时血清碱性磷酸酶的下降幅度超过15%，而仅以熊去氧胆酸治疗的患者只有29%的人达到这一结果。
这款药物在欧洲获得有条件上市许可，与熊去氧胆酸联合用于原发性胆汁性胆管炎，用于对熊去氧胆酸没有充分响应的成年患者，或作为单药用于不能耐受熊去氧胆酸的成年患者。据该公司称，这款药物的可及性解决了一个重要的未满足需求，因为高达40%的患者对熊去氧胆酸可能没有充分的响应，熊去氧胆酸是仅有的另一款可供用于治疗这种疾病的药物。
尽管熊去氧胆酸可供使用，但许多患者仍处于不良结局的重大风险中，没有替代治疗选择可供使用。奥贝胆酸现在有助于为这些患者填补一个重要的未满足需求，比利时鲁汶天主教大学医院的Nevens如是称，他也是3期POISE临床研究的主要研究者。
作为一个社区，我们优先考虑的是倡导变化，确保诊断有原发性胆汁性胆管炎的患者有最可能好的预后，Reic 称，他是欧洲肝病协会的会长。出于这种考虑，我们很高兴为对目前可供使用治疗药物没有充分响应或不耐受的患者取得这种进展。
按照有条件批准的条款，Intercept需要基于正在进行的4期COBALT结局研究及一项在肝损伤患者中进行的短期研究，为奥贝胆酸提供有关安全性及有效性分析的上市后更新资料。
注：本品已在美国、德国、英国等国上市销售，采购者以咨询为准
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OCALIVA 5mg & 10mg film-coated tablets
1. Name of the medicinal product
OCALIVA 5 mg film-coated tablets
OCALIVA 10 mg film-coated tablets
2. Qualitative and quantitative composition
OCALIVA 5 mg film-coated tablets
Each film-coated tablet contains 5 mg of obeticholic acid.
OCALIVA 10 mg film-coated tablets
Each film-coated tablet contains 10 mg of obeticholic acid.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Film-coated tablet (tablet)
OCALIVA 5 mg film-coated tablets
Yellow, 8 mm round tablet debossed with 'INT' on one side and '5' on the other side.
OCALIVA 10 mg film-coated tablets
Yellow, 7.6 mm X 7.4 mm triangular tablet debossed with 'INT' on one side and '10' on the other side.
4. Clinical particulars
4.1 Therapeutic indications
OCALIVA is indicated for the treatment of primary biliary cholangitis (also known as primary biliary cirrhosis) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA or as monotherapy in adults unable to tolerate UDCA.
4.2 Posology and method of administration
Posology
The starting dose is 5 mg once daily.
Based on an assessment of tolerability after 6 months, the dose should be increased to 10 mg once daily to achieve optimal response.
No dose adjustment of concomitant UDCA is required in patients receiving obeticholic acid.
Management and dose adjustment for severe pruritus
Management strategies include the addition of bile acid binding resins or antihistamines.
For patients experiencing severe intolerability due to pruritus, one of the following should be considered:
• Reducing the dosage of obeticholic acid to:
▪ 5 mg every other day, for patients intolerant to 5 mg once daily
▪ 5 mg once daily, for patients intolerant to 10 mg once daily
• Temporarily interrupting obeticholic acid dosing for up to 2 weeks followed by restarting at a reduced dosage.
• Continue to increase the dosage to 10 mg once daily, as tolerated, to achieve optimal response.
• Consider discontinuing treatment with obeticholic acid for patients who continue to experience persistent intolerable pruritus.
Special populations
Elderly (≥ 65 years)
Limited data exists in elderly patients. No dose adjustment is required for elderly patients (see section 5.2).
Patients with renal impairment
Limited data exists in patients with mild and moderate renal impairment and no data exists in severe renal impairment. No dose adjustment is required for patients with renal impairment (see section 5.2).
Patients with hepatic impairment
Limited data exists in patients with moderate to severe hepatic impairment. The recommended starting dosage for moderate (Child-Pugh Class B) and severe (Child-Pugh Class C) hepatic impairment is 5 mg once weekly. If an adequate reduction in alkaline phosphatase and/or total bilirubin has not been achieved after 3 months of OCALIVA 5 mg once weekly, and the patient is tolerating the medicinal product, increase the dose of OCALIVA to 5 mg twice weekly (at least three days apart between doses) and subsequently to 10 mg twice weekly (at least three days apart between doses) depending on response and tolerability. No dose adjustment is needed for mild hepatic impairment (Child-Pugh Class A) (see sections 4.4 and 5.2).
Paediatric population
There is no relevant use of obeticholic acid in the paediatric population in the treatment of primary biliary cholangitis (PBC).
Method of administration
The tablet should be taken orally with or without food.
For patients taking bile acid binding resins, obeticholic acid should be administered at least 4-6 hours before or 4-6 hours after taking a bile acid binding resin, or at as great an interval as possible (see section 4.5).
4.3 Contraindications
- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
- Complete biliary obstruction.
4.4 Special warnings and precautions for use
Liver related adverse events
Elevations in alanine amino transferase (ALT) and aspartate aminotransferase (AST) have been observed in patients taking obeticholic acid. Clinical signs and symptoms of hepatic decompensation have also been observed. These events have occurred as early as within the first month of treatment. Liver-related adverse events have primarily been observed at doses higher than the maximum recommended dose of 10 mg once daily (see section 4.9). Patients should be monitored during treatment with OCALIVA for elevations in liver biochemical tests and for the development of liver-related adverse events. Dosage adjustments are needed for patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment (see sections 4.2 and 5.2).
Severe pruritus
Severe pruritus was reported in 23% of patients treated with OCALIVA 10 mg arm, 19% of patients in the OCALIVA titration arm, and 7% of patients in the placebo arms. 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 binding resins or antihistamines, dose reduction, reduced dosing frequency, and/or temporary dose interruption (see sections 4.2 and 4.8).
4.5 Interaction with other medicinal products and other forms of interaction
Medicinal products that are affected by obeticholic acid
Warfarin
International normalised ratio (INR) is decreased following co-administration of warfarin and obeticholic acid. INR should be monitored and the dose of warfarin adjusted, if needed, to maintain the target INR range when co-administering obeticholic acid and warfarin.
Interaction with CYP1A2 substrates with narrow therapeutic index
Obeticholic acid may increase the exposure to concomitant medicinal products that are CYP1A2 substrates. Therapeutic monitoring of CYP1A2 substrates with narrow therapeutic index (e.g. theophylline and tizanidine) is recommended.
Medicinal products that affect obeticholic acid
Bile acid binding resins
Bile acid binding resins such as cholestyramine, colestipol, or colesevelam adsorb and reduce bile acid absorption and may reduce efficacy of obeticholic acid. When concomitant bile acid binding resins are administered, obeticholic acid should be taken at least 4-6 hours before or 4-6 hours after taking a bile acid binding resin, or at as great an interval as possible.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no data on the use of obeticholic acid in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of obeticholic acid during pregnancy.
Breast-feeding
It is unknown whether obeticholic acid is excreted in human milk. Based on animal studies and intended pharmacology, obeticholic acid is not expected to interfere with breast-feeding or the growth or development of a breast-fed child. A decision should be made whether to discontinue breast-feeding or to discontinue/abstain from obeticholic acid therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman (see section 5.3).
Fertility
No fertility data is available in humans. Animal studies do not indicate any direct or indirect effects on fertility or reproduction (see section 5.3).
4.7 Effects on ability to drive and use machines
Obeticholic acid has no or negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
Summary of the safety profile
The most commonly reported adverse reactions were pruritus (63%) and fatigue (22%). Adverse reactions leading to discontinuation were 1% in the OCALIVA titration arm and 11% in the OCALIVA 10 mg arm. The most common adverse reaction leading to discontinuation was pruritus. The majority of pruritus occurred within the first month of treatment and tended to resolve over time with continued dosing.
Tabulated list of adverse reactions
The adverse reactions reported with OCALIVA in the phase III clinical study are listed in the table below by MedDRA system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (cannot be estimated from the available data).
Table 1. Frequency of adverse reactions in PBC patients*

System Organ Class	Very common	Common
Endocrine disorders		Thyroid function abnormality
Nervous system disorders		Dizziness
Cardiac disorders		Palpitations
Respiratory, thoracic and mediastinal disorders		Oropharyngeal pain
Gastrointestinal disorders	Abdominal pain and discomfort	Constipation
Skin and subcutaneous tissue disorders	Pruritus	Eczema, Rash
Musculoskeletal and connective tissue disorders		Arthralgia
General disorders and administration site conditions	Fatigue	Oedema peripheral, Pyrexia

Adverse reactions are defined as events occurring at a rate of greater than or equal to 5% of patients on obeticholic acid treatment arm and at an incidence greater than or equal to 1% higher than in the placebo treatment arm.
Description of selected adverse reactions
Pruritus
Approximately 60% of patients had a history of pruritus upon enrollment in the phase III study. Treatment-emergent pruritus generally started within the first month following the initiation of treatment.
Relative to patients who started on 10 mg once daily in the OCALIVA 10 mg arm, patients in the OCALIVA titration arm had a lower incidence of pruritus (70% and 56% respectively) and a lower discontinuation rate due to pruritus (10% and 1%, respectively).
The percentages of patients who required interventions (i.e, dosage adjustments, treatment interruptions, or initiation of antihistamines or bile acid binding resins) were 41% in the OCALIVA 10 mg arm, 34% in the OCALIVA titration group, and 19% in the placebo group.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard.
4.9 Overdose
The highest single dose exposure of obeticholic acid in healthy volunteers has been at the 500 mg dose. Repeated doses of 250 mg have been administered for 12 consecutive days and some subjects experienced pruritus and reversible transaminase liver elevations. In PBC patients who received OCALIVA 25 mg once daily (2.5 times the highest recommended dosage) or 50 mg once daily (5 times the highest recommended dosage), a dose-dependent increase in the incidence of liver-related adverse reactions (e.g., ascites, primary biliary cholangitis flare, new onset jaundice), and transaminase and bilirubin elevations (up to greater than 3-times upper limit of normal [ULN]) were reported. In the case of overdose, patients should be carefully observed and supportive care administered, as appropriate.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Bile Acid Preparations, ATC code: A05AA04
Mechanism of action
Obeticholic acid is a selective and potent agonist for the farnesoid X receptor (FXR), a nuclear receptor expressed at high levels in the liver and intestine. FXR is thought to be a key regulator of bile acid, inflammatory, fibrotic, and metabolic pathways. FXR activation decreases the intracellular hepatocyte concentrations of bile acids by suppressing de novo synthesis from cholesterol, as well as, by increasing transport of bile acids out of the hepatocytes. These mechanisms limit the overall size of the circulating bile acid pool while promoting choleresis, thus reducing hepatic exposure to bile acids.
Clinical efficacy and safety
A phase III, randomised, double-blind, placebo-controlled, parallel-group, 12-month study (POISE) evaluated the safety and efficacy of OCALIVA in 216 patients with PBC who were taking UDCA for at least 12 months (stable dose for ≥ 3 months) or who were unable to tolerate UDCA and did not receive UDCA for ≥3 months. Patients were included in the trial if the alkaline phosphatase (ALP) was greater than or equal to 1.67 times upper limit of normal (ULN) and/or if total bilirubin was greater than 1 x ULN but less 2 x ULN. Patients were randomised (1:1:1) to receive once daily placebo, OCALIVA 10 mg, or OCALIVA titration (5 mg titrated to 10 mg at 6 months dependent on therapeutic response/tolerability). The majority (93%) of patients received treatment in combination with UDCA and a small number of patients (7%) unable to tolerate UDCA received placebo, OCALIVA (10 mg) or OCALIVA titration (5 mg to 10 mg) as monotherapy. ALP and total bilirubin were assessed as categorical variables in the primary composite endpoint, as well as continuous variables over time.
The study population was predominantly female (91%) and white (94%). The mean age was 56 years, with the majority of patients less than 65 years old. Mean baseline ALP values ranged from 316 U/L to 327 U/L. Mean baseline total bilirubin values ranged from 10 μmol/L to 12 μmol/L across treatment arms, with 92% of patients within normal range.
Treatment with OCALIVA 10 mg or OCALIVA titration (5 mg to 10 mg) resulted in clinically and statistically significant increases (p < 0.0001) relative to placebo in the number of patients achieving the primary composite endpoint at all study time points (see Table 2). Responses occurred as early as 2 weeks and were dose dependent (OCALIVA 5 mg compared with 10 mg at 6 months, p=0.0358).
Table 2. Percentage of PBC patients achieving the primary composite endpointa at month 6 and month 12 with or without UDCAb

OCALIVA 10 mgc (N = 73)	OCALIVA Titrationc (N = 70)	Placebo (N=73)
Month 6
Responders, n (%) Corresponding 95% CI	37 (51) 39%, 62%	24 (34) 23%, 45%	5 (7) 1%, 13%
p-valued	<0.0001	<0.0001	NA
Month 12
Responders, n (%) Corresponding 95% CI	35 (48) 36%, 60%	32 (46) 34%, 58%	7 (10) 4%, 19%
p-valued	<0.0001	<0.0001	NA
Components of primary endpointe
ALP less than 1.67-times ULN, n (%)	40 (55)	33 (47)	12 (16)
Decrease in ALP of at least 15%, n (%)	57 (78)	54 (77)	21 (29)
Total bilirubin less than or equal to 1-times ULNf, n (%)	60 (82)	62 (89)	57 (78)

a Percentage of subjects achieving a response, defined as an ALP less than 1.67-times the ULN, total bilirubin within the normal range, and an ALP decrease of at least 15%. Missing values were considered a non-response. The Fisher's exact test was used to calculate the 95% Confidence Intervals (Cis).
b In the trial there were 16 patients (7%) who were intolerant and did not receive concomitant UDCA: 6 patients (8%) in the OCALIVA 10 mg arm, 5 patients (7%) in the OCALIVA titration arm, and 5 patients (7%) in the placebo arm.
c Patients were randomized (1:1:1) to receive OCALIVA 10 mg once daily for the entire 12 months of the trial, or OCALIVA titration (5 mg once daily for the initial 6 months, with the option to increase to 10 mg once daily for the last 6 months, if the patient was tolerating OCALIVA but had ALP 1.67-times the ULN or greater, and/or total bilirubin above the ULN, or less than 15% ALP reduction) or placebo.
dOCALIVA titration and OCALIVA 10 mg versus placebo. P-values are obtained using the Cochran-Mantel-Haenszel General Association test stratified by intolerance to UDCA and pretreatment ALP greater than 3-times ULN and/or AST greater than 2-times ULN and/or total bilirubin greater than ULN.
e Response rates were calculated based on the observed case analysis (i.e., [n=observed responder]/[N=Intention to Treat (ITT) population]); percentage of patients with Month 12 values are 86%, 91% and 96% for the OCALIVA 10 mg, OCALIVA titration and placebo arms, respectively.
f The mean baseline total bilirubin value was 0.65 mg/dL, and was within the normal range (i.e., less than or equal to the ULN) in 92% of the enrolled patients.
Mean reduction in ALP
Mean reductions in ALP were observed as early as Week 2 and were maintained through Month 12 for patients who were maintained on the same dosage throughout 12 months. For patients in the OCALIVA titration arm whose OCALIVA dosage was increased from 5 mg once daily to 10 mg once daily, additional reductions in ALP were observed at Month 12 in the majority of patients.
Mean reduction in gamma-glutamyl transferase (GGT)
The mean (95% CI) reduction in GGT was 178 (137, 219) U/L in the OCALIVA 10 mg arm, 138 (102, 174) U/L in the OCALIVA titration arm, and 8 (-48, 32) U/L in the placebo arm.
Monotherapy
Fifty-one PBC patients with baseline ALP 1.67-times ULN or greater and/or total bilirubin greater than ULN were evaluated for a biochemical response to OCALIVA as monotherapy (24 patients received OCALIVA 10 mg once daily and 27 patients received placebo) in a pooled analysis of data from the phase III randomised, double-blind, placebo-controlled 12 month study (POISE) and from a randomised, double-blind, placebo-controlled, 3- month study. At month 3, 9 (38%) OCALIVA-treated patients achieved a response to the composite endpoint, compared to 1 (4%) placebo-treated patient. The mean (95% CI) reduction in ALP in OCALIVA-treated patients was 246 (165, 327) U/L compared to an increase of 17 (-7, 42) U/L in the placebo-treated patients.
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with obeticholic acid in all subsets of the paediatric population in PBC (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under a so-called 'conditional approval' scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review any new information which may become available at least every year and this SmPC will be updated as necessary.
5.2 Pharmacokinetic properties
Absorption
Obeticholic acid is absorbed with peak plasma concentrations (Cmax) occurring at a median time (tmax) of approximately 2 hours. Co-administration with food does not alter the extent of absorption of obeticholic acid.
Distribution
Human plasma protein binding of obeticholic acid and its conjugates is greater than 99%. The volume of distribution of obeticholic acid is 618 L. The volume of distributions of glyco- and tauro-obeticholic acid has not been determined.
Biotransformation
Obeticholic acid is conjugated with glycine or taurine in the liver and secreted into bile. These glycine and taurine conjugates of obeticholic acid are absorbed in the small intestine leading to enterohepatic recirculation. The conjugates can be deconjugated in the ileum and colon by intestinal microbiota, leading to the conversion to obeticholic acid that can be reabsorbed or excreted in faeces, the principal route of elimination.
After daily administration of obeticholic acid, there was accumulation of the glycine and taurine conjugates of obeticholic acid which have in vitro pharmacological activities similar to the parent drug. The metabolite-to -parent ratios of the glycine and taurine conjugates of obeticholic acid were 13.8 and 12.3, respectively, after daily administration. An additional third obeticholic acid metabolite, 3-glucuronide is formed but is considered to have minimal pharmacologic activity.
Elimination
After administration of radiolabeled obeticholic acid, greater than 87% is excreted in faeces. Urinary excretion is less than 3%.
Dose/Time proportionality
Following multiple-dose administration of 5, 10, and 25 mg once daily for 14 days, systemic exposures of obeticholic acid increase dose proportionally. Exposures of glyco- and tauro-obeticholic acid, and total obeticholic acid increase more than proportionally with dose.
Special populations
Elderly
There are limited pharmacokinetic data in elderly patients (≥ 65 years). Population pharmacokinetic analysis, developed using data from patients up to 65 years old, indicated that age is not expected to significantly influence obeticholic acid clearance from the circulation.
Paediatric population
No pharmacokinetic studies were performed with obeticholic acid in patients less than 18 years of age.
Gender
Population pharmacokinetic analysis indicated that gender does not influence obeticholic acid pharmacokinetics.
Race
Population pharmacokinetic analysis indicated that race is not expected to influence obeticholic acid pharmacokinetics.
Renal impairment
Obeticholic acid has minimal renal elimination with less than 3% of the dose recovered in urine. Based on population pharmacokinetic analysis, renal function did not have a meaningful effect on
the pharmacokinetics of obeticholic acid.
Hepatic impairment
Obeticholic acid is metabolised in the liver and intestines. The systemic exposure of obeticholic acid, its active conjugates, and endogenous bile acids is increased in patients with moderate and severe hepatic impairment when compared to healthy controls. Therefore, a modified dose regimen for patients with moderate or severe hepatic impairment is recommended to achieve plasma exposure levels similar to patients with no hepatic impairment (see section 4.2).
The impact of mild hepatic impairment (Child-Pugh Class A) on the pharmacokinetics of obeticholic acid was negligible, therefore, no dose adjustment is necessary for patients with mild hepatic impairment.
In subjects with mild, moderate and severe hepatic impairment (Child-Pugh Class A, B, and C, respectively), mean AUC of total obeticholic acid, the sum of obeticholic acid and its two active conjugates, increased by 1.13-, 4- and 17-fold, respectively, compared to subjects with normal hepatic function following single-dose administration of 10 mg obeticholic acid.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to fertility, reproduction and development.
Oral administration of obeticholic acid above the NOAEL to mice, rats, and dogs in pivotal, repeat dose toxicity studies resulted primarily in effects on the hepatobiliary system. These included increased liver weights, alterations in serum chemistry parameters (ALT, AST, LDH, ALP, GGT, and/or bilirubin), and macroscopic/microscopic alterations. All changes were reversible with discontinued dosing, and are consistent with and predict the dose-limiting toxicity in humans (systemic exposure at NOAEL was up to 24-fold higher than that seen at the maximum recommended human dose). In a pre- and post-natal toxicity study in rats, the tauro-conjugate of obeticholic acid was found in pups nursing from dams dosed with obeticholic acid
6. Pharmaceutical particulars
6.1 List of excipients
Tablet core
Microcrystalline cellulose (E460)
Sodium starch glycolate (Type A)
Magnesium stearate
Coating
Poly(vinyl alcohol), partially hydrolysed (E1203)
Titanium dioxide (E171)
Macrogol 3350 (E1521)
Talc (E553b)
Iron oxide yellow (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
High-density polyethylene (HDPE) bottles with a child resistant polypropylene closure and an aluminium foil induction seal.
Pack size: 30 or 100 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. Marketing authorisation holder
Intercept Pharma Ltd.
2 Pancras Square
London, N1C 4AG
United Kingdom
8. Marketing authorisation number(s)
OCALIVA 5mg film-coated tablets, 30
EU/1/16/1139/001
OCALIVA 5mg film-coated tablets, 100
EU/1/16/1139/003
OCALIVA 10mg film-coated tablets, 30
EU/1/16/1139/002
OCALIVA 10mg film-coated tablets, 100
EU/1/16/1139/004
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 12/2016
10. Date of revision of the text
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.
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Intercept公司肝病新药奥贝胆酸（Ocaliva）获FDA加速批准
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）近日获得FDA加速批准，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，或作为单药疗法用于对UDCA不耐受的原发性胆汁性胆管炎成人患者。UDCA是目前唯一获批治疗原发性胆汁性肝硬化（PBC）的药物。FDA此次批准并不让人感到意外，因为在今年4月初，FDA专家委员会已以17:0的结果全票支持批准Ocaliva。之前，FDA也已授予Ocaliva优先审查资格。
此次批准，使Ocaliva成为近20年来获批治疗PBC的首个新药。Intercept公司已计划在未来7-10天内将产品推向市场。业界对Ocaliva的商业前景非常看好。尽管PBC是Ocaliva获批的首个适应症，但一些分析人士表示，Ocaliva在未来将继续获批其他适应症，包括脂肪肝，而这可能撬开了一个更大的价值数十亿美元的市场。之前，行业知名调研机构EvaluatePharma曾发布报告预测，Ocaliva在2020年的销售额将高达30亿美元。
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，目前正开发用于原发性胆汁性肝硬化、非酒精性脂肪性肝炎及其他肝脏疾病和肠道疾病的治疗。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。
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%。
Intercept是一家美国生物制药公司，专注于开发和商业化创新疗法，用于慢性肝脏疾病的治疗。该公司的先导候选药物OCA是一种法尼酯X受体（FXR）激动剂，目前正开发用于多种慢性肝脏疾病的治疗，包括原发性胆汁性肝硬化（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。