Positive results have been obtained in ETC-1002-008, a phase 2b study evaluating the efficacy and safety of ETC-1002 monotherapy compared with ezetimibe monotherapy in patients with hypercholesterolaemia, with or without statin intolerance. ETC-1002 is a first-in-class, orally available, once-daily LDL-c lowering therapy. ETC-1002 has a dual mechanism of action that has the potential to regulate both lipid and carbohydrate metabolism. ETC-1002 inhibits ATP citrate lyase (ACL), a key enzyme in the cholesterol biosynthetic pathway, and activates AMPK. Both enzymes are known to play significant roles in the synthesis of cholesterol and glucose in the liver. By inhibiting cholesterol synthesis in the liver, ETC-1002 causes the liver to take up LDL particles from the blood, which reduces LDL-C levels.

The primary endpoint of greater LDL-c lowering from baseline with ETC-1002 compared with ezetimibe was met in the 12-week study (340 patients randomised, of whom 177 were statin-intolerant). ETC-1002 120 mg and 180 mg yielded 27 and 30% LDL-c reductions, respectively, both significantly different from the effect obtained with ezetimibe (-21%, P=0.0008 and P<0.0001). Patients receiving ETC-1002 120 mg in addition to ezetimibe 10 mg showed a mean LDL-c reduction of 43%, which was significantly different from those treated with ezetimibe alone (P<0.0001). LDL-c reductions were seen in the first two weeks of dosing and were maintained throughout the study period.

ETC-1002 monotherapy and combination therapy with ezetimibe also showed significantly greater reductions than ezetimibe in high-sensitivity C-reactive protein (hsCRP) than ezetimibe monotherapy.

ETC-1002 appeared to be safe and well-tolerated. Discontinuation rates due to an adverse event (AE) with ETC-1002 were comparable to those seen with ezetimibe. Rates of AEs and serious AEs were low and comparable between treatment groups. Elevations in liver enzymes were as expected and comparable to what is typically observed with approved LDL-c lowering therapies. Rates of muscle-related AEs in ETC-1002-treated patients were similar to those seen with ezetimibe, including patients with statin intolerance.

President and chief executive officer of Esperion Tim M. Mayleben concludes that “Our ability to show significant differences between ETC-1002 and ezetimibe in both LDL-cholesterol lowering and reductions in hsCRP demonstrate the potential of ETC-1002 as a new oral therapeutic option for patients with hypercholesterolemia, especially those with statin intolerance. The similarity in muscle-related adverse events between ETC-1002 and ezetimibe is especially encouraging."
Press release Esperion Therapeutics October 1 2014