Arrowhead Research this week announced that it has begun dosing patients in a phase I study of its siRNA-based hepatitis B treatment ARC-520.
Initiation of the study marks a key milestone for the company as it pursues a return on its 2011 acquisition of Roche’s RNA therapeutics assets, which included ARC-520 and cost Arrowhead nearly 10 percent of its equity.
The HBV drug also represents what some see as Arrowhead’s best chance at a marketable product. The company has another RNAi drug in the clinic — the solid tumor therapy CALAA-01 — but has made little mention of this candidate over the past couple of years after it hit some snags in phase I testing.
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, or DPCs.
Originally developed by Mirus Bio, which was acquired by Roche in 2008, DPCs were initially 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.
However, Roche researchers discovered that DPCs and the siRNAs did not need to be joined together so long as they were both targeted to the same cell type — a discovery that enabled them to be administered separately. They also tested various endosomolytic polymers with the DPC molecules, ultimately selecting a peptide with improved pharmacokinetics.
However, in late 2010 Roche made a highly publicized exit from the RNA therapeutics field as part of a broader restructuring effort. About a year later, it sold all related assets, including its 40-person Madison, Wisc.-based operations that had originally been Mirus, to Arrowhead in exchange for the equity stake and million-dollar late-stage milestones (GSN 11/27/2011).
Arrowhead picked up where Roche left off, and earlier this year published preclinical data showing that this co-injection strategy was safe and effective in knocking down a target gene in non-human primates, and that ARC-520 could silence HBV in rodent for up to one month following a single injection (GSN 2/26/2013).
Buoyed by these and other data, the company has now moved into a phase I trial that will test single, escalating doses of ARC-520. Healthy volunteers are randomized into cohorts of six individuals, and they will receive a single intravenous injection of the drug or placebo.
Arrowhead said that it expects this study, which is being conducted at a single center in Australia, to wrap up before the end of the year. Should the results be positive, the company aims to start a single-dose phase IIa trial of the drug in chronic HBV patients in Hong Kong next year.
A multi-dose phase IIb study is also planned for later in 2014.
A New Start?
In addition to offering Arrowhead a chance to pursue the blockbuster HBV market, ARC-520 gives the firm a shot to prove the potential of a new delivery system following some stumbles with another technology that had once been the heart of its RNAi efforts.
Arrowhead’s work with the gene-silencing technology had previously been primarily conducted within its Calando Pharmaceuticals subsidiary, which was founded to develop a cyclodextrin-based polymer delivery technology called Rondel.
Using that delivery system, Calando developed CALAA-01, which became the first formulated siRNA drug to enter the clinic with a phase I study in 2008. Despite indications that the drug was knocking down its target in tumor cells, it was found to cause certain undisclosed adverse events believed to be related to the siRNA payload.
Rather than move into phase II as planned, in 2011 Arrowhead instead began a phase Ib trial to evaluate a new dosing regimen that includes a pre-treatment stage in hopes of avoiding the adverse reactions (GSN 8/11/2011).
Since then, Arrowhead has said little about CALAA-01 and Rondel, instead focusing its public statements on DPCs and ARC-520.
An Arrowhead spokesperson recently told Gene Silencing News that the company was not disclosing any information on CALAA-01 yet, but that a final report from the phase Ib trial is set to be completed and filed with the US Food and Drug Administration “shortly.”
The spokesperson added that Arrowhead will provide an update on the drug during its next quarterly conference call scheduled for Aug. 5.