Arrowhead Offers Data on ARC-520, ARC-AAT at AASLD The Liver Meeting

Arrowhead Research Corporation ARWR, a biopharmaceutical company developing targeted RNAi therapeutics, today announced that initial data from the ongoing Phase 2a study of ARC-520, its RNAi therapeutic candidate for the treatment of chronic hepatitis B (HBV) infection, was presented today in the late-breaking poster session at the 2014 American Association for the Study of Liver Diseases (AASLD) Liver Meeting in Boston. Arrowhead also delivered a plenary presentation with new preclinical efficacy data on ARC-AAT, its RNAi therapeutic candidate for the treatment of liver disease associated with Alpha-1 antitrypsin deficiency. The Company will host an investor event and presentation to discuss these results that will be webcast tonight at 8:00 p.m. EST. Investors may access the webcast and presentation slides on the Events page of the Company's website at http://ir.arrowheadresearch.com/events.cfm. An audio only version of the live webcast may also be accessed by calling 844-825-4406 toll-free from the U.S., or 315-625-3230 for international callers, using conference ID 31449966. An archive of the call will be available for seven days and may be accessed by calling 855-859-2056 or 404-537-3406. Copies of the AASLD poster and plenary presentation will also be available to view on the Events page of the Company's website. “We presented some important advancements today for both ARC-520 and ARC-AAT,” said Christopher Anzalone, Ph.D., Arrowhead's President and Chief Executive Officer. “These programs and our expanding pipeline of RNAi therapeutics continue to generate exciting data that further validate the utility of the DPC delivery system. We have seen clear activity across multiple preclinical models and are now seeing activity in humans. We are still dose escalating in the ARC-520 Phase 2a, where dosing is complete in the 3 mg/kg cohort and screening has begun for 4 mg/kg. We believe that the initial data from the first two dose cohorts as well as safety data from the Phase 1 volunteer study are encouraging and support advancement of the program into multi-dose Phase 2b studies. We are currently preparing regulatory filings for the ARC-520 Phase 2b and the ARC-AAT Phase 1, both of which we expect to be filed this quarter. We intend to initiate those studies soon after receiving regulatory permission to begin.” ARC-520 Data In a Late-Breaking Poster titled, “Phase II, dose ranging study of ARC-520, a siRNA-based therapeutic, in patients with chronic hepatitis B virus infection,” interim data on ARC-520 was presented by Man-Fung Yuen, M.D., Ph.D., Chair of Gastroenterology and Hepatology, and Li Shu Fan Medical Foundation Professor in Medicine, The University of Hong Kong, and a principal investigator for the study. The poster included up-to-date safety data on ARC-520 from this study, an ongoing Phase 2a multicenter, randomized, double-blind, placebo-controlled, dose-escalation study, as well as a recently completed Phase 1 normal volunteer study. The nine dose group, Phase 1, normal volunteer trial was designed to characterize the safety profile of ARC-520 across a range of doses and evaluate pharmacokinetics. It was a single-center, randomized, double-blind, placebo-controlled, single dose-escalation, first-in-human study of ARC-520 administered intravenously to healthy adult volunteers for which partial data has been previously reported. All subjects received either placebo or ARC-520 in doses ranging from 0.01 mg/kg to 4.0 mg/kg. The study successfully enrolled all 54 subjects (36 received ARC-520, 18 placebo). The Phase 2a study has enrolled three dose cohorts including 24 patients, 18 receiving drug and 6 receiving placebo. Unblinded data is available for the first two cohorts. Cohort 3 data collection is ongoing and this cohort remains blinded. Full results for the first two dose cohorts at 1.0 mg/kg and 2.0 mg/kg and partial (blinded) safety results from the 3.0 mg/kg dose cohort were included in the poster. In both studies, there have been no reports of serious AEs, no dose limiting toxicities, no discontinuations due to AEs, and a modest overall occurrence rate of AEs without a clear dose-related increase in frequency or severity. There has been a modest occurrence rate of non-clinically significant abnormal laboratory tests. There were no reported drug related or clinically significant differences for vital signs or ECGs between subjects receiving drug versus placebo. To date, ARC-520 when administered as a single dose up to 4.0 mg/kg to healthy volunteers and up to 3.0 mg/kg to patients with chronic HBV appears to be well tolerated. Arrowhead also reported initial results for depth and duration of hepatitis B surface antigen (HBsAg) reduction in the Phase 2a study. In cohort 1 (1.0 mg/kg), the mean nadir of HBsAg was -39% (range -22 to -57) with a mean change on day 85 of -31% (range -14 to -39). In cohort 2 (2.0 mg/kg), the mean nadir of HBsAg was -51% (range -46 to -59) with a mean change on day 85 of -22% (range -7 to -40). For cohort 2, the percent reduction in HBsAg was statistically significant versus placebo (p < 0.05) for days 3 through 43 post-dose. For cohort 2, the mean day of HBsAg nadir was day 33 with a range of day 8 to day 57. Arrowhead believes that this is the first time that a reduction in HBsAg mediated through RNA interference has been demonstrated in patients with chronic HBV infection. This study is ongoing with follow up continuing on Cohort 3 (3.0 mg/kg) and recruitment underway for a fourth cohort of patients at 4.0 mg/kg. Preparations are underway to initiate a series of multi-dose Phase 2b studies of ARC-520, for which the Company plans to file with regulatory authorities in the fourth quarter of 2014. These studies are planned to have clinical sites in the US, Western Europe, Asia, and potentially other countries and/or regions. Several studies are currently contemplated, including ARC-520 in combination with entecavir or tenofovir as well as combination studies that add an immunostimulatory agent. ARC-AAT Data Arrowhead also presented data on ARC-AAT, its clinical candidate for the treatment of liver disease associated with Alpha-1 Antitrypsin Deficiency (AATD), a rare genetic disease that severely damages the liver and lungs of affected individuals. These patients synthesize a mutant form of AAT (Z-AAT) in the liver which is poorly secreted and accumulates, resulting in liver injury. The goal of treatment with ARC-AAT is to silence production of Z-AAT thereby preventing further accumulation of Z-AAT in the liver and potentially reversing pre-existing liver injury and fibrosis. The presentation in the prestigious Plenary Session titled, “A hepatocyte-targeted RNAi-based treatment for liver disease associated with alpha-1 antitrypsin deficiency,” was presented by Christine Wooddell, Ph.D., Group Leader, Arrowhead Research. AASLD President Dr. Adrian Di Bisceglie, MD, FACP also highlighted the presentation, along with just ten others, in the President's Press Conference as a program that holds great promise for patients. In preclinical studies with PiZ mice, which are genetically modified to produce the mutant human AAT (Z-AAT), ARC-AAT induced a greater than 95 percent reduction in circulating AAT after a single dose with a long duration of effect. Area covered by Z-AAT globules and globule size within the liver were significantly reduced after a single dose of ARC-AAT at day 15 post-dose (p < 0.005) and day 29 post-dose (p < 0.01). Multi-dose studies in PiZ mice showed that ARC-AAT was effective at reducing and preventing Z-AAT aggregates in the liver. At week 13 of the study, after 4 biweekly doses, the ARC-AAT treated group show 99% less soluble (monomer) Z-AAT and 79% less insoluble (polymer) Z-AAT, normalized to a saline control group. Thus, injection of ARC-AAT in transgenic mice expressing human Z-AAT resulted in prevention and reduction of Z-AAT globules and, importantly, liver inflammation. In primate studies, a 90% reduction of AAT in serum was observed after a single injection, which persisted for over ten weeks with greater than 80 percent knockdown observed at the six-week time point. Multi-dose studies in primates showed a sustained reduction of AAT with once every six weeks dosing, suggesting that once monthly or less frequent dosing may be sufficient to maintain approximately 80-90% knockdown in humans. The treated animals showed no changes in clinical chemistry (ALT, AST, BUN, Creatinine), indicating that ARC-AAT appeared to be well tolerated at these optimal therapeutic dose levels.