Clinical Trials

Date: 2017-07-31

Type of information: Results

phase: 2

Announcement: results

Company: Intercept Pharmaceuticals (USA - NY)

Product: obeticholic acid (OCA) in combination with statin therapy

Action mechanism:

• farnesoid X receptor agonist. Obeticholic acid (OCA) is a bile acid analog and a first-in-class farnesoid X receptor (FXR) agonist being developed for primary biliary cirrhosis (PBC), NASH and other chronic liver indications. Intercept has initiated a rolling New Drug Application with the FDA for PBC, and expects to complete the NDA and MAA submission in 2Q 2015. The commercial launch of OCA in the U.S. and Europe is planned in 2016. OCA was also recently granted breakthrough therapy designation by FDA for the treatment of NASH with liver fibrosis.

Disease: NASH (non-alcoholic steatohepatitis)

Therapeutic area: Liver diseases - Hepatic diseases

Country: USA

Trial details:

• CONTROL is a 16-week double-blind, placebo-controlled, dose-ranging study of 84 NASH patients with fibrosis and compensated cirrhosis, followed by a two-year long term safety extension open label phase . Lipid changes were assessed every four weeks over the course of the double-blind phase.

  • Statin-naïve or washout patients were randomized to receive one of three doses of OCA (5 mg, 10 mg or 25 mg) or placebo.
  • At week four, the lowest approved dose of atorvastatin (10 mg) was added in all patients.
  • At week eight, patients were titrated to the next highest prescribed dose of atorvastatin (20 mg).
  • At week 12, further titration of atorvastatin (up to 40 mg) was permitted at investigators' discretion.

  The study was designed to measure treatment differences within each group relative to baseline. The intent-to-treat (ITT) analysis is shown below and includes all patients who received at least one dose of study medication. (NCT02633956)

Latest news:

• • On July 31, 2017, Intercept Pharmaceuticals announced results from CONTROL, a placebo-controlled trial to prospectively characterize the lipid metabolic effects of obeticholic acid and concomitant statin administration in patients with nonalcoholic steatohepatitis with fibrosis or cirrhosis. The CONTROL trial met its primary objective by showing that newly initiated treatment with atorvastatin rapidly reversed obeticholic acid-associated increases in LDL to below baseline levels. Most of the effect was observed four weeks after initiation of the lowest available dose of atorvastatin and was sustained throughout the study period.

  CONTROL study was designed to measure treatment differences within each group relative to baseline. The intent-to-treat (ITT) analysis is shown below and includes all patients who received at least one dose of study medication.

  At week four, mean LDL levels increased in each of the obeticholic acid treatment groups, while remaining relatively unchanged in the placebo group. The addition of 10 mg of atorvastatin rapidly reversed mean LDL to below baseline levels in all obeticholic acid treatment groups at the first assessed time point (week eight), and this effect was sustained through week 16. The observed mean LDL reductions in the obeticholic acid groups were approximately 40 — 45 mg/dL while placebo was 48 mg/dL.

  (mg/dL)	Placebo (N=21)	OCA 5 mg (N=20)	OCA 10 mg (N=21)	OCA 25 mg (N=22)
  Mean LDL at Baseline	118	135	122	126
  Mean LDL at Week 4	113	153	141	158
  Mean LDL at Week 8 (+ atorvastatin 10 mg)	75	96	91	93
  Mean LDL at Week 16 (+ atorvastatin 10 — 40 mg)	70	95	82	85
  Mean LDL Change from Baseline at Week 16	-48	-40	-40	-45
  The primary efficacy analysis was based on the efficacy evaluable (EE) population, defined as those patients who completed the double-blind phase and received all doses of OCA and atorvastatin (n=67). The overall results for the ITT population were similar to those in the EE population.

  Lipid sub-fraction analysis showed that obeticholic acid-related increases in LDL were primarily driven by an increase in large buoyant LDL particles rather than small dense LDL particles. Changes in other lipid parameters were similar to those previously reported with obeticholic acid therapy in patients with NASH.
• Mild to moderate pruritus was the most common adverse event in patients treated with obeticholic acid, occurring in 5%, 5%, 10% and 55% in placebo, 5 mg, 10 mg and 25 mg obeticholic acid groups, respectively. Two patients discontinued treatment in the 25 mg obeticholic acid treatment arm due to pruritus. Co-administration of atorvastatin and obeticholic acid was generally well tolerated and did not result in any unexpected safety observations.
• The proportion of patients completing the double-blind period was similar across treatment groups (100%, 95%, 90% and 91% for placebo, OCA 5 mg, OCA 10 mg and OCA 25 mg, respectively). Of these patients, 77 of 79 (97%) chose to participate in the LTSE phase. During the ongoing LTSE phase, there has been one patient death due to acute renal and liver failure. While Intercept determined it could not be ruled out that this was possibly related to treatment, the principal investigator and the independent Data Safety Monitoring Committee determined the death was unlikely related to OCA.
• • On December 7, 2015, Intercept Pharmaceuticals announced the initiation of the Combination OCA aNd sTatins for monitoRing Of Lipids (CONTROL) Phase 2 clinical trial to evaluate the effect of obeticholic acid in combination with statin therapy on lipid metabolism in patients with nonalcoholic steatohepatitis (NASH). The first four weeks will evaluate three doses of OCA (5 mg, 10 mg, 25 mg) or placebo with no concomitant statin therapy. At week four, all patients will receive the lowest approved dose of atorvastatin (10 mg) and will titrate to the next highest prescribed dose of atorvastatin (20 mg) at week eight.. At week 12, physicians will be free to titrate the dose of atorvastatin at their discretion through to the end of study.

Is general: Yes