Arrowhead Pharmaceuticals, Inc., recently filed a regulatory submission in New Zealand to begin a phase 1/2 clinical trial of ARC-521, its RNAi-based therapeutic candidate for the treatment of chronic hepatitis B virus (HBV) infection. Pending approval, Arrowhead intends to proceed with ARC521-1001, a first-in-human study to assess single and multiple-doses of ARC-521 in healthy volunteers and HBV patients.

Chris Anzalone, Ph.D., president and CEO of Arrowhead Pharmaceuticals, said, “ARC-521 is our second pipeline product targeting chronic HBV and was designed to silence gene products from both HBV cccDNA and integrated HBV DNA. This is important because our clinical work with ARC-520 in HBV patients and our long-term chimpanzee study suggest that different patient groups can have different relative levels of cccDNA. We think having both ARC-520, which has been very active in patients with higher cccDNA, and ARC-521, which may be optimal for those with lower cccDNA, should provide us with the potential to treat all patients with HBV. We have an aggressive plan for the development of ARC-521 that includes an accelerated first-in-man phase 1/2 design intended to allow rapid transition into multi-dose patient cohorts.”

The application for approval of a clinical trial was submitted to the New Zealand Medicines and Medical Devices Safety Authority (MEDSAFE) for review by the Standing Committee on Therapeutic Trials (SCOTT). Arrowhead also intends to seek regulatory clearance to conduct ARC521-1001 in additional countries.

Arrowhead’s ARC-521 is being investigated for its potential to produce functional cures in patients with chronic hepatitis B virus (HBV) infection. ARC-521 intervenes upstream of the reverse transcription process where current standard-of-care nucleotide and nucleoside analogs act, and is designed to silence the production of all HBV gene products. The small interfering RNAs (siRNAs) in ARC-521 engage the body’s normal cellular RNAi machinery and direct specific cleavage of HBV RNA transcripts, thereby reducing the levels of HBV proteins and the RNA template used to produce viral DNA. Designed to complement ARC-520, ARC-521 targets HBV mRNA transcripts from both cccDNA and integrated DNA and is expected to be most suitable for those patients who tend to have lower levels of viral cccDNA. Arrowhead is investigating ARC-521 specifically to determine if significantly reducing circulating and non-circulating viral proteins and RNA will allow for re-constitution of an effective host immune response and ultimately HBsAg seroclearance resulting in functional cure. As many as 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 is planning to conduct a phase 1/2 single and multiple-dose study in healthy volunteers and HBV patients.