Noah Rosenberg

Efficacy and Safety of a Novel Dual Modulator of Adenosine Triphosphate-Citrate Lyase and Adenosine Monophosphate-Activated Protein Kinase in Patients With Hypercholesterolemia : Results of a Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Trial

OBJECTIVES The aim of this study was to assess the lipid-altering efficacy and safety of ETC-1002 in subjects with hypercholesterolemia. BACKGROUND ETC-1002 is a small molecule that modulates pathways of cholesterol, fatty acid, and carbohydrate metabolism and may have therapeutic benefits in treating hypercholesterolemia and other cardiometabolic risk factors. METHODS This multicenter, randomized, double-blind, placebo-controlled, parallel-group trial evaluated patients (n = 177) with elevated low-density lipoprotein cholesterol (LDL-C) (130 to 220 mg/dl), who were stratified by baseline triglycerides (not elevated [<150 mg/dl] or elevated [150-<400 mg/dl]) and randomized to receive 40, 80, or 120 mg of ETC-1002 or placebo once daily for 12 weeks. Outcomes included changes in LDL-C (primary endpoint), other lipids, and cardiometabolic risk factors; and safety. RESULTS ETC-1002 40, 80, and 120 mg lowered least-squares mean ± SE LDL-C levels by 17.9 ± 2.2%, 25.0 ± 2.1%, and 26.6 ± 2.2%, respectively, versus a reduction of 2.1 ± 2.2% with placebo (all, p < 0.0001); LDL-C lowering was similar between the subgroups with nonelevated and elevated triglycerides. ETC-1002 also lowered non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B, and LDL particle number (all, p < 0.0001) in a dose-dependent manner; HDL-C and triglyceride levels were relatively unchanged. Post-hoc analyses suggest that ETC-1002 may have favorable effects on other cardiometabolic risk factors. The ETC-1002 and placebo groups did not demonstrate clinically meaningful differences in adverse events or other safety assessments. CONCLUSIONS ETC-1002 significantly lowered LDL-C levels up to 27% across a broad range of baseline triglycerides and was generally safe and well tolerated. ETC-1002 has a novel mechanism of action and may be useful for reducing LDL-C. (A Study to Assess the Efficacy and Safety of ETC-1002 in Subjects With Elevated Blood Cholesterol and Either Normal or Elevated Triglycerides; NCT01262638).

Efficacy and Safety of ETC-1002, a Novel Investigational Low-Density Lipoprotein-Cholesterol–Lowering Therapy for the Treatment of Patients With Hypercholesterolemia and Type 2 Diabetes Mellitus

Objective— 8-Hydroxy-2,2,14,14-tetramethylpentadecanedioic acid (ETC-1002) is a small molecule with a unique mechanism of action shown in nonclinical studies to modulate pathways of cholesterol, fatty acid, and carbohydrate metabolism. In previous phase 2 clinical trials, once daily oral treatment with ETC-1002 significantly reduced low-density lipoprotein-cholesterol in patients with hypercholesterolemia. In this trial, the lipid-lowering efficacy of ETC-1002 was evaluated in patients with type 2 diabetes mellitus and hypercholesterolemia. Additional cardiometabolic biomarkers, including glycemic measures, were also assessed. Approach and Results— A single-center, double-blind, placebo-controlled trial evaluated 60 patients with type 2 diabetes mellitus and elevated low-density lipoprotein-cholesterol. Patients discontinued all diabetes mellitus and lipid-regulating drugs and were randomized to receive ETC-1002 80 mg QD for 2 weeks followed by 120 mg QD for 2 weeks or placebo for 4 weeks. ETC-1002 lowered low-density lipoprotein-cholesterol levels by 43±2.6% (least squares mean±SE), compared with a reduction of 4±2.5% by placebo at day 29 (P<0.0001; primary end point). Non–high-density lipoprotein-cholesterol and total cholesterol were also significantly lowered by ETC-1002 compared with placebo (P<0.0001). High-sensitivity C-reactive protein was reduced by 41% (median) compared with a placebo reduction of 11% (P=0.0011). No clinically meaningful safety findings were observed. Conclusions— ETC-1002 lowered low-density lipoprotein-cholesterol and other lipids and demonstrated improvement in high-sensitivity C-reactive protein in patients with type 2 diabetes mellitus and hypercholesterolemia without worsening glycemic control. ETC-1002 was well tolerated in this population. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT# 01607294.

ETC-1002 Reduces Blood Pressure in Hypercholesterolemic Patients with Mildly Elevated Blood Pressure

Methods: Normal human primary hepatocytes (Lonza Walkersville Inc.) were first incubated with palmitic acid (0.5 mM) for 24 h to induce fat accumulation. Cells were then treated with niacin (0-0.5 mM) for 24 h. Cellular fat accumulation and formation of reactive oxygen species (ROS, as an index of oxidative stress) were measured by staining with Nile Red O and DCFDA fluorescence respectively. In-vivo effect of niacin on prevention and regression of hepatic steatosis was assessed in high-fat fed rat model of NAFLD. The histology of liver tissue from animals was examined in paraffin embedded hematoxylin and eosin (H&E) stained sections. Results: Niacin (at 0.25 and 0.5 mM doses) significantly inhibited palmitic acid-induced fat accumulation in hepatocytes by 45-62%. This effect was associated with robust inhibition of diacylglycerol acyltransferase 2 (DGAT2) mRNA expression by niacin. Niacin, in a dose-dependent manner, significantly inhibited ROS production in hepatocytes. In experimental rat model of NAFLD, inclusion of niacin at 0.5% and 1% in the high-fat diet significantly decreased liver fat content, hepatic oxidative products, and prevented hepatic steatosis. Niacin treatment to rats with preexisting hepatic steatosis induced by the high-fat diet significantly regressed steatosis. Conclusion: These novel findings suggest that niacin, through inhibiting hepatocyte fat accumulation and lipid peroxidation products, effectively prevents and causes the regression of hepatic steatosis and NAFLD. Clinical development of niacin formulations and niacin-related compounds for the treatment of NAFLD may offer a very cost-effective opportunity in addressing the unmet need for the development of therapeutic agents for NAFLD and other fatty liver disease. N PBO (95% CI) p-value