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Arrowhead Ups Dose of HBV Drug in Phase IIb as It Pursues a Functional Cure

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NEW YORK (GenomeWeb) – As it continues to aim high with its investigational hepatitis B virus therapy ARC-520, Arrowhead Research this week announced that it has begun testing an even higher dose of the drug in patients in a single-dose Phase IIa trial.

According to company officials, the increase is part of a bid to ensure that the company can reach its goal of a one-log reduction in HBV surface antigen (s-antigen) — a key indicator of active infection — with ARC-520 treatment. Data from the trial are expected to be presented in November at the American Association for the Study of Liver Diseases annual meeting.

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.

In Phase I testing, the drug was found to be safe at doses up to two mg/kg in normal individuals, and the company set its sights on hitting the one-log s-antigen reduction mark at that dose level — while also evaluating one mg/kg doses — in a single-dose Phase IIa study initiated earlier this year in chronic HBV patients.

Dosing in both cohorts in this trial has now been completed, and interim blinded data show "clear activity at a modest level" for those in the lowest dose cohort, Arrowhead COO Bruce Given said during a conference call held to discuss Arrowhead's fiscal third-quarter financial results.

Meanwhile, the company has also seen the data for patients in the two mg/kg dose group up to six weeks after treatment with ARC-520 or placebo. "With the caveat that the data are still blinded, we believe that knockdown is clearly deeper in this group versus one mg/kg," he said.

Given added that Arrowhead also has data on five patients from this cohort through eight weeks, and that those believed to have received treatment show "surprisingly large reductions in surface antigen."

Arrowhead previously expanded its ongoing Phase I trial to include a three mg/kg dose cohort and, having found no increase in adverse events, recently amended the Phase IIa trial in order to begin dosing patients at this higher dose level.

During the call, Arrowhead President and CEO Christopher Anzalone noted that the company has also begun enrolling healthy volunteers to receive four mg/kg doses of ARC-520 in the Phase I trial in case the company wanted to pursue an even higher dose in patients.

Still, "we feel pretty good" about being able to achieve a one-log knockdown of s-antigen at three mg/kg, he added.

Based on the two mg/kg data, "the depth of knockdown seems to track reasonably well with [that observed in] non-human primate models," Anzalone said. "Of course, the durability of effect [in humans] is substantially longer, so that gives us confidence that three mg/kg will give us good, deep knockdown."

He noted that the one-log s-antigen reduction goal is an aggressive one and is perhaps more than what would be needed to get a functional cure in HBV patients. But in light of how patients respond to the current standard of care, interferon therapy, it is one worth pursuing.

"After a year of interferon, about 10 percent of patients will reach functional cure, and all of those patients that do get to functional cure will see about a half a log reduction in s-antigen and around one log after 24 weeks," Anzalone explained. "It's not clear that we need to reach that full log, but we do know that, under interferon therapy, if a patient does not see that sort of [s-antigen] reduction, there is no chance they will get to a functional cure. That's why that feels like a safe zone for us."

The drops in s-antigen levels observed with ARC-520, he added, are significantly more rapid than those seen in interferon-treated patients who reached a functional cure, and the differences in those kinetics may suggest that a full log reduction isn't necessary. "But … because we can do it safely, we felt most comfortable making that our goal."

With data from the Phase IIa trial expected late in 2014, Arrowhead is now aiming to begin a multi-dose Phase IIb study in the fourth quarter, testing ARC-520 in e-antigen negative and e-antigen positive patients receiving either of the oral antiviral agents entecavir and tenofovir, Given said.

He did not provide specific details about the trial's design, but said that it would include a long-term extension with the primary endpoint of achieving a functional cure as measured by s-antigen clearance with or without seroconversion.

"We also plan to initiate a number of smaller exploratory studies in 2015 including various dosing regimens and studies of ARC-520 in combination with immune stimulatory agents," Given said.

Fiscal Q3

For the three-month period ended June 30, Arrowhead's net loss was $11.6 million, or $.22 per share, versus a year-ago loss of $6.1 million, or $.23 a share.

Total operating expenses in the quarter were $12.7 million, up from $6.4 million a year earlier. Driving the expense increase was a surge in research and development spending to $6.4 million from $1.7 million, as well as a rise in general and administrative spending to $1.6 million from $899,633.

At the end of the quarter, Arrowhead had cash and investments totaling $188.5 million.

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