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

We reasoned that as long as s-antigen levels had not returned to baseline, by the time of the next dose, we might achieve an additive dynamic overtime – that overtime would give us a sustained reduction profile.

What we have seen however is a more drawn-out L-shaped knockdown curve or reduction in s-antigen is sustained over relatively long period of time. In fact, main peak knockdown at 2 mg/kg did not even occur until after 30-days post dosing. Therefore, we expect monthly dosing to produce a step-down or additive effect because subsequent dosing will be acting on top of sustained activity from prior doses.

We have seen this additive dynamic in animal models and expect to see it with repeat dosing in humans. In fact, other RNAi companies have used daily so-called loading doses in humans to create an additive step down effect on gene knockdown. Our monthly dosing could give us a similar effect but with far or less frequent dosing given our long duration of action. This provides us with the potential ability to achieve exactly what our experts believe is important, that is sustained in deep reduction of s-antigen over time.

In addition, remember that 1 and 2 mg/kg are just a first two doses of an ongoing dose escalation study. We’ve already completed dosing the 3 mg/kg cohorts and are screening for the 4 mg/kg cohort. Therefore, we have two powerful tools to achieve sustained and deep knockdown. The additive effect we expect to see upon multi dosing and deeper knockdown we expect to see as we increase dose. This may be viewed in the context of a favorable safety profile that has not produced dose limiting toxicities in any dose study. We believe this is a good position to be in.

We plan to complete the Phase 2a which we now expect to include 3 and 4 mg/kg cohorts and present a full picture of the study results when they are available. Depending upon the pace of enrollment, this may be available around the time of EASL conference in April of 2015. But that will depend on enrollments speed which we do not control.

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There is much we do not know about ARC-520 and how to optimize its effectiveness as a therapy. We are just now starting to scratch the surface. The best way to begin shipping away and how to address chronic HBV is to move into multi dose studies as soon as we can. We plan to begin regulatory submissions before the end of this year in support of these studies.

We will have clinical sites in the U.S., Western Europe and Asia in order to gain access to a large number of patients and variety of HBV genotypes. Multiple parallel studies are currently contemplated including ARC-520 in combination with entecavir or tenofovir, as well as combination studies with different immunostimulatory agents and various dose regimens.

We are pioneers in this field, so I expect that each study will open new questions and present new possible strategies to attach the virus. As such, the multiple Phase 2b studies will be necessarily iterative. Consider our addition of new studies that today we may not even imagine as indicative of strength not a weakness. We are looking for functional cures during the Phase 2b studies in a way to unlock as much value as possible from ARC-520 is to follow the data and build as large and diverse a data set as possible.

Let’s now move to ARC-5 to ARC-AAT.

During the year we expanded our pipeline and nominated ARC-AAT as our next clinical candidate for the treatment for liver disease associated with the genetic mutations which causes Alpha-1 Antitrypsin deficiency.

According to the patient efficacy group the Alpha-1 foundation, there may be as many as 100,000 potential patients in the U.S. So this could represent a relatively large orphan drug population.

Further, there is no current treatment for liver disease associated with Alpha-1 Antitrypsin deficiency. At AASLD, we presented pre-clinical data showing that ARC-AAT can induce deep levels of target knockdown in established animal models. The interest in this approach was such that we were assigned a plenary session spot and highlighted as one of only 11 most important abstracts at the meeting by the association president.

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We also demonstrated ARC-AAT could maintain 80% to 90% knockdown in non-human primates when dosed every six weeks. We recently filed in Australia for approval to begin a Phase 1 study of ARC-AAT.

Moving from our pipeline progress to corporate progress. During fiscal 2014 we strengthened our balance sheet with equity financings totaling approximately $172.6 million in net proceeds. This allows us to expand the scope of ARC-520 Phase 2b and conduct several studies in parallel that answer key questions about the drug.

More broadly, strong balance sheet allows us to move our candidates forward independently and attain more of the economics for our shareholders than if we are forced to seek a partner at an early stage.

We also hired additional staff in key areas including manufacturing, toxicology, chemistry, biology, quality assurance, regulatory and clinical operations to support rapid development of ARC-520, ARC-AAT and additional clinical candidates.

We took steps to improve our exposure to institutions by upgrading our NASDAQ listings, the NASDAQ global select market. And during the year we also added to the broad-market Russell 3000 Index and the small-cap Russell 2000 Index.

We are very pleased with the progress and results from the ARC-520 clinical studies and the ARC-AAT preclinical studies. As a product and a platform company, lessons learned from one drug candidate helped to inform development and derisk additional candidates. We believe we are moving past some of the key early risks of drug development which goes well for us and for our shareholders, as we enter mid stage studies of ARC-520 and as we embark on a period of pipeline expansion, that starts with ARC-AAT.

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