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Arrowhead Submits Amended Protocol for HBV Trial; Prepares Next Rx Candidate

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NEW YORK (GenomeWeb) – Officials from Arrowhead Research disclosed this week that it has submitted to the US Food and Drug Administration an amended protocol for a planned Phase IIb trial of its siRNA-based hepatitis B therapy ARC-520, which the agency had put on partial hold amid concerns about the size of doses being tested.

According to COO Bruce Given, the company does not expect the changes to impact the overall timing of the company's ARC-520 development strategy, which includes planned clinical trials in Europe and Asia. However, speaking during a conference call held to discuss Arrowhead's fiscal first quarter financial results, he stressed that the firm will not go forward with its US trial "until the FDA has blessed the new design."

Also during the call, Arrowhead President and CEO Christopher Anzalone highlighted the company's efforts to refine its core siRNA-delivery technology, noting that it intends to unveil a new clinical candidate by year-end. He also announced that Arrowhead has recently taken an option to buy undisclosed technologies related to a new form of RNAi molecules.

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 (DPCs). Arrowhead acquired the compound and delivery technology when it bought Roche's RNAi assets in late 2011.

Despite its promise, ARC-520 has traveled a bumpy road thus far. Arrowhead has long maintained that the drug's ability to cut levels of HBV surface antigen (s-antigen), which suppresses host immune responses and is an indicator of active infection, will be key to its success.

The company is in the process of completing a Phase IIa trial examining single doses of ARC-520 at 1 mg/kg, 2 mg/kg, 3 mg/kg, and 4 mg/kg in chronically infected HBV patients. In October the company released preliminary Phase II data that showed a less-than-expected reduction in s-antigen at the 1- and 2-mg/kg dose levels.

On the news, shares of Arrowhead plummeted, and since then the company has been named in a series of lawsuits for allegedly misleading investors about those data. Patients in the other dose cohorts have been treated, but the data remain blinded.

Despite the setback, Arrowhead pushed forward with its plan to test multiple doses of ARC-520 at 2 mg/kg and 4 mg/kg in parallel a Phase IIb trial, but early this year it announced that the FDA ordered that the company start at 1 mg/kg doses before moving into higher doses. Regulators also asked for a final study report from the Phase IIa trial.

During this week's conference call, Anzalone said that Arrowhead has submitted an amended protocol for the Phase IIb study to accommodate the FDA's requests, and suggested that there is still value in testing lower doses of ARC-520 than originally planned as 1 mg/kg appears to be an "active dose."

He added that starting at 1 mg/kg could also add to the safety data around ARC-520, while also further de-risking the delivery technology underlying the compound.

Given noted during the call that in tweaking its Phase IIb trial protocol, Arrowhead has been able to incorporate certain aspects of European and Asian clinical studies it was planning for ARC-520, allowing the company to "reduce the planned size of the core international trials and … simplify them in some ways that we expect should make them easier and faster to enroll."

As a result, Arrowhead is slightly behind schedule in submitting protocols for those trials to overseas regulators. "The protocol and accompanying documents should be finished this week or next and then will be provided to our [contract research organization] for final translation and submission," Given said.

Nonetheless, "we do not expect completion of the core global trials to be delayed relative to our original planning, as long as they meet with regulatory approval in those jurisdictions with normal review times," he added.

As work on ARC-520 proceeds, Arrowhead remains on schedule with its second clinical candidate, a treatment for alpha-1 antitrypsin deficiency called ARC-AAT, and expects to begin enrolling patients in a Phase I trial in Australia this month, with data available by the end of the year.

Meanwhile, Arrowhead has been optimizing the DPC technology for subcutaneous administration against targets in the liver, as well as for intravenous administration against targets outside the liver, Anzalone said.

Based on the progress of these efforts, he said that Arrowhead is aiming to nominate either its first subcutaneous candidate or its first extra-hepatitic candidate by the end of 2015.

At the same time, he said that Arrowhead has been evaluating different RNAi trigger technologies, specifically ones with novel structures and modifications that enable more robust gene silencing or provide additional freedom to operate.

As such, he said that Arrowhead acquired an exclusive option last quarter to purchase a suite of RNAi technologies and intellectual property for $7 million, but did not provide additional information about the nature of the option.

"We continue to assess the potential value of these platforms and IP for Arrowhead," he said.

Fiscal first quarter

For the three-month period ended Dec. 31, 2014, Arrowhead reported a surge in its net loss to $22.6 million, or $.41 a share, compared with $10.7 million, or $.28 a share, the year before.

Driving the loss increase was a rise in R&D spending to $17.7 million from $3.1 million, as well as jump in general and administrative costs to $2.1 million from $913,784. Total operating expenses climbed to $25.1 million from $7 million.

Revenues in the quarter were $170,750, up from $43,750, and were derived primarily from licenses to its technology.

At the end of 2014, Arrowhead had cash and cash equivalents totaling $104 million.

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