Obeticholic acid（OCA）是近年研制的一种新药，也被称为INT747或6-α乙基鹅去氧胆酸，是半合成的鹅去氧胆酸（CDCA）的衍生物，可激活法尼酯X受体（ FXR），具有抗淤胆、抗纤维化的效果，对PBC有一定疗效。
2014年4月12日，Intercept制药公司开发的药物Obeticholic acid对主要发生在中年妇女中的一种罕见肝脏疾病体征有明显的改善，降低了患者的肝移植需求及死亡风险。
在接受Obeticholic acid治疗的原发性胆汁性肝硬化症患者中，大约有一半的患者达到了研究的主要目标，相比之下，接受安慰剂治疗的患者中只有10%的患者达到研究的主要目标。
临床研究的复合终点是碱性磷酸酶至少下降15%，血清碱性磷酸酶的活性低于正常上限的1.67倍，而胆红素在正常范围内， 碱性磷酸酶是用来表示肝脏疾病严重程度的一种生物标记物。
“ 碱性磷酸酶是生存期真正最好的预后因子，” Frederik Nevens在一次电话采访中说，他是这项研究的主要研究者，也是鲁汶大学肝脏病学系主任。他称试验结果“非常、非常重要。”这项由217名患者参与的3期Poise研究结果在伦敦举行的欧洲肝脏研究协会(EASL) 年会上得到发布。
原发性胆汁性肝硬化(PBC)是将胆汁酸从肝脏输出的导管出现自身免疫破坏，导致有毒的胆汁酸逐渐积聚而引起。该疾病引起渐进性肝损伤，常常导致需要肝移植或死亡。
Obeticholic acid是一种新型药物，研究用于那些对旧标准治疗药物熊去氧胆酸没有充分应答或不能耐受的患者。Intercept制药表示，该公司打算在今年晚些时候向美国和欧洲提交这款药物的上市申请。鉴于这款药物用于治疗罕见疾病，它被美国FDA授予孤儿药资格，如果获得上市批准，它将获得7年的市场专营权。
Obeticholic acid还在测试用来治疗一种更为常见的脂肪肝——非酒精性脂肪肝炎。该款药物一项用于治疗此种适应症的2期临床研究因其确切疗效而被提前中止。Nevens表示，他预测这款使用方便、日服一次的药片会改变原发性胆汁性肝硬化的医疗实践。
患者在长达一年的研究中病情变得更加温和，大多数患者使用老药已大约10年时间。在试验中，患者接受5mg或10mg或安慰剂治疗。5mg用药组中，经过6个月治疗后对药物没有充分应答的患者，在剩余的6个月剂量增加到10mg。
5毫克剂量组及那些转换到更高剂量的患者中有46%的人达到研究的主要目标，而最初接受10mg治疗的患者有47%的人达到研究的主要目标。对达到主要目标的患者进行肝脏检测，检测结果显示病情实现好转。相比之下，“安慰剂组患者的病情有恶化倾向。
使用这款药物时最常见副作用是严重瘙痒，这也是疾病本身的一种症状。低剂量时瘙痒往往没那么严重，在早期试验中测试更高剂量时，瘙痒更加糟糕。10mg剂量组有10%的患者因瘙痒在试验中出组，但在起始剂量为5mg，后来又转换成10mg的患者中，仅有1%的患者中止治疗。总体来说，这款药物是安全的。
Obeticholic Acid - A novel treatment for chronic liver diseases
Product Description
Obeticholic acid (OCA) is a bile acid derivative that potently stimulates the farnesoid X receptor. Primary biliary cirrhosis (PBC), an orphan liver disease, is its lead indication in phase III development. The company is also testing OCA in a series of follow-on liver, gastrointestinal and metabolic indications that could represent substantially larger future commercial opportunities. This report reviews OCA’s clinical, regulatory and commercial prospects across the various indications.
POTENTIAL INDICATIONS FOR OBETICHOLIC ACID
1. Primary biliary cirrhosis (PBC)
2. Nonalcoholic steatohepatitis (NASH), a subset of Nonalcoholic fatty liver disease (NAFLD)
3. Portal hypertension
4. Bile acid diarrhea
EFFICACY PROFILE
1. Primary biliary cirrhosis
2. NASH
3. Portal hypertension
4. Bile acid diarrhea
SAFETY PROFILE
1. Primary biliary cirrhosis
2. NASH
3. Portal hypertension
REGULATORY LANDSCAPE
1. Primary biliary cirrhosis
- Phase III trial in primary biliary cirrhosis is underway
- UDCA as precedent
- Are biochemical markers adequate to demonstrate clinical benefit in PBC?
- The program has no SPA – potential implications
2. NASH
3. Portal hypertension
4. Bile acid diarrhea
COMPETITIVE LANDSCAPE
1. Farnesoid X receptor agonists
2. Primary biliary cirrhosis
3. NASH
4. Portal hypertension
5. Bile acid diarrhea
Obeticholic acid produces meaningful biochemical and clinical improvements in PBC cirrhosis patients
Results from an international Phase III study presented today at the International Liver CongressTM 2014 have shown obeticholic acid (OCA) given to patients suffering from Primary Biliary Cirrhosis (PBC) who previously had an inadequate response to, or have been unable to tolerate ursodeoxycholic acid (UDCA), produced meaningful biochemical and clinical improvements. UDCA is the only therapy currently approved to treat PBC.
Obeticholic acid at both a 10 mg dose and a 5 mg dose titrated to 10 mg, met the trial's primary composite endpoint of achieving a serum alkaline phosphatase (ALP) activity of less than 1.67 times the upper limit of normal (ULN), a total bilirubin within normal limits, and at least a 15% decrease in ALP.
The proportion of patients meeting the primary endpoint was: 47% in the 10 mg OCA group and 46% in the 5-10 mg OCA group vs. only 10% in the placebo group (both dose groups p<0.0001). In addition, both OCA dose groups met secondary endpoints of improvements in other liver function parameters, including gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT) and total bilirubin.
Presenting these results, EASL's Scientific Committee Member Dr. Frank Lammert, Professor of Internal Medicine at the Saarland University Medical Center, Homburg, Germany pointed out: "These trial results indicate that a statistically greater number of OCA-treated patients achieved the response criteria as defined by Global Primary Biliary Cirrhosis Study Group. We know that these endpoints have, in turn, been shown in previous studies to strongly correlate with clinical benefits and an improved long-term prognosis, with a reduced risk of liver transplantation and death."
"While UDCA has been the standard PBC therapy for the past 20 years, a significant percentage of patients fail to get an adequate response with this treatment, or are unable to tolerate it. We therefore need new therapies to prevent PBC from progressing to cirrhosis and liver failure, and this study suggests that OCA has the potential to be a much needed advance for these patients," Dr. Frank Lammert added.
PBC is a chronic disease that primarily occurs in women. It is characterised by the destruction of bile ducts in the liver, which in turn leads to liver scarring. Long-term damage from PBC over the years can result in cirrhosis and liver failure. PBC affects around 30 people per million, with an estimated prevalence of 12,000 - 15,000 in the UK. It has been reported that PBC is more prevalent in some geographic areas, such as Northern Europe and Northern America.
OCA is a new bile acid analogue (6alpha-ethyl-chenodeoxycholic acid) and first-in-class agonist of the nuclear receptor (FXR), which represents the central bile acid sensor in humans. It is being studied in PBC, as well as non-alcoholic steatohepatitis (NASH) and other liver and intestinal diseases.
Study methodology and adverse event data
This Phase III study enrolled 217 patients with primary biliary cirrhosis who had either failed to get an adequate response with UDCA, or had been unable to tolerate it. Patients were randomised to placebo or one of two doses of OCA, with the lower dose titrated to the higher strength after six months based on clinical response. Patients who were able to tolerate UDCA were allowed to continue on it; the median UDCA dose was 15.3mg/kg; 7% of patients were UDCA-intolerant. All three treatment groups were well matched. Mean age: 55.8yrs, female: 91%, Caucasian: 94%.
Pruritus, generally mild to moderate, was the most frequently reported adverse event associated with OCA treatment (placebo: 38%, OCA 10 mg: 68%, OCA 5-10 mg titration: 56%).
However, only a few patients withdrew due to pruritus: none in the placebo group, seven (10%) of the patients in the 10 mg OCA group, and only one (1%) of the patients in the OCA 5-10 mg titration group.
Apart from pruritus, the incidence of adverse events was generally similar across both OCA and placebo groups (placebo: 90%, OCA 10 mg: 86%, OCA 5-10 mg titration group: 89%). Overall, serious adverse events (SAEs) occurred in (10%) of the patients and, although there were more SAEs in the OCA treatment groups, none were considered drug-related and there were no apparent patterns in the SAEs.
PBC patients typically have significantly elevated HDL cholesterol levels; modest decreases in HDL were observed in both OCA dose groups, similar to those seen in the prior PBC clinical trials. In addition, slight decreases in triglycerides, but no changes in LDL cholesterol were observed in the OCA dose groups.
Other new data further support role of obeticholic acid in PBC
In addition to these new Phase III data, there are three other presentations on OCA at this year's International Liver CongressTM, which further support the potential role of this new drug in treating PBC.
- Two 12-week, double-blind, placebo-controlled Phase 2 trials of OCA in PBC patients with persistently high ALP (&#8805;1.5-10x ULN) and bilirubin <2x ULN, showed OCA resulted in a highly significant improvement in the biochemical response criteria which are associated with improved transplant-free survival versus placebo, in both the OCA monotherapy and UDCA-combination therapy studies.
- Having previously demonstrated the efficacy of 10mg and 50mg doses of OCA, given as monotherapy, in achieving highly significant reductions in ALP and other biochemical markers, compared with placebo, an open label, long-term study extension has shown that OCA treatment resulted in a durable improvement in ALP and other liver chemistry. UDCA was added in 11 of the patients. Pruritus, while prevalent appeared to diminish in incidence and severity with continued therapy.
- In an experimental rat model of cholestasis, FXR-agonism was shown to restore ileal permeability and decrease bacterial translocation (which is known to drive infectious complications of cirrhosis), potentially showing a crucial protective role for FXR in the gut-liver axis.
European Association for the Study of the Liver