Staff reviewers at the FDA have supported the use of obeticholic acid (OCA, Intercept Pharmaceuticals) as monotherapy in patients with primary biliary cirrhosis (PBC) who did not respond to standard-of-care treatment. PBC results from autoimmune destruction of the bile ducts. The reviewers were unable to assess the drug’s safety in patients with severe disease and recommended a less-frequent starting dose for such patients.
The FDA’s Gastrointestinal Drug Advisory Committee is scheduled to meet on April 7 to vote on the drug. The FDA is not obliged to follow the advice of its advisory panels, but it usually does so.
OCA is an analog of the naturally occurring bile acid chenodeoxycholic acid (CDCA), to which a single alpha-ethyl group was added to the 6-carbon position. CDCA is the natural ligand of the farnesoid X receptor, a nuclear receptor expressed at high levels in the liver and intestine, which regulates bile acid homeostasis. OCA is approximately 100- fold more potent than CDCA.
OCA is manufactured as 5-mg and 10-mg tablets, to be administered orally once daily. Intercept Pharmaceuticals has proposed a regimen starting with a dosage of 5 mg daily for the first three months followed by titration up to 10 mg daily based on tolerance to the medication (primarily pruritus) and biochemical response.
The phase 3 clinical development program for OCA consisted of a one-year, randomized, placebo-controlled trial, which was followed by an open-label, long-term extension. In addition to a placebo arm, the study included two OCA dosing regimens: a fixed-dose, 10-mg arm and a titration arm in which OCA was initiated at a lower dose (5 mg), which was up-titrated to 10 mg at month 6, depending on the patient’s tolerance to treatment and biochemical response, the latter being prespecified as a reduction in alkaline phosphatase and total bilirubin. The patients enrolled in this study were adults with PBC who had been receiving ursodeoxycholic acid (UDCA) for at least 12 months.
Both OCA treatment groups showed a statistically significant difference (P < 0.0001) in the proportion of patients achieving a response at month 12 when individually compared with placebo. The response rates at 12 months were 46.6% (34/73) for OCA 10 mg; 45.7% (32/70) for OCA titration; and 9.6% (7/73) for placebo.
Pruritus was the most common treatment-emergent adverse event in clinical trials of OCA. In addition, increases in low-density lipoprotein-cholesterol (LDL-C) and decreases in high-density lipoprotein-cholesterol (HDL-C) were observed in most of the healthy volunteers and PBC patients treated with OCA in clinical studies. Elevations in transaminases and bilirubin occurred during OCA trials, especially with dosages greater than 10 mg daily, and some patients with underlying liver disease developed transaminase elevations and hepatic-related adverse events at the 10-mg per day dosage.