DINUCLEOTIDE ISOMER AS A NOVEL ANTIVIRAL

DESCRIPTION (provided by applicant): Acute and chronic liver infections caused by Hepatitis C virus (HCV) constitute a major worldwide public health crisis with significant unmet medical need. About 180 million people are chronically infected with HCV worldwide with US (4.4 million) and Europe (12.8 million) representing approximately 10% of world's chronic HCV carriers. Worldwide, more than 1 to 2 million deaths occur every year due to liver cirrhosis and liver cancer. Significant numbers of liver transplant recipients have continued needs for effective anti-HCV therapy. The market for anti-HCV therapeutics is estimated to grow to US 5 billion by 2010. Despite decades of work and billions of dollars of investment, the treatment options for HCV remain extremely limited with inadequate therapeutic benefit - modest viral load reductions during treatment, viral rebound upon cessation of therapy, drug-induced toxicity, and emergence of drug resistance remain serious problems. Thus, new classes of drugs with different mechanisms of action that can be used in combination with other drugs are urgently needed for HCV therapy. There is great interest in the pharmaceutical and biotechnology industry to develop newer, safer antiviral drugs with novel mechanism of action that can be used in combination with other drugs, to combat viral resistance to drugs and viral rebound. Our team, at Spring Bank Technologies, Inc., (SBT) has recently discovered that SB 9200, a first-inclass, novel nucleotide analog, is a potent antiviral agent active against HCV, with high safety index. SB 9200 is synergistic with other anti-HCV agents such as nucleoside analogs, interferon, protease inhibitors, and ribavirin. SB 9200 represents potentially the next generation anti-HCV therapeutic. However, SB 9200 is a mixture of two isomeric forms - designated as Rp-SB 9200 and Sp-SB 9200 - resulting from the asymmetry of the inter-nucleotidic thiophosphate linkage. Given the overwhelming historical evidence for differences in biological activity of drug isomers, it is critically important that the active isomer of SB 9200 be identified and taken up for further development. The studies outlined in this two-year SBIR Phase1 application (NIAID Advanced Technology SBIR) will be carried through support from Academic and Industry Collaborators and are designed to select a single isomer of SB 9200 for further pre-clinical development that has: (a) enhanced antiviral potency, (b) high safety index, and (c) improved bioavailability by way of a novel formulation. The objectives of the current application are consistent with the USFDA's current guidelines and policy requirements for isomeric mixtures of drugs. Further continuing studies, in a follow-up Phase II SBIR application, could lead to an Investigational New Drug Application with USFDA for initiation of human clinical trials. In addition, the knowledge from SB 9200 isomer studies presented in this application will be of immense value as SBT's nucleotide-based drug discovery platform is applied to other therapeutic areas such as inflammation, cardiovascular diseases, and cancer. PUBLIC HEALTH RELEVANCE: Acute and chronic liver infections caused by Hepatitis C virus (HCV) constitute a major worldwide public health crisis affecting over 180 million people for which there is significant unmet medical need.1-3 The studies outlined in this two-year SBIR Phase1 application (NIAID Advanced Technology SBIR) are designed to select a lead candidate for further pre-clinical development as a first-in-class, next generation antiviral agent that has enhanced potency, high safety and improved bioavailability for the treatment of HCV infection. Further continuing studies, in Phase II SBIR application, could lead to an Investigational New Drug Application with USFDA and follow-up clinical trials.