Study of AVI-4065 in Healthy Volunteers and Chronic Active HCV Patients

Hepatitis C virus (HCV) is the most common blood-borne infection in the United States and a worldwide public health problem of epidemic proportions. Benign in the acute phase of infection, HCV infection usually becomes chronic in 70% of those originally infected. Chronic HCV infection leads to inflammation of the liver (hepatitis), cirrhosis, end-stage liver disease, and hepatocellular carcinoma. In the United States alone, there are over 2.7 million individuals with chronic HCV hepatitis. Standard treatment of chronic HCV hepatitis is combination therapy for 24 to 48 weeks with alpha interferon and ribavirin. This combination has limited efficacy, poor tolerability, and significant expense in terms of drug and ancillary laboratory testing. It is well recognized that new treatment options are needed which are more efficacious, potent, less toxic, and less expensive.

AVI BioPharma has pursued discovery of a drug against HCV using proprietary Neugene® or Phosphorodiamidate Morpholino Oligomer (PMO) synthetic chemistry. Neugene (PMO) compounds, as a drug class, are considered safe in humans and do not activate complement, alter clotting times, or bind to α-adrenergic receptors (which can produce hypotension) like the phosphorothioate antisense compounds. One PMO, AVI-4065, has been identified as likely to inhibit all 5 genotypes of HCV based on in vitro and in vivo animal models. There are specific data that confirm that AVI-4065 can inhibit HCV RNA dependent PNA polymerase (RdRp encoded in NS5) and the HCV protease (NS3), in a non-competitive inhibitory fashion. The 50 percent Effective Concentration (EC50) is 308 nM, and the efficacy is nearly 100% at 3 μM. These data suggest that AVI-4065 is capable of inhibiting HCV protein translation in a robust manner at concentrations that should be achievable in patients. In rigorous GLP safety pharmacology and toxicity models in a variety of animal species at dosage levels up to 5 times the maximum anticipated human dosage level, inclusive of non-human primates, AVI-4065 was considered safe, well tolerated and without dose-limiting toxicities. Additionally, AVI-4065 Injection was safe and well-tolerated in the three dose-escalating groups of 31 healthy volunteers (Part I) with no serious adverse events. Adverse events that did occur were few, self-limited and mild to moderate and did not require intervention; this observation held true for the first HCV patients receiving AVI-4065 Injection.

AVI BioPharma's first human use of AVI-4065 Injection involved an open-label, multi-center, exploratory, dose escalating design in healthy adult volunteers. The objective of this part of the study was to assess safety, tolerability and to design a potentially therapeutic dosage regimen. The objective of the second part of the study is to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics and signals of HCV virus response in cohorts of HCV patient volunteers that are interferon and ribavirin treatment failures.

The ability of the drug to effect baseline HCV RNA levels over the study duration will be evaluated using a conventional PCR-based assay. If there are promising results from this phase of the clinical trial (viz., a 2 log decrease in HCV RNA levels from baseline within study surveillance), it will provide the rational basis for additional clinical testing of AVI-4065 Injection among HCV patients that are treatment refractory (viz., relapsers and non-responders).