Several important findings are emerging. First, the safety profile of ARC-520 appears to be similar in patients as in healthy volunteers. Second, ARC-520 is clearly active and decrease in production of s-antigen. And third, the duration effect is longer than we expected, which has very positive implications for upcoming multi dose Phase 2b studies. These are good data. As far as we know, this is the first reliable report demonstrating clear reduction of s-antigen in humans after its single dose.
As such and because many believe that decrease in s-antigen could lead to a functional cure of chronic HBV, physicians and HBV experts we spoke with at the recent AASLD liver meetings shared our excitement. We reported mean peak knockdown for 39% with 1 mg/kg of ARC-520 and 51% with 2 mg/kg.
Simply put, this has been a lofty and unmet goal in the HBV field for years, and we just accomplished it. With these preliminary data, let me tell you why we are so confident about the program. Our goal is not to clear s-antigen directly with ARC-520 but rather to decrease it to a level that derepresses immune system such as it may take over and control the virus. If successful, this is potentially allowed to functional cure because no drug has been able to do this consistently to precise level of reduction required to enable this process is unknown.
Before we started the single dose 2a study in patients, our goal was to find a dose in humans that peaks at 90% reduction. This somewhat arbitrary goal was set because we expected a U-shaped knockdown curve characterized by rapid reduction, followed by equally rapid release such that 30-days after dosing s-antigen levels would be approaching baseline.
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.
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.