Abstract 9595: A Novel Niacin Analog (ARI-3037MO) Induces Favorable Plasma Lipid Changes Without Flush in Single and Multiple Ascending Dose Placebo Controlled Trials in Normal Healthy Volunteers

Abstract

INTRODUCTION: Despite niacin’s (NA) beneficial effects on lipids, it’s use is limited by side effects, such as flushing, itching, and increases in liver enzymes and blood glucose. These effects, particularly flushing, lead to poor compliance and persistence in clinical use. ARI-3037MO is an orally active, novel, NA analog that produces significant lipid altering effects at least as effective as NA on low density lipoproteins (LDL-C), triglycerides (TG) and high density lipoproteins (HDL-C) in preclinical studies without flushing.

METHODS: To evaluate safety and pharmacokinetics of ARI-3037MO in humans, we conducted a single ascending dose (SAD) trial and a multiple ascending dose (MAD) trial in healthy volunteers. In SAD study, five doses of ARI-3037MO QD were evaluated in 30 subjects (n=6 per dose; 17 males, 13 females). Ten additional subjects received matching placebo. In MAD trial, four doses of ARI-3037MO [(0.5g (n=8), 1g (n=8), 2g (n=9) & 3.5g (n=9)] QD were evaluated in 34 healthy volunteers (24 males, 10 females) for 14 or 28 days (2g QD cohort only). Eight additional subjects received matching placebo. RESULTS: In SAD trial all doses (0.5g - 6g/day) of ARI-3037MO, were well tolerated with no evidence of flushing, itching or other skin changes even at the 6g QD dose. No liver function or glucose abnormalities were observed. There was a reduction in TG (-56.7 +/- 37.0 mg/dl; mean+/- SEM; p < 0.05 ANOVA) and an increase in HDL-C (+ 7.7 +/- 1.6 mg/dl; p < 0.05 ANOVA) in the 6g cohort. In MAD trial, all doses were well tolerated with no evidence of flushing, itching or other skin changes even at the highest dose. No liver function or glucose abnormalities were observed. There was a significant reduction in TGs with 2g dose given for 28 days as well as a trend toward reduction in LDL-C. Following single or multiple dosing, ARI-3037MO was rapidly absorbed and plasma drug levels showed good dose proportionality. CONCLUSION: The absence of any adverse effects (including flush, increases in liver enzymes and blood glucose) at all doses in the SAD and MAD studies, combined with encouraging lipid effects in these short duration trials indicates that ARI-3037MO represents a potential transformational niacin-based therapy for patients with dyslipidemia and metabolic syndrome.