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Arrowhead Presents Preclinical Data on HBV Candidate, Subcutaneous Delivery Tech


Arrowhead Research last week released new preclinical data on its lead drug candidate, the hepatitis B virus treatment ARC-520, reporting that the agent could trigger up to multi-log reductions in the levels of circulating viral antigens, while lowering levels of the virus' replicative intermediates, in mouse models.

The company also provided new non-human primate data on its recently acquired dynamic polyconjugate siRNA-delivery system, showing that tweaks to the technology have enabled subcutaneous delivery with near complete target knockdown.

The data were presented at this year's Oligonucleotide Therapeutics Society meeting in Boston.

The so-called DPC technology was originally developed by Wisconsin-based Mirus Bio, which was acquired by Roche in 2008 for $125 million in cash (GSN 7/24/2008). However, about a year ago, Roche sold off Mirus to Arrowhead for an equity stake and the promise of milestone payments as part of an overall exit from the RNA drugs space (GSN 10/27/2011).

In their original form, DPCs were composed of an endosomolytic polymer linked to an siRNA, which was then modified with carboxy dimethylmaleic anhydride derivatives containing polyethylene glycol and a tissue-specific targeting ligand. After the DPC was taken into a cell via endocytosis, the decreasing pH of the maturing endosome unmasked the polymer, which disrupted the endosomal membrane and released the siRNA into the cytoplasm.

According to David Lewis, Arrowhead's vice president of biology and former program director at Mirus, a lot of advancements were made with the technology during its time in Roche's hands, but little was made public.

“DPCs haven’t been standing still,” he said. “The technology has been growing.”

Part of that growth includes the discovery that the DPC and the siRNA payload, which is cholesterol conjugated, do not need to be linked so long as they are both decorated with targeting ligands to the same cell type.

“We found that we could actually target the delivery polymer separately from the siRNA and still get very efficient delivery,” Lewis told Gene Silencing News, noting that a paper better describing this process in currently in press.

“This was a key finding because it made manufacturing a little more straightforward,” eliminating the step of linking the siRNA and the polymer, he noted. “More importantly, it allowed us to explore different types of polymers that weren’t amenable to siRNA attachment.”

Among the polymers considered were peptides synthesized to have the same endosomolytic properties as the polymers in the first-generation DPCs, Lewis said.

Not only could these peptides be cost-effectively scaled up, but they are highly biodegradable. “That really allows you to think about multi-dosing … without accumulation of your delivery vehicle and possibly cumulative toxicity,” he said.

To test this version of the DPC technology, which is being used in ARC-520, Arrowhead administered the drug to two different mouse models of HBV. In the first, an infection is artificially established via hydrodynamic tail vein injection of the virus, which is then expressed in about 5 percent to 20 percent of hepatocytes. The second model is a transgenic mouse that expresses the virus in 100 percent of its liver cells.

In the first animal model, treatment with a single dose of ARC-520 resulted in multi-log reductions in circulating viral antigens and HBV DNA lasting out to one month. In the transgenic mouse, ARC-520 significantly reduced viral mRNA, as well as RNA and DNA replicative intermediates in the liver.

On these and other data, Arrowhead remains on track to begin phase I testing of single, escalating doses of ARC-520 in chronically infected HBV patients around the third quarter of next year.

Changes to DPCs' endosomolytic polymer core were not the only advances made with the technology, Lewis noted. Arrowhead researchers have also developed a novel masking chemistry that is activated by proteases in the endosomes, rather than acidification, which boosts the DPCs' stability and has enabled subcutaneous delivery.

In non-human primate experiments, Arrowhead found that these DPCs against coagulation factor 7 had similar efficacy when administered subcutaneously as when delivered intravenously at the same dose levels. At one mg/kg, both led to a greater than 99 percent knockdown of their target, with the subcutaneous version's effect extending out more than seven weeks with no signs of toxicity. At 0.5 mg/kg, treatment led to greater than 90 percent targeting inhibition.

Arrowhead said that it is developing this subcutaneous formulation for oncology applications, but Lewis declined to comment on which specific indications might be under consideration. He did, however, highlight the advantages of such a route of administration including patient self-administration and reduction in cost of therapy over intravenous drugs.