Arrowhead Research Corp. reported new top-line data on its lead RNAi therapy ARC-520, demonstrating that it achieved significant hepatitis B virus (HBV) surface antigen reductions during a phase IIa study, particularly in treatment-naïve patients who tested positive for HBV e-antigen (HBeAg-positive), which is associated with chronic HBV infections and is used as a marker of active viral disease.

The new data appeared to put the program on stronger footing after sentiment about its prospects turned frosty last year over concerns that the drug might not perform as well as expected. Arrowhead shares (NASDAQ:ARWR) rose 45 cents, or 6.7 percent, on Thursday closing at $7.19, regaining ground but still valued about 54.2 percent less than a year ago. (See BioWorld Today, Oct. 10, 2014.)

In the new top-line results, HBeAg-positive patients on a background of chronic entecavir receiving a 4-mg/kg single-dose of ARC-520 showed a mean maximal 92 percent (1.2 log) reduction in circulating HBeAg and a best reduction of 98 percent (1.7 log). Similar mean maximal reductions were also demonstrated in HBV core-related antigen (HBcrAg) from both HBeAg-negative and -positive patients, the company said.

In a separate cohort of HBeAg-positive patients not previously treated with nucleotide or nucleoside (NUC) analogues, the best peak HBV s-antigen (HBsAg) reduction was 99 percent (1.9 log) with a mean maximum HBsAg reduction of 1.05 log through day 15 following ARC-520 treatment – substantially higher than results from NUC treatment-experienced cohorts.

During an analyst day event held to review and explain the new data, Arrowhead's president and CEO Chris Anzalone said his team believed it to be the highest knockdown ever reported in a human using RNAi and that he was optimistic the new data would translate into strong clinical outcomes for ARC-520 and follow-on candidates against other indications.

A long-term chimp study run by the Southwest National Primate Research Center and findings from the clinical study, also reported Thursday, suggested that HBV cccDNA decreases during the HBV life cycle, especially with the transition from HBeAg-positive to -negative. HBV DNA integrated into host DNA appears to maintain significant HBsAg production as cccDNA declines, a process that is accelerated with NUC treatment.

Of nine chimps that were first suppressed with NUCs and then treated with six to 11 monthly doses of ARC-520, four HBeAg-positive chimps demonstrated 99 percent (2 log) mean peak reduction in HBsAg, and one of the four experienced signs of immune reactivation during therapy, Arrowhead said. Four HBeAg-negative chimps demonstrated 81 percent (0.7 log) mean peak reduction in HBsAg; and one chimp transitioning from HBeAg-positive to HBeAg-negative demonstrated peak HBsAg reduction of 87 percent (0.9 log).

Robert Lanford, a director at the primate research center, said the results "have revealed some important new insights about HBV biology and have introduced new ideas about effective ways to intervene in the HBV lifecycle."

Of 84 humans that have received ARC-520, no adverse events have been rated as serious or severe, the company said, and no discontinuations had occurred due to adverse events. No adverse safety signals were detected in the chimps, either.

ARC-520 is designed to silence expression of cccDNA. That design and the new clinical data validating the approach bodes well for the candidate, since NUC-naïve HBeAg-positive patients are expected to be richest in cccDNA and an estimated 95 percent of people chronically infected with HBV are currently NUC-naïve. At least half of those patients are also likely to be HBeAg-positive, making them "especially attractive to study and a key focus for multidose studies going forward," the company said.

RBC Capital Markets analyst Michael Yee characterized the new data as "incremental positive findings," noting that investor expectations for the program were "very low given initial data in 2014 and the stock has been off the radar for many investors." Furthermore, he pointed out that the positive data would be good for more than just Arrowhead investors, since the glow of good news could rub off on companies such as Arbutus Biopharma Corp. (formerly Tekmira Pharmaceuticals Corp.), which is carrying ahead the RNAi candidate TKM-HBV in phase I and seven other HBV programs, and Alnylam Pharmaceuticals Inc., which also has an early RNAi-based program in HBV, called ALN-HBV.

Arbutus shares (NASDAQ:ABUS) rose 73 cents, or 11.1 percent to $7.30 on Thursday. Alnylam shares (NASDAQ:ALNY) fell $2.53 to $90.77.