Arrowhead Research Corporation (ARWR) Q4 2014 Results Earnings Call Transcript

With that overview, I would now like to turn the call over to our COO and Head of Development, Dr. Bruce Given. Bruce?

Bruce Given – COO and Head, R&D

Thanks, Chris, and good afternoon, everyone. We made a lot of progress in 2014 in our lead candidate ARC-520 in addition to expanding our pipeline to include ARC-AAT. It’s a testament to the potential of both product candidates that we were selected to present data on ARC-520 in a late breaker poster session and on ARC-AAT in the plenary session at AASLD earlier this month.

The following has reviewed these data. We completed nine dose cohorts in our Phase 1 trial of ARC-520. The study was designed to characterize the safety profile of ARC-520 across the range of doses and to evaluate pharmacokinetics.

It was a randomized double blind placebo controlled single dose escalation first in human study of ARC-520 administered intravenously to help the adult volunteers. All subjects received either placebo or ARC-520 in doses ranging from 0.01 to 4 mg/kg. The study successfully enrolled 54 subjects at a single center with 36 receiving ARC-520 and 18 receiving placebo. There are no reports of serious AEs, no dose-limiting toxicities, no discontinuations due to AEs and a modest overall rate of AEs, without a clear dose related increase in frequency or severity.

There is a modest occurrence rate of non-clinically significant abnormal laboratory test in placebo and ARC-520 treated subjects. There were no reported drug related or clinically significant differences for vital signs or ECGs between subjects received in drug versus placebo.

One occurrence in each of moderate flushing and urticarial rash seen at dose levels of 0.3 mg/kg and 2 mg/kg respectively, led to the subsequent reduction in infusion rate of ARC-520, as well as the introduction of pretreatment with an oral over-the-counter antihistamine.

Since the introduction of these mitigations, no signs of hypersensitivity or infusion reactions have been seen. There are no changes in ALT, AST or CK considered to be clinically significant by the study investigator. So in conclusion, ARC-520 when administered as a single dose up to 4 mg/kg to healthy volunteers, appears to be well tolerated.

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In March 2014, we began our Phase 2a multi center randomized double blind placebo controlled dose escalation study to determine the depth and duration of hepatitis B surface antigen reduction after a single intravenous dose of ARC-520 in combination with entecavir in patients with chronic HBV infection.

We are also assessing safety and tolerability and multiple additional secondary and exploratory end points. At each dose levels that we valuated, a cohort of eight patients are enrolled with six being dosed with ARC-520 and two being dosed with placebo.

Single doses of ARC-520 are being evaluated at, to-date, three ascending doses 1, 2 and 3 mg/kg have been completed and screening for dose escalation of 4 mg/kg is actively underway.

In the first three dose cohorts, 24 patients were successfully dosed, 18 of which received drug and six received placebo and un-blinded data is available for the first two cohorts.

For interim results for 1 and 2 mg/kg and partial still blinded safety results from the 3 mg/kg cohort were reported at the AASLD liver meeting earlier this month. To-date there have been serious AEs, no dose-limiting toxicities, no discontinuation and a modest overall occurrence rate of AEs. All reported AEs were either deemed unrelated to study drug or unlikely related by the principal investigator.

Safety labs continue to lack indication of end-organ toxicity with the lowest occurrence rate of abnormal laboratory testing ARC-520 and placebo treated patients. And no observed relationships to timing overdose.

ARC-520 activity is assessed by measuring percent change of s-antigen from baseline. We believe this is the first time that a reduction in s-antigen mediated through RNA interference, has been reported in chronic HBV patients.

Initial results indicate that a single injection of ARC-520 results in significant reduction in s-antigen for up to 43 days. In cohort 1, the mean nadir of s-antigen was minus 39% for the range of minus 22% to minus 57%.

In cohort 2, the mean nadir of s-antigen was minus 51% with a range of minus 46% to minus 59%. For cohort 2, the percent reduction in s-antigen was statistically significant versus placebo for days 3 through 43 post dose. For cohort 2, the mean day of s-antigen mater was the day 33.

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Turning to ARC-AAT, we also presented data from this product at AASLD this month.

ARC-AAT is our clinical candidate for the treatment of liver disease associated with Alpha-1 Antitrypsin Deficiency. A rare genetic disease that severally damages the liver and lungs of affected individuals. These patients synthesize the mutant form of AAT called Z-AAT. Greater than 90% of which is produced in the liver which is poorly secreted and accumulates in the liver resulting in injury.

The goal of treatment with ARC-AAT is to silence production of Z-AAT production in the liver thereby preventing further accumulation of Z-AAT and potentially reversing pre-existing liver disease and fibrosis.

In preclinical studies with PiZ mice, which are genetically modified to produce the mutant human Z-AAT, ARC-AAT induced a greater than 95% reduction in circulating AAT after a single dose with a long duration of effect.

The 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 and at day 29 post dose, the two time points measured.

Multidose studies in PiZ mice showed that at week 13 of the study after four biweekly doses, the ARC-AAT treated group showed 99% less soluble Z-AAT, which is the monomer form of the protein synthesized by the liver and 79% less insoluble Z-AAT, which is the polymer that forms when the monomers cannot be normally secreted. It is this polymeric form that is contained in the globules. Thus, injection of ARC-AAT in transgenic mice expressing human Z-AAT resulted in prevention of formulation of new globules and then reduction in size and number of preexisting Z-AAT globules and importantly associated liver inflammation.

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