A Safe and Tolerable Niacin Analog for Treatment of Nonalcoholic Steatohepatitis

DESCRIPTION provided by applicant Nonalcoholic steatohepatitis NASH characterized by liver steatosis with hepatocellular injury and inflammation is a potentially serious condition with up to of patients progressing to cirrhosis with complications of portal hypertension liver failure and hepatocellular carcinoma NASH is highly prevalent in patients with type diabetes T D and is an escalating health problem due to the global epidemic of T D Currently control of lipids by diet and exercise is the only approved treatment but long term effectiveness is questionable because many patients are unable to comply with the required dietary and lifestyle changes emphasizing the need for an effective pharmacotherapeutic approach The thiazolidines and vitamin E can improve liver histology in NASH patients but they are handicapped by formidable adverse effects The investigational agent obeticholic acid has been shown to improve the biochemical and histological features of NASH but drug safety requires further evaluation in the light of potentially adverse effects on blood lipids A new compound ARI MO can reverse the elevation of the enzyme markers of liver damage in hyperlipidemic hamsters and reduce circulating triglycerides and body weight ARI MO is a synthetic analog of nicotinic acid NA which itself has been reported to reverse hepatic steatosis in a hyperlipidemic model NA significantly reduced liver lipid in a small clinical trial but clinical acceptance in NAFLD NASH patients is unlikely given its association with hepatoxicity impaired insulin sensitivity and flushing ARI MO does not interact with the high affinity receptor for NA GPR A which mediates the latter two adverse effects but preclinically and clinically ARI MO retained beneficial effects on lipid levels and inflammation ARI MO did not impair glucose control cause flushing or show any signs of hepatotoxicity in human phase I trials suggesting feasibility as a drug candidate in NAFLD NASH The next step is to examine efficacy in NAFLD NASH patients with moderate biopsy proven steatohepatitis in a month study The Specific Aim is to demonstrate that ARI MO reduces intrahepatic lipid content and improves liver function via beneficial changes in liver function tests In order to advance into a placebo controlled proof of concept phase II clinical study in NASH patients SBIR phase ARI MO must meet specific Benchmarks at least a reduction in intrahepatic lipid content measured by MRI spectroscopy and a or greater reduction in the alanine transaminase marker of liver disease A study director at an advanced clinical site Beth Israel Deaconess Medical Center a homogeneous study population selected by liver histology indicative of reversible disease and the safety profile of ARI MO provide confidence that the study can be successfully executed to yield definitive measurable outcomes PUBLIC HEALTH RELEVANCE Nonalcoholic steatohepatitis NASH is an escalating public health problem linked to the global diabetes epidemic and is characterized by liver steatosis accompanied by hepatocellular injury inflammation and risk of progression to cirrhosis with complications of portal hypertension liver failure and hepatocellular carcinoma Effectiveness of diet and exercise to control NASH is limited by patient compliance moreover existing therapeutic agents such as the thiazolidines and vitamin E and an otherwise promising investigational agent obeticholic acid are handicapped by significant safety concerns Efficacy of the new investigational agent ARI MO will be tested in NAFLD NASH patients in a trial with intrahepatic lipid and liver enzyme endpoints