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ETC-1002 Reduces Blood Pressure in Hypercholesterolemic Patients with Mildly Elevated Blood Pressure
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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.
Journal of Clinical Lipidology, Vol 8, No 3, June 2014 ETC-1002 inhibits ATP-citrate lyase (ACL) and activates AMP-activated protein kinase (AMPK) in the liver. Objective/Purpose: Four Phase 2a, double-blind, parallel group, placebo (PBO)-controlled studies were pooled to assess the blood pressure effects of ETC-1002 in hypercholesterolemic patients with systolic blood pressure (SBP) $ 120 mmHg and/or diastolic blood pressure (DBP) $ 80 mmHg at baseline. Methods: Patients with hypercholesterolemia and a baseline SBP $ 120 mmHg and/or DBP $ 80 mmHg receiving ETC-1002 in 4 PBO-controlled studies were pooled for analysis. Data were analyzed using mixed model ANCOVA with treatment as a covariate. Additional sensitivity analyses were conducted to investigate the effect of baseline blood pressure value, study and study treatment interaction as model covariates. Results: ETC-1002 reduced SBP by -3.64 mmHg (95% CI 5 -7.24, -0.04, p50.05) and DBP by -1.26 mmHg (95% CI 5 -4.01, 1.49, p50.37). When baseline blood pressure and study were included as covariates, ETC-1002 reduced SBP by –6.68 mmHg (95% CI 5 -11.27, -2.08, p50.005) and DBP by -2.24 mmHg (95% CI 5 -5.85, 1.37, p50.22). Results shown are placebo corrected least squares mean change from baseline across the 4 pooled studies. Conclusion: ETC-1002 significantly reduced systolic blood pressure in patients with mildly elevated baseline blood pressure. These data support further clinical evaluation of the effects of ETC-1002 on blood pressure in patients. Change in Blood Pressure from Baseline (mmHg)
N†
172 ETC-1002 Reduces Blood Pressure in Hypercholesterolemic Patients with Mildly Elevated Blood Pressure Roger S. Newton, PhD, Diane E. MacDougall, MS, Jeffrey C. Hanselman, MS, Janice R. Margulies, MS, James Roy Johnson, PhD, Christie M. Ballantyne, MD, Paul Davis Thompson, MD, Michael A. Weber, MD, Noah L. Rosenberg, MD, (Plymouth, MI)
Lead Author’s Financial Disclosures: Dr. Newton is employed by and is an owner (stock and stock options) in Esperion Therapeutics Inc., the company that is developing ETC-1002 and sponsored the studies. Study Funding: Yes Funding Sources: This study was funded by Esperion Therapeutics, Inc. Background/Synopsis: ETC-1002 is an oral investigational drug being developed to lower LDL-cholesterol (LDL-C) and improve other cardiometabolic risk factors.
LS Mean Difference from PBO (95% CI)
p-value
ANCOVA with Treatment as Covariate SBP 185 -3.64 (-7.24, -0.04) 0.0478 DBP 109 -1.26 (-4.01, 1.49) 0.3660 ANCOVA with Baseline, Study and Study Treatment Interaction as Covariate SBP 149 -6.68 (-11.27, -2.08) 0.0047 DBP 87 -2.24 (-5.85, 1.37) 0.2204 †
Modified Intent-to-Treat (mITT) population, active and PBO combined.
173 Effects of Evolocumab on Lipoprotein Particles & Subclasses in Hypercholesterolemic & Heterozygous Familial Hypercholesterolemia Subjects on Statin† Ren Xu, MSc, Clapton Dias, PhD, Matt Peach, MSc, Lisa Hamilton, MSc, Bing Gao, PhD, Brian Smith, PhD, Blaire Cooke, PhD, Simon Jackson, PhD, Adam Shaywitz, MD, PhD, Dan Fitzpatrick, PhD, Rob Scott, MD, Scott M. Wasserman, MD, (Seattle, WA)
Lead Author’s Financial Disclosures: Ren Xu, MSc is employed by Amgen Inc.
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.
Journal of Clinical Lipidology, Vol 8, No 3, June 2014 ETC-1002 inhibits ATP-citrate lyase (ACL) and activates AMP-activated protein kinase (AMPK) in the liver. Objective/Purpose: Four Phase 2a, double-blind, parallel group, placebo (PBO)-controlled studies were pooled to assess the blood pressure effects of ETC-1002 in hypercholesterolemic patients with systolic blood pressure (SBP) $ 120 mmHg and/or diastolic blood pressure (DBP) $ 80 mmHg at baseline. Methods: Patients with hypercholesterolemia and a baseline SBP $ 120 mmHg and/or DBP $ 80 mmHg receiving ETC-1002 in 4 PBO-controlled studies were pooled for analysis. Data were analyzed using mixed model ANCOVA with treatment as a covariate. Additional sensitivity analyses were conducted to investigate the effect of baseline blood pressure value, study and study treatment interaction as model covariates. Results: ETC-1002 reduced SBP by -3.64 mmHg (95% CI 5 -7.24, -0.04, p50.05) and DBP by -1.26 mmHg (95% CI 5 -4.01, 1.49, p50.37). When baseline blood pressure and study were included as covariates, ETC-1002 reduced SBP by –6.68 mmHg (95% CI 5 -11.27, -2.08, p50.005) and DBP by -2.24 mmHg (95% CI 5 -5.85, 1.37, p50.22). Results shown are placebo corrected least squares mean change from baseline across the 4 pooled studies. Conclusion: ETC-1002 significantly reduced systolic blood pressure in patients with mildly elevated baseline blood pressure. These data support further clinical evaluation of the effects of ETC-1002 on blood pressure in patients. Change in Blood Pressure from Baseline (mmHg)
N†
172 ETC-1002 Reduces Blood Pressure in Hypercholesterolemic Patients with Mildly Elevated Blood Pressure Roger S. Newton, PhD, Diane E. MacDougall, MS, Jeffrey C. Hanselman, MS, Janice R. Margulies, MS, James Roy Johnson, PhD, Christie M. Ballantyne, MD, Paul Davis Thompson, MD, Michael A. Weber, MD, Noah L. Rosenberg, MD, (Plymouth, MI)
Lead Author’s Financial Disclosures: Dr. Newton is employed by and is an owner (stock and stock options) in Esperion Therapeutics Inc., the company that is developing ETC-1002 and sponsored the studies. Study Funding: Yes Funding Sources: This study was funded by Esperion Therapeutics, Inc. Background/Synopsis: ETC-1002 is an oral investigational drug being developed to lower LDL-cholesterol (LDL-C) and improve other cardiometabolic risk factors.
LS Mean Difference from PBO (95% CI)
p-value
ANCOVA with Treatment as Covariate SBP 185 -3.64 (-7.24, -0.04) 0.0478 DBP 109 -1.26 (-4.01, 1.49) 0.3660 ANCOVA with Baseline, Study and Study Treatment Interaction as Covariate SBP 149 -6.68 (-11.27, -2.08) 0.0047 DBP 87 -2.24 (-5.85, 1.37) 0.2204 †
Modified Intent-to-Treat (mITT) population, active and PBO combined.
173 Effects of Evolocumab on Lipoprotein Particles & Subclasses in Hypercholesterolemic & Heterozygous Familial Hypercholesterolemia Subjects on Statin† Ren Xu, MSc, Clapton Dias, PhD, Matt Peach, MSc, Lisa Hamilton, MSc, Bing Gao, PhD, Brian Smith, PhD, Blaire Cooke, PhD, Simon Jackson, PhD, Adam Shaywitz, MD, PhD, Dan Fitzpatrick, PhD, Rob Scott, MD, Scott M. Wasserman, MD, (Seattle, WA)
Lead Author’s Financial Disclosures: Ren Xu, MSc is employed by Amgen Inc.