By William Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Medical Director, Pharmacy, Northern California Kaiser Permanente, and Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA.

Drs. Elliott and Chan report no financial relationships relevant to this field of study.

The FDA has approved a first-in-class farnesoid X receptor agonist for the treatment of primary biliary cholangitis (PBC). Obeticholic acid was granted fast track and orphan drug designations and was approved under the FDA’s accelerated approval program. It is marketed as Ocaliva.

INDICATIONS

Obeticholic acid is indicated for the treatment of PBC in combination with ursodeoxycholic acid (UDCA) in adults with inadequate response to UDCA or as monotherapy in patients unable to tolerate UDCA.1

DOSAGE

For patients who have not achieved an adequate response to UDCA after a least one year or are intolerant, the recommended starting dose is 5 mg once daily.1 If response is not adequate after three months, the dose may be increased to a maximum dose of 10 mg daily. For patients who experience intolerable pruritus, an antihistamine or bile acid-binding resin may be added. The dose can be reduced from 5 mg daily to every other day or from 10 mg daily to 5 mg once daily. The tablets may be taken with or without food. Obeticholic acid is available in 5 mg and 10 mg tablets.

POTENTIAL ADVANTAGES

Obeticholic acid provides an FDA-approved treatment option for patients who have not responded adequately to or are unable to tolerate UDCA.

POTENTIAL DISADVANTAGES

Approximately 20% of patients reported severe pruritus.1 Monitor patients with liver biochemical tests for the development of liver-related adverse events.

COMMENTS

Obeticholic acid is semisynthetic bile acid derivative that is a farnesoid X receptor agonist. This receptor is involved in regulating bile acid homeostasis (i.e., synthesis, secretion, transportation, and detoxification).2 Obeticholic acid has shown anti-inflammatory and antifibrotic activity in animal models. The efficacy and safety was demonstrated in a randomized, double-blind, placebo-controlled, 12-month study in subjects with PBC. This included patients who were on UDCA for at least 12 months, were unable to tolerate UDCA, or had not received UDCA. Patients presented with alkaline phosphatase (ALP) 1.67 times the upper limit of normal (ULN) or total bilirubin one to less than two times ULN. The mean alkaline phosphatase (ALK) was 323.2 u/L (2.74 x ULN) and 90% had early Rotterdam Disease Stage. Exclusion criteria included clinically significant hepatic decompensation events, severe pruritus, or Model for End-Stage Liver Disease (MELD) score of ≥ 15. Subjects were randomized to obeticholic acid 10 mg daily (n = 73), titration of 5 mg for six months with the option to increase to 10 mg daily due to inadequate response (n = 70), or placebo (n =73). The primary endpoint, assessed at 12 months, was defined as a composite of three criteria: ALP < 1.67 times the ULN, total bilirubin less than or equal to ULN, and an ALP decrease of at least 15%. The study population was mainly white (94%) and female (91%). ALP is a biomarker predictive of transplant-free survival.3 The response rates were 48% (95% confidence interval [CI], 36-60) for the 10 mg group, 46% (95% CI, 34-58) for the titration group, and 10% (95% CI, 4-19) for placebo. Reduction in ALP was observed by week two and plateaued by month three. Frequently reported adverse events were pruritus, fatigue, and reduction of high-density lipoprotein cholesterol.1

CLINICAL IMPLICATIONS

PBC is a rare, autoimmune, chronic liver disease leading to cirrhosis and ultimately liver failure and death. Previously, UDCA was the only approved treatment. Approximately 33-40% of patients fail to achieve biochemical response, and 5-10% cannot tolerate the drug.3,4 Obeticholic acid may be an effective therapy for approximately 50% of those patients with inadequate response to or unable to tolerate UDCA. The cost is $5,700 for a 30-day supply.

REFERENCES

  1. Ocaliva Prescribing Information. Intercept Pharmaceuticals, Inc. May 2016.
  2. Ali AH, Carey EJ, Lindor KD. Recent advances in the development of farnesoid X receptor agonists. Ann Transl Med 2015;3:5-21.
  3. FDA. FDA approves Ocaliva for rare, chronic liver disease. Available at: http://bit.ly/280DgTr. Accessed July 20, 2016.
  4. Trivedi PJ, Hirschfield GM, Gershwin ME. Obeticholic acid for the treatment of primary biliary cirrhosis. Expert Rev Clin Pharmacol 2016;9:13-26.