Therapeutic Safety and Efficacy of REP 2139 (REP 9AC') in HBV Infected Patients

Chronic hepatitis B is a long term condition caused by infection of the body with the hepatitis B virus (HBV). This infection often results in inflammation or scarring of the liver and can eventually lead to liver cirrhosis and liver failure. These infections are also one of the major causes of the development of hepatocellular carcinoma (liver cancer).

Although some drugs have been approved to treat chronic hepatitis B infections, they do not provide a complete cure except in rare cases (a cure generally means that a person loses the hepatitis B virus from the blood and the liver and develops a durable immunological control of subsequent HBV infection). However, these drugs do significantly decrease the risk of liver damage and liver cancer arising from the presence of a chronic liver infection by slowing or stopping the production of infectious virus. Thus the primary problem associated with currently available drugs is the lack of clearance of the virus from the hepatocytes which necessitates long term treatment with these drugs. There is clearly a need to identify new drugs that can benefit patients with chronic hepatitis B infections. Nucleic acid-based polymers (NAPs) are a new class of broad-spectrum antiviral compounds which act against HBV infection by blocking the release of the surface antigen protein (HBsAg) from infected hepatocytes. In the human patients in the REP 101 protocol, the previous NAP clinical candidate, REP 9AC (REP 2055), rapidly induced pronounced reductions in or clearance of serum HBsAg in 7 out of 8 patients. HBsAg is the major immunoinhibitory mechanism by which HBV maintains its chronicity and by reducing or eliminating HBsAg from the blood, REP 9AC appears able to elicit restoration of durable immunological responses in patients capable of clearing the HBV infection. The performance of REP 9AC in providing sustained virologic responses (SVRs) in patients with chronic HBV infection appeared to be far superior than any compound currently approved for the treatment of HBV infection

REP 9AC' (REP 2139) is a modified version of its predecessor, REP 9AC (REP 2055). Both are 40mer phosphorothioate oligonucleotides comprised of alternating adenosine and cytidine nucleotides and in the case of REP 9AC, has been shown to have low toxicity and to be highly effective in treating hepatitis B infection in human patients. The modifications in REP 9AC' significantly improve the stability and reduce the pro-inflammatory activity of REP 9AC' compared to that of REP 9AC while retaining all the antiviral activity found in REP 9AC. Both these modifications (5-methylation of cytosines and 2' O methylation of the ribose sugar in each nucleotide) are naturally occurring modifications in human nucleic acid and are known to be well tolerated in clinical trials. It is expected that REP 9AC' will be able to achieve a more robust antiviral activity in patients with chronic HBV with significantly lower dosing requirements and fewer side effects than REP 9AC.

Current interim data analysis from the still ongoing REP 101 assessing the activity of REP 9AC in patients with chronic HBV infection indicates the following:

1. REP 9AC exposure in eight patients has been generally well tolerated at doses up to 600mg / week and 400mg / day (for seven continuous days). Administration related side effects include mild to moderate pro-inflammatory reactions during the drug administration (itching and fever) which disappear after drug administration is complete. Chronic side effects include mild elevations in blood anticoagulation (international normalized ratio ~1.5) and serum hypocalcemia (which is easily mitigated with a mineral supplement).
2. REP 9AC has achieved serum HBsAg reduction or clearance in all patients compliant with the proscribed dosing regimen (7 out of 7).
3. In these seven patients, 5 have demonstrated restoration of at least a partial immunological control of their infection (appearance of serum anti-HBs and the establishment of a lower serum HBV DNA setpoint).
4. Of the five patients achieving having an immunological response, three have achieved a SVR off treatment with as few as 20 weeks of REP 9AC treatment with complete and durable immunological control over their infection for 18, 12 and 10.5 months.
5. Suboptimal stability of REP 9AC is a likely factor impairing the performance of the drug.