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.
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.
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.
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.