NEW YORK (GenomeWeb) – As it presses ahead with Phase II development of its flagship hepatitis B therapy ARC-520, Arrowhead Research is banking on the drug's ability to cut levels of the virus's surface antigen (s-antigen), a key indicator of active infection, the company's top executive said this week.
According to Arrowhead President and CEO Chris Anzalone, treating HBV has proven especially challenging because blocking viral replication alone is not enough to clear the virus, unlike with hepatitis C.
"High levels of … s-antigen can immunosuppress a patient with chronic HBV even when viral replication is blocked to undetectable levels," he said, speaking during a conference call held to discuss Arrowhead's fiscal second quarter financial results.
As such, in the Phase II portion of ARC-520's development, Arrowhead is hoping its drug can trigger at least one log of s-antigen knockdown — the minimum level of reduction believed to be needed to result in a functional cure, he said.
Should that level of s-antigen suppression not be achieved at an ARC-520 dose level of 2 mg/kg — the highest tested in ongoing Phase II trials — Anzalone said that the company intends to start evaluating doses of 3 mg/kg.
Doing so, however, is not expected to affect the timing of ARC-520's development, he noted.
Meanwhile, Arrowhead has recently selected its next pipeline candidate, although specific details about the new program won't be made public until an analyst event scheduled for June 19.
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.
After its former lead RNAi candidate, the cancer drug CALAA-01, was dropped amid poor performance in the clinic, Arrowhead has made ARC-520 the centerpiece of its research and development efforts.
Thus far, the agent has proven promising. In late 2013, Arrowhead reported preliminary Phase I data that showed ARC-520 to be safe at doses up to 2 mg/kg. Last year the company also released data showing that the drug could induce a greater than 90 percent reduction in circulating HBV DNA while cutting s-antigen levels in a chimpanzee that was chronically infected with HBV.
Notably, the non-human primate experiments also indicated that treatment triggered an immunological flare associated with derepression of the adaptive immune response — a possible indication that the animal's immune system was being restored.
On the non-human primate and Phase I data, earlier this year Arrowhead kicked off a Phase IIa single-dose study of ARC-520. The trial is set to enroll 16 e-antigen-negative chronic HBV patients, who will receive either a 1 mg/kg or 2 mg/kg dose of ARC-520, or placebo, along with the oral antiviral agent entecavir.
"Because of the reliability of RNAi as a mechanism and the highly predictive nature of non-human primate data for human knockdown, we expect to see deep and durable s-antigen knockdown in the Phase IIa," Anzalone said this week. "Should we see that … it would appear we have a safe and effective drug candidate, and the final hurdle would be to demonstrate that reducing s-antigen levels leads to functional cure of HBV."
If the 2 mg/kg dose isn't sufficient to achieve the one log of s-antigen knockdown Arrowhead is shooting for, he said that the company is prepared to amend the trial's protocol to begin testing a 3 mg/kg dose.
Anzalone said that Arrowhead believes that it can achieve its s-antigen knockdown goal through multiple doses of ARC-520, but would prefer to be able to hit this target with a single dose in order to have flexibility in later clinical trials.
"The more knockdown that we can demonstrate with a single dose, the greater flexibility we've got," he said.
Anzalone also stressed that going to a 3 mg/kg dose in Phase IIa will not change Arrowhead's ability to release top-line data from the study in the third quarter of this year as planned, nor will it change the timing of additional clinical trials, including a multi-dose Phase IIb study initiated in April.
Arrowhead is also planning on launching additional multi-dose Phase IIb studies beginning this summer, which will answer "key questions about the response of different patient populations to ARC-520."
Although details about these upcoming trials won't be released until later this year, Arrowhead COO Bruce Given said during the conference call that they will likely include a multi-arm study comparing patients treated with a nucleoside analog (NUC) such as entecavir alone to those receiving the NUC treatment in addition to one of two dose levels of ARC-520.
As it continues work on ARC-520, Arrowhead is also getting ready to take the wraps off of its next drug candidate, which Anzalone said would be for a rare liver indication. The company plans to disclose the program at the upcoming analyst meeting and file an investigational new drug application to begin testing it in humans around the end of the year.
For the three-month period ended March 31, 2014, Arrowhead posted a net loss of $13.9 million, or $0.31 a share, compared with a year-ago net loss of $6.8 million, or $0.41 a share.
Operating expenses in the quarter jumped to $11.3 million from $5.4 million, with research and development spending surging to $5.2 million from $2.1 million as Arrowhead ramped up ARC-520's development.
At the end of the quarter, Arrowhead had $194.7 million in cash and investments, which Anzalone said is sufficient to fund ARC-520's development into Phase III testing and move its next clinical candidate through clinical proof of concept.