FDA approves Ocaliva for rare, chronic liver disease.

May 31, 2016

2016-06-01 (1)The U.S. Food and Drug Administration granted accelerated approval for Ocaliva (obeticholic acid) for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as a single therapy in adults unable to tolerate UDCA.

DESCRIPTION

OCALIVA is a farnesoid X receptor (FXR) agonist. Chemically, obeticholic acid is 3α,7α-dihydroxy- 6α-ethyl-5β-cholan-24-oic acid. It is a white to off-white powder. It is soluble in methanol, acetone and ethyl acetate. Its solubility in water is pH dependent. It is slightly soluble at low pH and very soluble at high pH.

2016-06-01

CLINICAL PHARMACOLOGY

 Mechanism of Action

  • Obeticholic acid is an agonist for FXR, a nuclear receptor expressed in the liver and intestine.
  • FXR is 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 increased 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

INDICATIONS AND USAGE

  • OCALIVA, a farnesoid X receptor (FXR) agonist, is indicated 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.
  • This 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.

DOSAGE AND ADMINISTRATION

Dosage Regimen

  • Starting Dosage The recommended starting dosage of OCALIVA is 5 mg orally once daily in adult patients who have not achieved an adequate biochemical response to an appropriate dosage of UDCA for at least 1 year or are intolerant to UDCA.
  • Dosage Titration If an adequate reduction in ALP and/or total bilirubin has not been achieved after 3 months of OCALIVA 5 mg once daily, and the patient is tolerating OCALIVA, increase the dosage of OCALIVA to 10 mg once daily
  •  Maximum Dosage The maximum recommended dosage of OCALIVA is 10 mg once daily.

Safety

The FDA’s approval is based on a reduction in the level of the biomarker alkaline phosphatase (ALP), as a surrogate endpoint which, based on multiple levels of evidence (mechanistic, clinical trial, epidemiologic), could be relied upon to be reasonably likely to predict clinical benefit, including an improvement in transplant free-survival. The safety and efficacy of Ocaliva were demonstrated in a controlled clinical trial with 216 participants. After twelve months, the proportion of participants achieving reductions in ALP levels was higher among Ocaliva-treated participants compared to placebo-treated participants.

WARNINGS AND PRECAUTIONS

  • Liver-Related Adverse Reactions: Monitor for elevations in liver biochemical tests and development of liver-related adverse reactions; weigh the potential risk against the benefits of continuing treatment. Do not exceed 10 mg once daily. Adjust the dosage for patients with moderate or severe hepatic impairment. Discontinue in patients who develop complete biliary obstruction.
  • Severe Pruritus: Management strategies include the addition of bile acid binding resins or antihistamines; OCALIVA dosage reduction and/or temporary dosing interruption.
  •  Reduction in HDL-C: Monitor for changes in serum lipid levels during treatment.

ADVERSE REACTIONS

Most common adverse reactions (≥ 5%) are: pruritus, fatigue, abdominal pain and discomfort, rash, oropharyngeal pain, dizziness, constipation, arthralgia, thyroid function abnormality, and eczema.

The FDA granted Ocaliva fast track designation &Orphan drug designation.Ocaliva was approved under the agency’s accelerated approval program, which allows the approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients. An improvement in survival, progression to cirrhosis, or other disease-related symptoms in patients being treated with Ocaliva has not yet been established, although a confirmatory trial is currently ongoing.

Ocaliva is manufactured by New York, New York-based Intercept Pharmaceuticals, Inc.

 

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