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Arrowhead Offers Timeline for HBV Candidate, Plans Two Phase I Trials

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Arrowhead Research's top executive this week broke out details on the company's efforts to move its RNAi-based hepatitis B virus treatment ARC-520 into the clinic, stating that the firm will run two phase I trials in order to speed up the generation of key human data.

Arrowhead expects that both studies will begin this year, in line with previous estimates, President and CEO Chris Anzalone added, speaking during a conference call held to discuss the company's fiscal first quarter financial results.

Notably, Anzalone made no mention of CALAA-01, the phase I RNAi cancer drug first developed by Arrowhead subsidiary Calando Pharmaceuticals. Last summer, he said that a phase I trial of the agent was nearing completion, but that no decision was made on making the data public.

ARC-520 comprises cholesterol-conjugated siRNAs against HBV and a proprietary delivery technology called dynamic polyconjugates, or DPCs, which were invented by researchers at Mirus Bio. Mirus was later acquired by Roche, then sold to Arrowhead in 2011 (GSN 10/27/2011).

According to Anzalone, investigational new drug application-enabling toxicology studies of ARC-520 are on track to be completed next week, and “thus far, the results have been positive and as expected.”

Meantime, manufacture of a clinical supply of ARC-520 is ongoing and expected to wrap up in the next few months, putting Arrowhead “on schedule to file with regulatory authorities in the second calendar quarter of this year,” he said.

He said that Arrowhead is now planning on conducting two phase I studies, the first being a trial in healthy volunteers in a Western country, most likely Australia, slated to begin in the third quarter of the year.

“This study will establish a safety profile relatively rapidly and may enable us to begin the study in patients at a higher dose, thereby accelerating the path to meaningful results,” Anzalone said.

A second trial in chronic HBV-infected patients will begin before year-end in Hong Kong, where HBV is prevalent and patient recruitment expected to be rapid.

“Conducting a phase I in HBV patients achieves several goals in a short amount of time,” he said. “Most critically, it allows us to get an early efficacy readout in patients with chronic disease.

“We hope to be able to measure the drug's ability to knock down production of new virions, as well as viral proteins is including S antigen, E antigen, and the core protein that forms the capsid,” he added. “The knock down of viral proteins is what many in the field believe will revive the host immune response and potentially provide a functional cure. It is also something that no current therapy can reliably do, creating an attractive opportunity for us.”

Anzalone also said that Arrowhead is continuing to work on new RNAi compounds that will take advantage of the DPC platform, and that a new clinical candidate is expected to be unveiled later in 2013.

He did not discuss CALAA-01, which uses a cyclodextrin-based polymer delivery vehicle and which has traveled a rocky road during its development. Despite phase I data in 2010 showing the drug could knock down its intended target mRNA and protein inside a tumor through an RNA interference mechanism, Arrowhead later decided to run a phase Ib study to further examine adverse effects linked to the siRNA payload.

A company spokesperson told Gene Silencing News that Arrowhead is still "looking for a path forward" for CALAA-01.

The drug's unmodified siRNA payload, he wrote in an email, was believed to be "adequate" when combined with the polymer delivery technology, but "the industry has progressed a lot" since it was originally developed. "Various chemical modification patterns are now known to be superior even in nanoparticles."

The spokesperson said that tests are underway to determine whether the drug will be effective in its current format or whether it can be improved with chemical modifications or changes to the delivery system. Additionally, Arrowhead is testing CALAA-01 head-to-head with tumor-targeted DPC formulations of the drug.

Additional details will be made public in the coming months, he added.

Fiscal First Quarter

For the three-month period ended Dec. 31, 2012, Arrowhead reported a net loss of $4.6 million, or $0.33 a share, versus a year-ago loss of $2.5 million, or $0.25 share.

Total operating expenses in the quarter were $5 million, up from $4.1 million the year before, while net cash used in operations climbed to $3.8 million from $2.7 million.

At the end of 2012, Arrowhead had cash totaling $2.9 million, compared with $3.4 million at the end of 2011.

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