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Arrowhead, Regulus Present Data on Hepatitis Programs at Liver Meeting


Arrowhead Research and Regulus Therapeutics this week announced the presentation of preclinical data on their hepatitis drug candidates.

Arrowhead unveiled non-human primate data suggesting that its siRNA-based hepatitis B agent can reactivate a compromised immune system, while Regulus offered insights into the mechanism of active of its microRNA-targeting hepatitis C therapy.

The findings were presented at the annual meeting of the American Association for the Study of Liver Disease. According to the companies, the data support the continued development of their respective therapeutics: Arrowhead's ARC-520 is slated to move into a phase IIa trial in early 2014, and Regulus' RG-101 is expected to begin phase I testing around the same time.


ARC-520 comprises two distinct siRNAs targeting highly conserved genomic regions across the major HBV genotypes, and is formulated with a proprietary delivery technology called dynamic polyconjugates. Arrowhead acquired the compound when it bought Roche's RNA drug assets in late 2011.

Earlier this year, Arrowhead released data showing that its drug could induce a greater than 90 percent reduction in circulating HBV DNA in a chimpanzee that was chronically infected with the virus (GSN 3/14/2013).

A few months later, ARC-520 entered a phase I study, which tested single doses of the drug ranging from 0.01 mg/kg to 2 mg/kg against placebo in 24 healthy volunteers. Preliminary data indicated that the compound was safe enough to move into a single-dose phase IIa trial in HBV patients in Hong Kong planned for next year (GSN 10/10/2013).

Ahead of that clinical trial, Arrowhead has presented additional data from its chimp study, indicating that ARC-520 not only lowered levels of HBV DNA and two key viral antigens — hepatitis B e-antigen and hepatitis B surface antigen, which are both indicators of an active and replicating virus — but also appeared to trigger important immunological flare associated with derepression of the adaptive immune response.

Specifically, following the decrease in the chimp's HBV surface antigen levels, a rise in the enzyme alanine aminotransferase was observed, which pointed to immunological activity occurring in the animal's liver. The increases in key chemokine and cytokine mRNAs observed in the chimp were also "consistent with an immunological event," Arrowhead researchers wrote in a poster presented at AASLD.

Commenting on the data, Arrowhead President and CEO Chris Anzalone noted that it is believed that HBV surface antigen is immunosuppressive, which likely prevents patients from clearing the virus, leading to chronic infection.

"The theory is that if you can knock out [surface antigen], you can enable the immune system to come back up," which would result in a functional cure, he told Gene Silencing News. "The problem is no one has been able to do that."

Based on the non-human primate data, however, Arrowhead is cautiously optimistic that ARC-520 is able to inhibit HBV surface antigen enough to enable immune derepression, which could result in seroconversion.

Anzalone added that the drug's effect on HBV surface antigen may also prove to be greater in humans than it was in the chimp given the animal's extremely high-level viremia.

"I don't think we'll see a human as infected as this animal," he said.


Regulus' RG-101 is an inhibitor of miR-122 that incorporates Alnylam Pharmaceuticals' GalNAc conjugate delivery. Although Regulus is working with GlaxoSmithKline on the disease, earlier this year it announced that it would be advancing the drug on its own, with an eye to beginning human testing early next year (GSN 5/16/2013).

At AASLD this week, Regulus released new in vivo data on RG-101 that the company said supports the agent's continued development.

According to Regulus, in mice and non-human primates, the drug is rapidly taken up in the liver and metabolized to the active oligonucleotide, which has a 14-day tissue half-life, after subcutaneous administration.

Potency of RG-101 in the liver, as measured by derepression of the miR-122 target gene AldoA, was also achieved at "significantly lower liver concentrations of oligonucleotide" following doses of 1 mg/kg to 10mg/kg, compared to similar doses of unconjugated drug.

Meanwhile, in a human chimeric liver mouse model infected with HCV, a single subcutaneous dose of RG-101 at 3 mg/kg, 10 mg/kg, or 30 mg/kg led to as much as a 2-log reduction in HCV viral load titer — an effect similar to that observed with oral direct-acting antivirals as monotherapy in the mouse model, Regulus said.

RG-101 also demonstrated a positive safety profile, with no adverse events observed with doses up to 450 mg/kg in mice and 45 mg/kg in non-human primates. AldoA levels in non-human primates were maximally elevated at 1 mg/kg, the company noted.

Additional preclinical toxicology and safety pharmacology studies examining multiple doses of RG-101 are ongoing.

"We believe that therapies that target host-encoded factors essential for HCV replication may act as attractive combination agents because they may demonstrate activity across all HCV genotypes and may have a high barrier to resistance,” Regulus CSO Neil Gibson said in a statement. “We continue to be encouraged by the preclinical data seen to date and believe that RG-101 has the potential to be a best-in-class host factor agent."