Germany's Federal Institute for Drugs and Medical Device has granted approval to Arrowhead Research Corporation's Clinical Trial Application for ARC-520, its clinical candidate for chronic hepatitis B infection (HBV).

The company now has regulatory clearance in Germany for two additional phase 2b multiple-dose studies of ARC-520 to be conducted in parallel. Arrowhead awaits final IRB approval from the sites, which are expected shortly, and in addition, the company is engaged with regulatory authorities from Hong Kong and South Korea to open additional sites for these studies. Arrowhead will provide guidance in the future on timing for release of data from these studies.

"ARC-520 is leading the way in studying the use of RNAi drugs as new treatment options for chronic HBV. We are very pleased to receive regulatory clearance in Europe to conduct the parallel design phase 2b multiple-dose studies that we proposed," said Bruce D. Given, M.D., Arrowhead's chief operating officer.

"We view these studies as the front end of a set of global multiple-dose studies designed to identify the right agents, doses, and regimens that can achieve functional cures. Based on multiple-dose data from our recently disclosed chimpanzee study and the long duration of activity ARC-520 has demonstrated in the single-dose phase 2a study in patients, we are starting with doses of 1mg/kg and 2mg/kg in parallel. We have incorporated an interim analysis in both studies to get an early read on whether we may want to interrogate higher doses. ARC-520 continues to be well tolerated and we have not seen any signal suggesting that we are approaching a maximum tolerated dose through 4mg/kg, the highest dose studied in humans to date."

The studies titled Heparc-2002 and Heparc-2003 will enroll patients with chronic HBV infection that are e-antigen (HBeAg) negative and HBeAg positive, respectively. Each study is a multicenter, randomized, double-blind, placebo-controlled, multi-dose study intended to evaluate two dose levels in parallel of ARC-520 in combination with entecavir or tenofovir in patients with immune active chronic HBV infection. The 2002 and 2003 studies are planned to enroll up to 60 and 90 patients, respectively. In each study, patients will be randomized to receive four doses, once every 4 weeks, of either 1 mg/kg ARC-520, 2 mg/kg ARC-520, or placebo at a ratio of 1:1:1.

For each patient, the duration of the study is approximately 33 weeks, from screening to the day 169 follow-up visit. For each study, a planning interim analysis will be performed when 54 patients have completed their day 71 visit. This analysis will be used to plan future studies only and will not impact the enrollment or conduct of Heparc-2002 and -2003. Based on the interim results, the company will decide whether higher multiple-doses would be likely to lead to increased activity, in which case higher doses may be evaluated in one or more additional studies.

The primary objective of the 2002 and 2003 studies is to evaluate the depth of hepatitis B surface antigen (HBsAg) decline in response to multiple doses of ARC-520 compared to placebo as a measure of drug activity. Secondary objectives include the assessment of safety and tolerability and multi-dose pharmacokinetics of ARC-520 when co-administered with entecavir or tenofovir, in addition to other exploratory objectives.

Arrowhead's RNAi-based candidate ARC-520 is being investigated in the treatment of chronic HBV infection. The small interfering RNAs (siRNAs) in ARC-520 intervene at the mRNA level, upstream of the reverse transcription process where current standard of care nucleotide and nucleoside analogues act. Arrowhead is investigating ARC-520 specifically to determine if it can be used to achieve a functional cure, which is an immune clearant state characterized by hepatitis B s-antigen negative serum with or without sero-conversion. Arrowhead has completed a phase 1 single ascending dose study in normal volunteers and the company is conducting single dose phase 2a studies and multiple dose phase 2b studies in chronic HBV patients. Approximately 350-400 million people worldwide are chronically infected with the hepatitis B virus, which can lead to cirrhosis of the liver and is responsible for 80 per cent of primary liver cancers globally.

Arrowhead Research Corporation is a biopharmaceutical company developing targeted RNAi therapeutics.