ACL inhibitor ETC-1002 (Esperion) met its primary end point of greater LDL-cholesterol lowering from baseline with ETC-1002 compared with ezetimibe, according to a study.
ACL (ATP citrate lyase) inhibitors reduce cholesterol synthesis in the liver and, therefore, increase expression of LDL receptors in the liver that remove cholesterol from the blood.
ETC-1002-008 was a randomized, double-blind, active comparator-controlled, parallel group, multicenter Phase 2b study evaluating the efficacy and safety of ETC-1002 monotherapy versus ezetimibe monotherapy in patients with hypercholesterolemia, with or without statin intolerance, treated for 12 weeks. Secondary objectives were to characterize the dose response; assess the effect of ETC-1002 on additional lipid and cardiometabolic biomarkers; characterize the safety, tolerability and rates of muscle-related adverse events and assess lipid-lowering efficacy in combination with ezetimibe versus ezetimibe monotherapy.
A total of 348 patients with hypercholesterolemia were washed out of any lipid-regulating therapies prior to a run-in period of 5 weeks. Ninety-nine patients were randomly assigned to receive ETC-1002 120 mg; 100 patients were randomly assigned to receive ETC-1002 180 mg; 99 patients were randomly assigned to receive ezetimibe 10 mg; 26 patients were randomly assigned to receive ETC-1002 120 mg + ezetimibe 10 mg; and 24 patients were randomly assigned to receive ETC-1002 180 mg + ezetimibe 10 mg. A total of 177 patients had a history of statin intolerance.
In patients who received ETC-1002 as monotherapy, there were 27% and 30% reductions in LDL-cholesterol at doses of 120 mg and 180 mg, respectively. These reductions were significantly different from ezetimibe alone (P=.0008 and P<.0001, respectively). In patients who received the combination of 120 mg of ETC-1002 and 10 mg ezetimibe, substantial LDL-cholesterol reductions of 43% were significantly different from ezetimibe alone (P<.0001). In patients who received the combination of 180 mg of ETC-1002 and 10 mg ezetimibe, substantial LDL-cholesterol reductions of 48% were significantly different from ezetimibe (P<.0001). These reductions occurred within the first 2 weeks of dosing and continued throughout the treatment period.
Additionally, ETC-1002 monotherapy and ETC-1002 in combination with ezetimibe demonstrated significantly greater reductions than ezetimibe in high-sensitivity C-reactive protein (hsCRP), an important marker of inflammation in coronary disease.
ETC-1002 appeared to be safe and well tolerated.
“ETC-1002 represents a potentially important option in the continuum of care for patients with hypercholesterolemia, as, if approved, it represents an opportunity to provide patients with an oral option before they need to be treated with the, likely more costly, biologics,” said Tim Mayleben, president and CEO of Esperion. “This is especially important for patients who cannot tolerate statins.”
One of the most common statin side effects is muscle pain.
“For patients with hypercholesterolemia, including those with statin intolerance, ETC-1002 is a potential new LDL-C lowering therapy with greater LDL-C lowering than ezetimibe alone, and a similar tolerability profile,” Mayleben said.
“Moving forward, the potential approval of [ETC-1002] can offer patients with hypercholesterolemia another options to manage their condition more effectively,” according to FormularyWatch advisor Abimbola Farinde, PharmD, MS, who serves on the faculty at Columbia Southern University, Orange Beach, Ala. “This offers another opportunity to target and manage cholesterol levels.”
Esperion plans to discuss its phase 3 clinical trial designs with FDA in mid-2015 and intends to start the late-stage program by the end of 2015.