FDA accepts Arisaph's ARI-3037MO IND for phase I human clinical trial

Arisaph Pharmaceuticals, Inc., a privately held drug discovery biopharmaceutical company, today announced that the U.S. Food and Drug Administration (FDA) has accepted the Company's recently submitted Investigational New Drug (IND) application to evaluate ARI-3037MO in a phase I human clinical trial in healthy volunteers.  ARI-3037MO, a proprietary new chemical entity, is a once-daily, niacin analog being developed for the treatment of dyslipidemia. In preclinical pharmacology studies, the compound produced greater lipid responses than niacin in a relevant animal model of hyperlipidemia.  Additionally, ARI-3037MO showed an extremely favorable safety profile, including the absence of flushing, in non-clinical drug safety studies. The Company believes that an efficacious and well tolerated niacin analog will be more widely utilized than existing forms of niacin in treating hypercholesterolemia, a disorder that afflicts as many as 93 million Americans according to data published by the American Heart Association.

"The FDA's acceptance of our IND is a major milestone for Arisaph, particularly considering that we developed the compound from lead selection to IND filing in about 9 months," said Christopher P. Kiritsy, President and Chief Executive Officer of Arisaph Pharmaceuticals.  "With ARI-3037MO, we have designed a once a day, structural analog of niacin that retains niacin's beneficial biological effects on lipids without producing the irritating side effect of flushing."    

As part of the IND submission, Arisaph completed comprehensive nonclinical drug safety studies, including 28-day toxicology studies in rats and dogs.  The results show that ARI-3037MO has a favorable safety pharmacology profile and a wide therapeutic index.  One of the major challenges with current forms of niacin is that they are dose limited because of adverse side effects, such as gastrointestinal intolerance, liver enzyme elevations and flushing. The Company believes that ARI-3037MO can produce greater therapeutic benefits than existing forms of niacin as a result of mitigating such adverse side effects.  

In preclinical studies involving hamsters fed a high-fat diet, ARI-3037MO showed robust changes in lipids, including LDL and HDL cholesterols and triglycerides (TGs).  Specifically, once-daily treatments of ARI-3037MO lowered both LDL cholesterol and TGs greater than 70% from placebo.  In comparison, higher doses of niacin reduced LDL cholesterol and TGs approximately 50% from placebo.  Additionally, ARI-3037MO increased the proportion of HDL cholesterol to a greater extent than niacin.  ARI-3037MO treated hamsters showed a significant increase in ATP-binding cassette transporter A1 (ABCA1), apolipoprotein A-1 (ApoA1), and adiponectin compared to the vehicle control animals.  The ABCA1 and ApoAI increases are noteworthy, as the proteins that result from these transcripts are involved in the synthesis and maturation of HDL.  

"Significant lipid changes coupled with the increased mRNA levels for certain regulatory proteins involved in HDL synthesis and reverse cholesterol transport offers compelling evidence to support the mechanism based efficacy of this niacin analog," commented, Dr. Ernst Schaefer, Professor of Medicine, Tufts University School of Medicine. "The availability of an effective and tolerable niacin replacement would be a major advancement for the treatment of mixed lipid disorders."

In addition to the compelling preclinical efficacy, ARI-3037MO did not induce "flushing" as measured by changes in capillary blood flow via the ear in mice. Such capillary blood flow measurements have translated well in evaluating the effects of niacin on flushing in human clinical trials. Additionally, flushing was not observed during clinical observations in 28-day rat and dog toxicological studies or in several other nonclinical studies, in which ARI-3037MO was administered in various doses to multiple species.  Flushing, representative of tingling and/or redness of the skin, is the principal side effect of niacin and in some patients can be extremely uncomfortable.  Consequently, many patients fail to achieve efficacious dosing or discontinue niacin therapy altogether, resulting in poor patient compliance and adherence.  Based on preclinical results, the Company believes that ARI-3037MO represents an advancement in treating mixed lipid disorders in patients with coronary heart disease.