Eteplirsen: Surrogate Endpoint and Likely to Predict Clinical Benefit:
1Q cc: Excellent change from emphasis on statistically significance of 6MWT to long term stablization of 6MWT in 9-12 yrs old relative to natural disease history.
William Tanner - Lazard Capital Markets Thanks for taking the question. I have a few. Chris, just as it relates to the information that the company did provide to the FDA, can you give us a sense or the scope of what was provided, as compared with that submitted initially, and I guess, wondering the extent to which the topics were winnowed down to maybe a more smaller, more manageable number of them, and just trying to determine, is it possible that there will be another iteration, or do you think that you will actually get the decision after the FDA reviews these data?
Chris Garabedian - President and CEO Yeah Bill, so let me clarify. So we have not submitted those two documents, as we sit here today. But I can provide some color on what we provided previously, and what we are providing coming up. We are in the stages of finalizing those documents, and we decided that the importance of these documents was more important than getting it in a week or two earlier, and so we have really gone even deeper than we had previously of combing through the literature, talking to other experts on their thoughts and advice of making the most compelling arguments for dystrophin as a surrogate and how our clinical data would support that. You see some of the evidenced in the communication around the natural history studies, and what we would expect from this age cohort, and the six minute walks that we started out, prior to dystrophin production.
So we believe the two issues have been sufficiently narrowed. In that I describe it as two sides of a coin. One is to show that the dystrophin that we are producing is functional and is of a quantity and quality that is meaningful, based on the Becker patient, and studies that have been done with the natural phenotype of Becker of which the dystrophin we are producing, the truncated dystrophin is akin to the Becker dystrophin that exists in those patients, as well as the preclinical studies, those that have been done in animal models of DMD, there is dystrophic mice, dystrophic dogs, both of which have used eteplirsen or other treatment modalities to show that dystrophin that's produced, of this kind, produces functional benefit in the animal. Then of course, our own clinical data, that suggests the clinical benefit that is produced from the dystrophin we are creating.
And then the other side of the coin is to make a stronger argument on our clinical outcomes, and six minute walk and other measures where we see a stability, then we would not expect to see from the natural course of this disease. So, when you even look at things like pulmonary function or cardiac function or muscle strength, if you just look, that all of these patients now are approaching 11 years of age on average, and they are doing pretty well or better than we would expect them to do, based on natural history. So we need to make that argument as compellingly, as we make the dystrophin argument, and we think each argument bolsters the other. So if we make a stronger case on the dystrophin, then you can look at the clinical outcomes through a lens that would be more supportive.
Likewise, if we strengthen our clinical outcomes argument, then you start to look at the dystrophin data through a lens that says, these are probably linked and would reasonably predict this clinical outcome.
So that is what we have narrowed our focus on, and -- or are concentrated on, and we think these two reviews are coming together very nicely, and we think this will provide the agency, with the sufficient information they need to make a decision. Obviously, there is no guarantee, if the FDA's prerogative to always request more information or delay a decision etcetera, but we don't believe that would be the case, because the FDA has been very responsive, we think they understand the urgency of this program, of making sure that they are clear, so we can be clear, when we are communicating to the DMD community of our intention, to try to get this drug to the market as soon as we can, and that's all I can provide at this point.
Potential design and dose of ph3 confirmatory trial:
Ritu Baral - Canaccord Genuity Thanks for taking the question guys. Mine is on the Phase III/IV confirmatory study. Just given the recent conferences, where you have had a lot of access to the KOLs and the patient community, could you bracket for us, the low end or the high end of potential size and duration of this trial, if you could just give us an idea what the range might be, and also, Ed, specifically, you and I have talked about all the different potentials for the comparator arm or comparator dataset of the trial, if you could give us your current thoughts. And the third part of that question is -- and this is for Sandy, potentially, what do you think the biggest levers are in that trial design for cost and duration of the trial, duration to data?
Chris Garabedian - President and CEO Yeah so Ritu, let me try to address on most of those questions and Ed is not on the call today. But basically, on the size, we've said repeatedly that we think a 60 to 80 patient treated study is sufficient. If you look at, let's say the PTC study that was 180 patients, they had two dose arms, so they had 60 patients treated versus a placebo 60-patient arm, with two dose cohorts. All right.
Now, Prosensa has done a two to one randomization, so 120 to 60 patients. So we think with the data we have to-date, to guide are powering on both dystrophin and six minute walk results, and the consistency that we are seeing and the lack of variability. That is the sufficient treated population. Now the question you raise is, the control arm is the question that we want to resolve, with our discussion with the FDA. Obviously, it can range from a placebo arm to a non-exon-51 amenable population that would have the same inclusion criteria, but would avoid the challenges of and ethical considerations of doing a placebo study, with a kind of a known active agent like eteplirsen; then there is always the natural history comparison, because we have an emerging dataset on the natural history of this, which is getting easier to compare, as I just did in the call today on greater than seven years of age, and start cutting these date more specifically, to compare it to a treated cohort.
The size of the overall study, if we had a control arm, then that depending on, if it's a one to one, right, that would be a 60 plus 60 or 80 plus 80. If its two to one, it would be a 60 plus 30 or 80 plus 40 population.
Heather Behanna - JMP Securities Hey guys, thanks for taking the question. Just a follow-up slightly on the manufacturing vein. Can you give us any color on discussions you've had with FDA or internal agencies on which dose you will use moving forward?
Chris Garabedian - President and CEO Yeah, we have made our case for 30 mgs per kg based on the fact that the biochemical data supports that 30 mgs per kg is producing as much, and actually numerically more 48 weeks than the 50 milligram per kilogram dose. Again, the stability we see, even in the 30 mg patients now is very good and sufficient, and so again, that is our stance. Again, the confirmatory study design has not been finalized at this time, and so we expect further discussions with the FDA. But as I stated earlier, Heather, I mean, you can only accomplish so much in these FDA meetings. We have a very ambitious set of questions and topics that we'd like to cover. The FDA knows this, they are encouraging that there will be opportunities to discuss all of these issues, over the coming months and quarters, and so we expect to do that.
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