Replies to post #156831 on Biotech Values

[Double_Bagel]

She had some good points, and some missed points, and some debatable points. I don't have time to write a full article like she did. Here are some points:

We need a "Like" button on IHub, so we can like responses like these :-). Thanks for your detailed analysis.

[dav1234]

excellent analysis

[ghmm]

SRPT:

Nice response jq.

I think they have a chance to convince FDA for accelerated approval filing - I am not a person who are so sure of things of one way or the other like so many others do.

Do you care to quantify the chance?

Do you know offhand if the FDA has guidelines for what are acceptable endpoints in MD?

[biotech jim]

The data on muscle fiber expression of dystrophin is nice, but based on my past (direct experience) and current view of the agency, the 6 MWT will drive approval. Need more patient data and also longer time frame for treatment to determine whether the increased expression translates to function.

I would like to rigorously analyze their cellular expression data, as these types of "quantitative" studies are not always so.

[researcher59]

Jq1234 - re SRPT - great post, thanks for your expert insights into the issue of accelerated FDA approval.

[jq1234]

SRPT Announces FDA Will Consider Accelerated Approval for Eteplirsen After Further Review of Data on Dystrophin and Clinical Outcomes

Eteplirsen Manufacturing and Clinical Activities Continue as Planned

CAMBRIDGE, MA--(Marketwired - Apr 15, 2013) - Sarepta Therapeutics, Inc. (NASDAQ: SRPT) today provided an update on its discussions with the U.S. Food and Drug Administration (FDA) regarding a potential application for accelerated approval of eteplirsen for the treatment of Duchenne muscular dystrophy (DMD). The FDA has requested that Sarepta provide additional information from the existing eteplirsen dataset to inform a decision on the acceptability of this dataset for a New Drug Application (NDA) filing under the Subpart H Accelerated Approval regulatory pathway. This feedback was provided in meeting minutes from Sarepta's End-of-Phase II meeting with the FDA's Division of Neurology Products that occurred last month.

Specifically, Sarepta received feedback on both the acceptability of dystrophin as a surrogate endpoint that would reasonably predict clinical benefit in DMD patients and the acceptability of the eteplirsen safety database for a Subpart H Accelerated Approval filing.

"We are encouraged by our interactions with the FDA and their Division of Neurology Products and we view their request for more data as a reflection of the thorough and comprehensive approach that the Agency takes in evaluating a new surrogate marker," said Chris Garabedian, president and chief executive officer of Sarepta Therapeutics. "We are confident that the method in which we've collected dystrophin, the degree and consistency of the dystrophin levels, and the supporting clinical data will provide the Agency the information it needs to determine if dystrophin is a feasible surrogate marker that is reasonably likely to predict clinical benefit."

At the End-of-Phase II Clinical Meeting in March, there was a productive discussion on the suitability of dystrophin as a surrogate marker, including a presentation by Sarepta detailing the methodologies used to analyze dystrophin in the studies and supportive data suggesting that the dystrophin produced is functional. As follow up to the discussion, and as reflected in the meeting minutes from the Division of Neurology Products, the Agency requested two written summaries: "a coherent and comprehensive summary to support dystrophin as a surrogate" and "a detailed discussion of all clinical outcomes in the eteplirsen study."

Furthermore, the meeting minutes contained the following statement:

"The Agency stated that they had not made a final decision regarding acceptability of the proposed Subpart H (Accelerated Approval) NDA filing, and that the Agency would consider the additional data submitted by the sponsor before making a final decision."

Sarepta also discussed the eteplirsen and phosphorodiamidate morpholino oligomer (PMO) safety database at the End-of-Phase II meeting and asked if the 38 patient eteplirsen safety database was sufficient for a Subpart H Accelerated Approval filing. While Sarepta will continue to collect long-term safety from the ongoing eteplirsen extension study for a potential submission, the meeting minutes stated that: "In the event (the Agency) agrees to file the Subpart H NDA submission, additional safety data to support approval could come from the first few months of the... pivotal confirmatory study." Sarepta still intends to begin dosing patients in a pivotal confirmatory study in the first quarter of 2014.

Sarepta is preparing to submit the dystrophin and clinical outcomes summaries and will be requesting a follow-up meeting with the FDA to discuss these later this quarter. As a result, the End-of-Phase II CMC meeting with the FDA is now expected to occur in the third quarter, however all eteplirsen manufacturing and clinical development activities continue as planned and are not anticipated to delay the potential timeline of an Accelerated Approval NDA submission.

http://finance.yahoo.com/news/sarepta-therapeutics-announces-fda-consider-201020560.html

[jq1234]

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.

http://seekingalpha.com/article/1419841-sarepta-therapeutics-ceo-discusses-q1-2013-results-earnings-call-transcript?part=single

[iwfal]

SRPT -

Quote:
However, when we look at the relationship between percentage of dystrophin-positive fibers and mean change in the six-minute walk test (6MWT), there is no clear correlation between eteplirsen dose, percentage of dystrophin-positive fibers and 6MWT performance.


2) She misses the point here because she is asking one to one correlation between surrogate endpoint and final endpoint. The perfect example of this relationship between surrogate endpoint and final endpoint is ORR vs OS in oncology. Follow her logic, someone with PR definitely needs to show longer OS than someone with SD to make ORR as valid surrogate endpoint for OS. This is further from truth in reality. However unperfect correlationship between ORR and OS, it doesn't prevent FDA from giving accelerated approval by using ORR as surrogate endpoint for unmet medical needs in well defined patient population.

I would suggest her point is, overall, valid because the FDA generally wants proof of correlation. And without virtually 1:1 correlation with this small a set of patients it won't reach the level of 'proof'. (Note that I am not saying that 1:1 correlation is always required for a surrogate, only that the FDA probably wants proof of correlation and that is impossible to do in a trial this small unless the correlation is virtually perfect.)

More specifically:

1) the two 30 patients who could no longer complete the 6mwt appear to have had a very good dystrophin response (they, combined with the 2 continued 30 patients, had 52% increase at 48 weeks).

2) Two patients in the 30 group could no longer complete the 6mwt at 24 weeks, but no one in the placebo group had the same issue.

3) The 30 group had better dystrophin than the 50 group and yet worse 6mwt.

All told it will be interesting to see how the FDA treats this. My further comment - if I were the FDA, presented with partial data and with the company presenting only the good side of the data, I'd certainly want full access to the data before rejecting it. That said, I am not betting on that (or the opposite). Just exploring enough to understand the decision when it is made.

BTW - It will be interesting to see if the above items were just spurious bad luck. But it wouldn't completely surprise me if there were, for instance, an autoimmune issue that causes some patients to be harmed. Immunity issues have a tendency to crop up in odd (non-obvious) ways in replacement therapies (i.e. therapies that insert into the body complex, new-to-the-body, protein products).