奥贝胆酸治疗原发性硬化性胆管炎的效果如何？

The effect of treating primary sclerosing cholangitis (PBC) is very good. A number of clinical studies on PBC have found that obeticholic acid can significantly reduce the levels of various liver biochemical indicators such as alkaline phosphatase (ALP), TBil and ALT in patients. These research results further support the FDA's approval of obeticholic acid for the treatment of PBC patients.

About obeticholic acid

Obeticholic acid tablets were approved for marketing in the United States in May 2016. The original research company is Intercept Pharmaceuticals, with the trade name OCALIVA. The approved indication is the treatment of primary biliary cholangitis (PBC). Obeticholic acid is a semi-synthetic derivative of the human primary bile acid chenodeoxycholic acid (CDCA). It is a selective farnesoid derivative X receptor (FXR) agonist that is 100 times more active than CDCA and has anti-cholestasis and hepatoprotective properties.

Obeticholic acid in the treatment of primary sclerosing cholangitis

Nevens et al. conducted a 12-month double-blind placebo-controlled phase III clinical trial, in which 217 PBC patients with poor response or intolerance to UDCA were randomly assigned to a 10 mg obeticholic acid group, a 5-10 mg obeticholic acid group, and a placebo group at a ratio of 1:1:1. The following three conditions are defined as the primary experimental endpoint: serum ALP value is lower than 1.67 times the upper limit of normal value, and reduced by at least 15%, and TBil must return to normal levels [1].

After 12 months, compared with 10% of patients in the placebo group, 46% and 47% of patients in the 5-10mg obeticholic acid group and 10mg obeticholic acid group achieved the primary experimental endpoint respectively. It can be seen that a smaller dose of obeticholic acid can also achieve similar clinical effects, but there are relatively fewer treatment interruptions due to itching. Subsequent open-label clinical trials verified that the levels of ALP and TBil in the experimental group were not further reduced, while the placebo group achieved similar therapeutic effects after receiving obeticholic acid (initial dose: 5 mg, adjusted according to efficacy) treatment. From the data point of view, the ALP level of the placebo group dropped by nearly 100U/L at the end of the experiment, close to 1.67 times the upper limit of normal value, and TBil dropped to 0.6~0.7mg/dl.

Adverse reactions of obeticholic acid

Itching is the most common clinical symptom of PBC patients, which seriously affects the patient's quality of life and can disrupt sleep, suppress emotions, and even lead to suicide. A study on the incidence of itching in PBC patients showed that about 69% of 165 patients were troubled by itching, and 75% of the patients had itching symptoms before being diagnosed with PBC.

In addition to aggravating itching symptoms, obeticholic acid also affects changes in blood lipids, manifested by a decrease in HDL-C levels. A significant decrease in total cholesterol levels was observed in both phase II and phase III clinical trials, and its changes were closely related to the decrease in HDL-C. However, in the later stages of the trial, HDL-C levels showed a stable trend and did not decrease further.

Zhang et al. found that FXR agonists can upregulate the expression of hepatic scavenger receptor B1 and thereby increase the intestinal excretion of HDL-C. However, there have been no reports that the reduction in HDL-C levels caused by obeticholic acid increases the risk of cardiovascular disease.

Summary

At present, obeticholic acid is a new treatment era for patients with UDCA-insensitive PBC, and more reliable and suitable drug doses are yet to be studied in large-scale clinical trials. With the progress of follow-up research, obeticholic acid may become the drug of choice for long-term treatment of PBC in the future.

References

[1] Lin Weiguo, Lu Baochun. Application of obeticholic acid in the treatment of primary biliary cholangitis [J]. Zhejiang Medicine, 2018, 40(14): 1630-1633.

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