Arrowhead Research Corporation is a biopharmaceutical
company developing targeted RNAi therapeutics.
Hepatitis B virus is the world’s most common serious liver infection, with an estimated 350 million patients worldwide that are chronically infected. There are thought to be approximately 2 million patients in the U.S., 14 million in Western Europe, over 100 million in the Asia Pacific Region, and another 220+ million throughout the rest of the world. HBV can lead to cirrhosis of the liver and is responsible for 80% of primary liver cancers globally. The death toll for HBV is estimated to be as high as one million per year.
Based on the naturally occurring mechanism of RNA interference and Arrowhead’s Dynamic Polyconjugate delivery system, drug candidate ARC-520 has the potential to treat chronic hepatitis B virus infection in a fundamentally different manner than current therapies. The goal is 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 is on track to conduct a phase 1 single ascending dose study in normal volunteers in mid-2013, which the company expects will be followed by a phase 2a study in chronic HBV patients in Hong Kong.
Current treatment options include interferon, which is difficult to use due to highly disruptive side effects, and nucleotide or nucleoside analogues, referred to collectively as NUCs. The best NUCs are very good at suppressing viremia, the production and release of new viral particles, but are not capable of directly suppressing the production and release of viral proteins including s-antigen and e-antigen. Neither interferon nor NUCs provide meaningful rates of functional cure.
ARC-520 uses a different mechanism than NUCs
RNAi in general, and the siRNAs in ARC-520 specifically, act in a fundamentally different way than NUCs. These siRNAs intervene at the mRNA level, upstream of where nucleotide and nucleoside analogues act, and have been shown to deeply knock down all HBV gene products, including proteins and the viral intermediates necessary to produce viral DNA. Many experts in the field believe that knocking down key viral antigens may revive the host adaptive immune response and potentially achieve a functional cure.
In animal models of HBV infection, a single co-injection of the DPC delivery vehicle with cholesterol-conjugated siRNA targeting HBV sequences resulted in multi-log knockdown of HBV RNA, proteins and viral DNA with long duration of effect.
Treatment in mouse model of HBV infection
Treatment with ARC-520 in a non-transgenic mouse model for HBV infection resulted in strong reduction of serum viral markers, notably the following:
Decreased viral DNA
Treatment in an HBV-infected Chimpanzee
A low dose of ARC-520 induced rapid and deep reductions in viral particles and key viral antigens in a chimpanzee chronically infected with hepatitis B virus. The treatment was well-tolerated and led to a 95% reduction in circulating viral DNA, and approximately 90% reductions in hepatitis e-antigen (HBeAg) and s-antigen (HBsAg). The chimp being treated had exceptionally high titers of circulating HBV DNA and HBsAg that measured 1,000 to 10,000-fold higher than the average chronic hepatitis B patient. The HBV infection has been chronic for over thirty years and has persisted despite prior therapy with multiple anti-viral drugs and therapeutic vaccine exposures. Notably, these results were achieved despite a mismatch in sequence between the viral DNA and one of the siRNAs included in ARC-520.
Arrowhead is currently testing ARC-520 in hepatitis B patients in a Phase 2 clinical study.