General Information

Cholbam (cholic acid) is a primary bile acid synthesized from cholesterol in the liver. Patients with bile acid synthesis disorders due to single enzyme defects with peroxisomal disorders (including Zellweger spectrum disorders) lack the enzymes needed to synthesize cholic acid, a primary bile acid normally produced in the liver from cholesterol. The absence of cholic acid in these patients leads to reduced bile flow, accumulation of potentially toxic bile acid intermediates in the liver (cholestasis), and malabsorption of fats and fat-soluble vitamins in the diet.

Cholbam is specifically indicated for the treatment of bile acid synthesis disorders due to single enzyme defects and for the adjunctive treatment of peroxisomal disorders including Zellweger spectrum disorders in patients who exhibit manifestations of liver disease, steatorrhea or complications from decreased fat soluble vitamin absorption. Cholbam is approved for use in children aged three weeks and older, and adults.

Cholbam is supplied as a capsule for oral administration. The recommended dosage is 10 to 15 mg/kg administered orally once daily, or in two divided doses, in pediatric patients and in adults.

Mechanism of Action

The active ingredient in Cholbam is cholic acid, a primary bile acid synthesized from cholesterol in the liver. In bile acid synthesis disorders due to SEDs in the biosynthetic pathway, and in PDs including Zellweger spectrum disorders, deficiency of primary bile acids leads to unregulated accumulation of intermediate bile acids and cholestasis. Bile acids facilitate fat digestion and absorption by forming mixed micelles, and facilitate absorption of fat-soluble vitamins in the intestine. Endogenous bile acids including cholic acid enhance bile flow and provide the physiologic feedback inhibition of bile acid synthesis. The mechanism of action of cholic acid has not been fully established; however, it is known that cholic acid and its conjugates are endogenous ligands of the nuclear receptor, farnesoid X receptor (FXR). FXR regulates enzymes and transporters that are involved in bile acid synthesis and in the enterohepatic circulation to maintain bile acid homeostasis under normal physiologic conditions.

Clinical Trial Results

The FDA approval of Cholbam was based on the following trials:

Bile acid synthesis disorders due to single enzyme defects:

A single arm trial assessed 50 patients treated over an 18 year period. An extension trial followed 21 of these patients and enrolled an additional 12 patients with interim efficacy data available for an additional 21 months. On average, patients were 4 years of age at the start of cholic acid treatment (range 3 weeks to 36 years). Response to treatment was evaluated by improvements in baseline liver function tests and weight. Responses were noted in 64% of patients with evaluable data. Two-thirds of patients survived greater than three years.

Peroxisomal disorders, including Zellweger spectrum disorders:

A single arm treatment trial assessed 29 patients treated over an 18 year period. An extension trial followed 10 of these patients and enrolled an additional two patients with interim efficacy data available for 21 additional months. The majority of patients were less than 2 years of age at the start of cholic acid treatment (range 3 weeks to 10 years). Response to treatment was evaluated by improvements in baseline liver function tests and weight. Responses were noted in 46% of patients with evaluable data. Forty-two percent of patients survived greater than 3 years.