Abstract 396: High Doses of a Novel Niacin Analog Are Devoid of Clinically Relevant Adverse Events in Safety Trials in Healthy Volunteers
Introduction: High doses of niacin has beneficial effects on lipids and coronary outcomes. However, the use is limited due to side effects at higher doses, as shown by trials such as HPS2 THRIVE, including flushing, myopathy and increases in blood glucose. These dose limitations blunt the lipid responses and potential therapeutic effects of niacin in reducing coronary risk. ARI-3037MO is an orally active, novel niacin analog that induces beneficial changes in Low Density Lipoproteins (LDL), Triglycerides (TG) and in High Density Lipoproteins (HDL) in preclinical studies without evidence of flushing, liver toxicity or changes in blood glucose. Additionally, in a single ascending dose clinical trial in healthy volunteers, ARI-3037MO did not provoke flushing and produced significant changes in TGs and HDL at the highest dose.
Methods: We evaluated the effect of repeat dosing high doses of ARI-3037MO on safety parameters in two separate studies in healthy volunteers. In the first placebo controlled trial, daily doses of 2g and 3.5g of ARI-3037MO were administered for 14 days to 9 subjects per group with 8 subjects receiving placebo. The 2g cohort was extended to 28 days of dosing. In the second trial, 7 subjects received 3g BID (total daily dose of 6g) administered for 24 days with 6 subjects receiving placebo.
Results: In both studies, ARI-3037MO was well tolerated with no flushing or skin changes, no abnormalities in liver function tests or changes in blood glucose. There was also no effect on oral glucose tolerance test after 24 days of dosing with 3g BID. There was a trend toward lipid reduction in both of the studies, with the 3g BID dose showing a reduction of -19% in TGs, -7.4% in LDL-C, and a significant reduction of -8.7% in Apo B (p<0.05). Similarly, the 3g BID dose significantly increased HDL-C by 7.0% (p<0.05). In both studies, the effect of ARI-3037MO on lipids improved with the duration of dosing.
Conclusion: The lack of niacin like adverse effects with very high doses of ARI-3037MO indicates that ARI-3037MO has a wide therapeutic index. This safety and tolerability profile with encouraging lipid effects suggest that ARI-3037MO represents a promising therapy for management of mixed hyperlipidemia, especially in the setting of metabolic syndromes and type II diabetes.
Author Disclosures: C. Benedict: None. J. Neutal: None. C. Kiristy: None. W. Bachovchin: None.
- © 2014 by American Heart Association, Inc.