- Low dose atorvastatin rapidly reversed OCA associated LDL changes
NEW YORK, NY, USA I July 31, 2017 I Intercept Pharmaceuticals, Inc. (Nasdaq:ICPT) (Intercept), a biopharmaceutical company focused on the development and commercialization of novel therapeutics to treat progressive non-viral liver diseases, today announced results from CONTROL, a placebo-controlled trial to prospectively characterize the lipid metabolic effects of obeticholic acid (OCA) and concomitant statin administration in patients with nonalcoholic steatohepatitis (NASH) with fibrosis or cirrhosis. The CONTROL trial met its primary objective by showing that newly initiated treatment with atorvastatin rapidly reversed OCA-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 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 (LTSE) open label phase which is currently ongoing. Lipid changes were assessed every four weeks over the course of the double-blind phase. Details of the study design are as follows:
- 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.
At week four, mean LDL levels increased in each of the OCA 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 OCA 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 OCA 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 OCA-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 OCA therapy in patients with NASH.
Mild to moderate pruritus was the most common adverse event in patients treated with OCA, occurring in 5%, 5%, 10% and 55% in placebo, 5 mg, 10 mg and 25 mg OCA groups, respectively. Two patients discontinued treatment in the 25 mg OCA treatment arm due to pruritus. Co-administration of atorvastatin and OCA 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.
“The majority of NASH patients in CONTROL were statin eligible according to AHA treatment guidelines, and statins are recommended for patients with NASH in both AASLD and EASL treatment guidelines,” said David Shapiro, M.D., Chief Medical Officer of Intercept. “In CONTROL, we have shown that statin therapy can have an important role in managing LDL when co-administered with OCA in NASH patients with fibrosis and cirrhosis.”
Conference Call on July 31st at 8:30 a.m. ET
Intercept will discuss the CONTROL results during its second quarter 2017 financial results conference call and webcast on July 31st at 8:30 a.m. ET. The live event will be available on the investor page of Intercept’s website at http://ir.interceptpharma.com or by calling (855) 232-3919 (toll-free domestic) or (315) 625-6894 (international) five minutes prior to the start time (no passcode is required). A replay of the call will be available on Intercept’s website approximately two hours after the completion of the call and will be archived for two weeks.
About CONTROL
CONTROL is a randomized, double-blind, placebo-controlled trial to characterize the lipid metabolic effects of OCA and cholesterol management effects of concomitant statin administration in NASH patients. CONTROL enrolled 84 NASH patients who were naïve to statin therapy or underwent a statin washout, and includes a 16-week double-blind phase followed by an optional two-year long-term safety extension phase.
About Nonalcoholic Steatohepatitis
NASH is a serious progressive liver disease caused by excessive fat accumulation in the liver that induces chronic inflammation, resulting in progressive fibrosis (scarring) that can lead to cirrhosis, eventual liver failure, cancer and death. There are currently no medications approved for the treatment of NASH. The proportion of liver transplants attributable to NASH has increased rapidly in past years and by 2020 the disease is projected to become the leading indication for liver transplant.
About Intercept
Intercept is a biopharmaceutical company focused on the development and commercialization of novel therapeutics to treat progressive non-viral liver diseases, including primary biliary cholangitis (PBC), nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC) and biliary atresia. Founded in 2002 in New York, Intercept now has operations in the United States, Europe and Canada. For more information about Intercept, please visit www.interceptpharma.com.
SOURCE: Intercept Pharmaceuticals
