Sarepta Therapeutics Inc (SRPT) 2012 Q1 法說會逐字稿

Good day, ladies and gentlemen. Welcome to the first quarter 2012 AVI BioPharma earnings conference call. (Operator Instructions).

Thank you, Sonia. And thank you for joining today's call. Earlier today, we released our financial results for the first quarter of 2012. The press release is available on our website at www.AVIbio.com and our 10Q was filed earlier today. Joining me on the call are Chris Garabedian, our President and Chief Executive Officer and Mike Jacobsen, our Vice President of Finance.

I would like to note that during this call, we'll make a number of statements that are forward-looking, including statements about the development and clinical status of AVI's product candidate and the potential efficacy, clinical results, intellectual property position, revenues, expenses, potential funding from the government and other sources and collaboration and partnering opportunities.

These forward-looking statements involve risks and uncertainties, any of which are beyond AVI's control. Any such risks could materially and adversely affect the business, results of operation and the trading price of AVI's common stock. For a detailed description of risks and uncertainties we face, you're encouraged to review the official Corporate documents filed with the Securities & Exchange Commission. With that, let me turn the call over to Chris Garabedian, AVI's President and Chief Executive Officer. Chris?

Thank you, Erin. Good afternoon, everyone and thank you for joining us. I'm pleased to provide you with an update and overview of our activities and accomplishments since our last call along with our financial performance in the first quarter of 2012. We reached a very important milestone in our DMD program this quarter. We announced on April 2 that our Phase IIB study of eteplirsen in Duchenne muscular dystrophy met its primary end point by demonstrating significant levels of novel dystrophin in treated patients after 24 weeks of eteplirsen, our lead drug candidate for DMD, compared to placebo patients.

This is also an important study for the muscular dystrophy community, in that is the first placebo-controlled study to demonstrate that robust and consistent levels of dystrophin protein, the essential protein that Duchenne muscular dystrophy patients are lacking can be produced with drug therapy. We believe this provides tremendous promise for patients with DMD as we know that the production of dystrophin is critical for healthy muscle function and may be the key component to slow or halt the progression of the disease.

As we announced on our call on April 2, the primary efficacy end point defined in our protocol and our statistical analysis plan was the increase of dystrophin positive fibers as a percentage of normal compared to baseline and then compared to our placebo group. We met our primary end point with a high degree of statistical significance with a P value of 0.002 at our 24-week time point in our 30-milligram per kilogram cohort. We also achieved a higher level of dystrophin production than what we were anticipating, an average of more than 20% dystrophin positive fibers or approximately 23% as a percentage of normal.

A level that the medical literature would suggest should translate to favorable clinical outcomes and less progressive muscle degeneration and disease over time. This is based on animal models of Duchenne, along with the known natural history of Becker's muscular dystrophy, and the levels of dystrophin that are seen in this milder form of muscular dystrophy. Most importantly, we observed consistency across all of the patients in this cohort with a range of 15.9% to 29% of novel dystrophin fibers. To clarify, this is not a relative percentage increase but an increase in the percentage of absolute fibers identified as dystrophin positive or in other words, as a percentage of normal.

In our previous study that only dosed eteplirsen for 12 weeks at lower doses, we only observed two patients out of 19 that showed dystrophin positive fibers of 15% or greater, while all of the patients were over 15% in this 24-week cohort. Our biopsies that were taken after 12 weeks of eteplirsen at the 50 milligram per kilogram level, showed low and variable levels of dystrophin production which was consistent with the majority of patients in our previous studies, underscoring the need to dose beyond 12 weeks to get consistent and meaningful levels of dystrophin in the muscle.

In the four patients on eteplirsen that received biopsies after 24 weeks of treatment, the increases in dystrophin positive fibers seen by immunohistochemistry analysis were further verified by the increased overall dystrophin intensity per fiber calculated in the muscle sample of over 20% intensity per fiber on average. And we had clear production of dystrophin protein overall as shown by Western Blot analysis. Mechanism of action of eteplirsen was also verified by RT-PCR in showing exon skipping on the muscle biopsy samples in this cohort as well.

Importantly, proper molecular function of the newly-created dystrophin was demonstrated in this study and a recent publication which showed that eteplirsen induced dystrophin stimulated the correct localization and function of other components of the sarcoglycan and dystroglycan complexes such as alpha, beta and gamma sarcoglycans, beta sarcoglycan, and N-NOS, neuronal nitric oxide synthase, key components that provide further evidence that the dystrophin we're producing is a functional dystrophin protein.

Another important objective of this study was to evaluate the safety profile of eteplirsen. At doses that are the highest ever evaluated using our morpholino drug chemistry, the safety profile of eteplirsen at 24 weeks continues to show tremendous promise as a potentially safe drug for long-term use. This is an important characteristic of a drug for a disease that might require life-long treatment.

Through 24 weeks of treatment, there were no serious adverse events, no treatment-related adverse events of any kind and no treatment-related changes detected on any safety laboratory parameters including several biomarkers of renal function. The study also collected data on exploratory clinical outcomes over the course of 24 weeks and an analysis was conducted using the six-minute walk test, the standard clinical end point that has been used in other DMD trials and has served as a basis of approval for drugs to treat other neuromuscular conditions.

An exploratory analysis of performance on the six-minute walk test comparing eteplirsen-treated patients versus placebo patients was conducted. However, the analysis was confounded by two patients in the 30-milligram per kilogram cohort that showed rapidly progressive decline immediately after being enrolled in the study. Specifically, these two patients had the lowest baseline scores on the six-minute walk test entering into the study, were both below 250-meters by week four and were the only boys who lost more than 50 meters by week 12. We now know based on our dystrophin data, that this is too early to expect a treatment effect.

For these reasons, we excluded these two patients from our analysis. Of the remaining patients, all of which were relatively stable across both treated and placebo cohorts, the eteplirsen-treated patients demonstrated a benefit of approximately 18 meters over 24 weeks.

Importantly, these six eteplirsen-treated patients had an average decline of only 3.2 meters from baseline or less than 1% of their baseline scores which we view as essentially no progression over this time point. However, the placebo patients had an average baseline decline of 21 meters over this same time frame. While this was an exploratory analysis on a subset of patients and was not a statistically significant difference given the small sample size, it is an encouraging sign of a potential treatment effect as we await results at 48 weeks.

To put this data in the appropriate context, several drugs have been approved on six-minute walk test results that have shown a benefit of 25 to 30 meters over the course of one year to 18 months. If we double this treatment effect that we saw at 24 weeks, we believe we would have a meaningful level of clinical benefit at 48 weeks. We are hopeful that we may see further separation between the six treated patients I've described and the four placebo patients at the 48 week time point.

Even though the placebo patients are now on study drug, we don't expect they will generate meaningful levels of dystrophin until beyond 12 weeks of dosing and possibly up to 24 weeks, while we presume the six treated patients will all have levels above the 15% to 20% range as they enter into the next 24 weeks of the study. This study, which we have named Study 202, which is our extension study to the placebo-controlled study, Study 201, continues to assess the long-term safety and efficacy of open label eteplirsen.

As a reminder, we now have six patients on 30 mg/kg per week and six patients on 50 mg/kg per week. And we will have 4i week safety and efficacy data in eight of these patients and 24 week data in four of the original placebo patients later this year. We also have a third biopsy that will occur at the 48 week time point in the original treated patients and after 24 weeks of treatment in the original placebo patients who crossed over to study drug. These biopsy data will be important to understand the steady state or potential plateau levels of dystrophin.

This dystrophin dataset will answer many questions including how much the dystrophin levels increase in the 30 milligram cohort between 24 and 48 weeks, how much more dystrophin is produced at 50 milligrams per kilogram at 48 weeks compared to 30 milligrams per kilogram. In addition, we will have 24 week dystrophin data at 50 milligrams per kilogram for the first time from two of the original placebo patients and we will also have two additional patients with biopsies after 24 weeks of treatment at the 30 milligram per kilogram dose to compare to the previous cohort where we've showed robust and consistent levels of dystrophin production.

We believe these additional biopsy results along with the additional long-term clinical outcomes and safety will be useful in our discussions with the FDA as we discuss the fastest path toward approval. We will plan to put the results from Study 201 and Study 202 along with our long-term animal tox program results into a briefing document to request an end of Phase II meeting with the FDA in the fourth quarter of this year. The purpose of that meeting with the FDA will be to discuss the design of our pivotal study including gaining feedback on the acceptable end points for approval.

We are still planning to initiate a larger confirmatory pivotal study for eteplirsen in 2013. Our strategic shift since we unveiled our data set -- I'm sorry, one strategic shift since we unveiled our data set at the American Academy of Neurology is our willingness to broaden the type of strategic partnership on DMD that we will consider. With a robust proof of concept now in our lead program with eteplirsen, we believe this is highly reproducible across other exon skipping targets.

We currently are showing good progress on our two collaborations on exon 45 and exon 50 drug candidates where we are receiving grants to support the IND enabling work to move these two candidates into clinical development. We are also in discussions with granting authorities and foundations for the pursuit of other exon skipping drug candidates. A strategic partner that can bring more resources to bear on our broader DMD program can be a win-win for AVI and for the DMD community in that it may allow us to accelerate the development of other DMD drugs and toward an eventual class approval for our exon skipping drug platform. This will enable us to provide treatments for the broader group of DMD patients who can benefit from exon skipping drugs.

Now I'll turn our attention to our government-sponsored infectious disease programs where we continue to advance our two drug candidates for the treatment of life-threatening hemorrhagic fever viruses of Ebola and Marburg. We continue to prepare for our multiple ascending dose or MAD studies in healthy volunteers for both drugs and we're looking forward to exploring multiple doses and potentially higher doses than the nine milligrams per kilogram that we proved safe in single ascending dose studies.

This will help us understand and possibly widen the therapeutic window for not only our Ebola and Marburg drug candidates but for future applications against emerging viral and bacterial targets utilizing this same backbone chemistry. These MAD studies are still planned to start in the second half of this year. We are currently in a study on our Ebola drug candidate where we're evaluating the active components of the drug as a single agent versus the combination drug AVI6002 that had been previously tested, similar to how we demonstrated that AVI7288 on a stand-alone basis for Marburg was efficacious as a single agent. We expect to announce top-line results from this Ebola study looking at single agent components versus the combination in the coming weeks.

Lastly, on the corporate front, we announced a departure of Peter Lindley, our Chief Scientific Officer, who has resigned from the Company effective June 1. Peter was a tremendous help to me in reshaping our research efforts and priorities for our early drug discovery efforts and the research organization is left in a better position than where it was when he started at AVI.

As we announced last year, we had a reduction in staff in December that included members of our research organization and curtailed many of our nonessential research activities to focus more of our resources on our clinical stage program. While I would have liked to have provided Peter with a larger research staff and budget, we were not able to pursue many of the research ideas that Peter had for our technology due to resource constraints.

We're sad to see him leave and we wish Peter the best as he determines what he will do after his departure from AVI. That concludes my corporate update and with that, I'll turn it over to Mike Jacobson who will give you a financial update for this quarter. Mike?

Thanks, Chris. And hello, everyone. For the first quarter of 2012, AVI reported an operating loss of $6.9 million. This compared to an operating loss of $5.5 million in the first quarter of last year. The increase is the result of a $3.1 million decrease in government research and contract revenue partially offset by a $1.7 million decrease in our G&A expense.

Revenue for the first quarter of 2012 was $11.2 million compared to $14.3 million one year ago. $2.4 million of the decrease was due to the completion of the H1N1 flu contract in June of last year and the remaining $700,000 was due to the timing of some subcontracting activities on our on-going Ebola/Marburg contract. R&D expenses were $14.8 million in both the current quarter and the first quarter of last year.

But the nature of the spending has changed somewhat between the years. Our spending on DMD increased by $1.8 million due primarily to the on-going Phase IIB trials and we had an additional $400,000 in spending on our other proprietary research. These increases were offset by a $1.2 million reduction in spending on the H1N1 contract that was completed in June of 2011, a $600,000 reduction in subcontractor spending on our on-going Ebola/Marburg contract, and a $400,000 decrease in personnel-related costs.

G&A expenses in the first quarter this year were $3.3 million compared to $5 million in the first quarter of last year. The $1.7 million decrease was primarily due to a $1.1 million decrease in personnel costs related to the December, 2011, reorganization and an executive severance package that we recorded in the first quarter of 2011. In addition, legal and professional services decreased by $500,000. The net loss for the first quarter of 2012 was $17.7 million or $0.13 per share compared to net income in the first quarter of last year of $1.8 million or $0.02 per share.

The $19.5 million change in our net loss was primarily due to $18.2 million in the non cash expenses associated with the change in the valuation of our outstanding warrant which we recorded as other income and expense. The remainder, $1.3 million, was related to an increase in our operating loss. Turning to the balance sheet, we had cash and cash equivalents of $30.6 million at the end of this quarter.

Taking into consideration the funding from our on-going Ebola and Marburg contracts, we believe we have sufficient cash to fund our operations for at least the next 12 months. With that, I'll turn the call back over to Chris.

Okay, thank you, Mike. Operator, you can open up the call to questions.

(Operator Instructions.) Your first question comes from the line of Charles Duncan with JMP Securities.

Hi, Chris. Thanks for taking my questions and congratulations on the recent progress. My first question was regarding the ongoing 48 week study. I'm wondering if you're looking -- if beyond maybe a six-minute walk test. Are you going to be able to show or explore other measures of clinical benefit such as grip strength?

Yes, thanks, Charles. Yes, we're collecting other parameters on clinical outcomes and we believe that the six-minute walk test is again the most accepted clinical end point that has shown some meaningfulness to both regulatory authorities and the broader DMD community. When we looked at some of the other clinical outcomes, we did not see as much -- I should say we saw more variability in those responses.

It did not seem to be as telling -- a little noisier than the six-minute walk test and the ambulatory walking scores. So I think right now we're going to be looking at the six-minute walk test to tell us the potential treatment effect but we will continue to look at these other parameters to see if they enhance and underscore that signal that we would see in the six-minute walk test. But this is a long-term study and one of the reasons we decided to look at a lot of clinical outcomes is that we expect this cohort to be followed indefinitely, beyond 48 weeks, and we want to understand if some of these other parameters over the longer term show more of a signal of stability. It is very possible that some of these other clinical parameters like Gower's maneuver or [four] stair climb tests, show slower or more rapid decline than walking scores. And we're using this to better understand what are those important clinical outcomes over the longer term.

Okay. That makes sense. And then with regard to the 48 week study versus say the 24 results, I guess to me, it seems somewhat intuitive. I don't want to minimize the amount of work that's been done here. But to think that a protein could take longer to lay down and have an impact. But when you consider the variables that you could change, ie, longer dosing or more dose-intensity such as frequency, what was kind of your thought process there?

Yes, well, part of the reason for the study design we chose for our 24-week program was to better understand what it takes to produce those meaningful levels of dystrophin. I think we got our answer which is that there is a period of time that you need to accumulate that steady state level of dystrophin on a more consistent basis. Because we achieve that at the lower dose of the two doses we studied, we think it underscores that duration of dosing is probably more important than dose level.

We also show that once weekly dosing may be enough in terms of frequency and that we wouldn't necessarily have to go to more frequent dosing or three times weekly or continuous infusion or something like that. The 48-week biopsy data, as I described in the introductory remarks, I think will be even more telling about do we continue to increase dystrophin? Is there a steady state that's reached? Is there a dose response between the 50 milligram per kilogram and the 30 milligram per kilogram cohort? So I think we have a good signal already based on the 24-week data but I think we're going to get an even more robust signal and answer a lot more questions with the third biopsy data. And that will probably shape our thinking about a pivotal study and what dose and what regimen we would bring into a pivotal confirmatory study.

Okay. Last question is regarding partnering strategy. You mentioned some new thinking along those lines. I guess I'm wondering when you think it might be the best time for you to -- strategic time for you to do a partnership. Would it be before you commenced a pivotal program or do you think that you could take this further on down the goal line?

Yes, well, we think that the 48-week data will definitely enhance -- I mean we're hopeful that it will enhance the excitement around this program and would lead to better economics around a potential deal with a partner. First I've shifted somewhat in my openness and willingness to consider a partnership because we now know that it may take a longer study, potentially a larger study where we would need to stratify patients or be more selective about inclusion criteria, or power the study with a larger sample size to show a treatment effect.

All of those factors would add time and money and given the robust signal we've seen to date, we think there may be a win-win to have a good partner with deeper pockets to accelerate this program now that we believe it is pretty derisked. In terms of dystrophin, in terms of safety, it is really just a matter of longer and potentially larger studies. So we are currently pursuing discussions with partners and in terms of timing, obviously I think the feeling of a lot of partners is well, we'll wait for the 48-week data to do a partnership and we'll pay more later. It seems to be the conventional wisdom in the industry. But there is a scarcity value here.

We think this is a very hot asset and I think for the right partner, we believe they could lock in exclusivity before the 48-week data in an option-type structure where we could get an up-front fee to lock in exclusivity with a larger milestone payment coming after the 48-week data, after the program's further derisked but that partner would have to pay that milestone to continue to be our partner in the program. So we think there are ways to structure deals that mitigate the risk of waiting for the 48-week data but also giving the partner something to lock in or to lock out other potential suitors. So we're open on the timing but I think there is a way to see a partnership happen sooner rather than later and before the 48-week time point.

Thanks for the added color, Chris.

Great.

Your next question comes from the line of Ted Tenthoff with Piper Jaffray. Ted Tenthoff: Great. Thanks for taking the question. Can you hear me okay?

Yes.

Excellent. I was thinking, too, as you were mentioning about some of these other clinical end points, the importance of potential grip strength in non-ambulatory boys. Just from my experience, there's a lot of frustration from parents where the boys have already crossed over to using a wheelchair where they're really not being included in trials. So just for longer term access, it is really an interesting and I think important point to look at those other clinical outcomes and strength factors as well. My question had to deal with some of the RT-PCR and other data that you showed with respect to the quality of the dystrophin that was actually being expressed. I was wondering if you could just kind of highlight that. How important is that going to be to the FDA with respect -- just in terms of augmenting the general effect that you've seen at the 30 mg/kg dose at 24 weeks?

Thank you, Ted. Let me just comment on your comments about the non-ambulatory population. So we have two of those patients, those two boys I described, they could not complete the six-minute walk test without assistance by the end of that study. They had progressed quite rapidly. However they were in the cohort where we showed high and consistent levels of dystrophin. And they continue to receive the drug. And in fact, it may be more important in those two boys to capture some of the grip strength and we have other things like the nine hole peg test which is a common non-ambulatory measure. So those two boys are still in the study, still receiving drug and we still continue to capture some of the clinical outcomes that could be a signal.

I think one possibility of why the industry has started with the ambulatory population is that there are well-validated clinical outcomes that have gained approval for other drugs that happen to be walking tests or tests of an ambulatory patient. I think we will hopefully show some benefit in these upper extremity or strength testing of the upper extremities that could, if the drug is safe and we're showing the biochemical marker of dystrophin to be present, that that could lead to a broader approval or indication for the drug. So I just wanted to highlight that since you had brought it up.

Regarding the other kind of biochemical measures of dystrophin, this is probably the number one question we get which is these levels look very impressive and they seem to be consistent with the literature in terms of likely translating to clinical benefit but how do you know that the dystrophin is functional? And what I highlighted in my notes up front is that we now have two studies in which eteplirsen induced dystrophin showed the connectivity in the sarcolemma, the cell membrane, basically restoring the dystroglycan complex which is the thing you want to see to prove that this is a functional dystrophin protein.

And this was outlined in an article that was published earlier this year in molecular therapy by Sebastian Cirak who was a colleague of Francesco Muntoni, who did our UK studies prior to this study, Phase IIB study. And Francesco Muntoni was the lead author on that study. And they did show evidence of restoration of the beta dystroglycan, the alpha sarcoglycan, and neuronal nitric oxide synthase, which basically shows restoration of dystroglycan complex at both ends of the dystrophin. We're very encouraged by that. And again further encouraged that not only did we hit our primary end point which most in the field believe of all of the different ways you can measure dystrophin that the percent of positive fibers is better characterized in the literature as the most correlated to clinical benefit. We also wanted to look at the other measures such as dystrophin intensity per fiber, and again we saw increases of over 20% of dystrophin intensity in those fibers that were positive for dystrophin.

And we also showed evidence of protein expression by Western Blot and as I mentioned, by RT-PCR. All of those patients showed a good exon skipping in that analysis. So, overall, we believe that this is the most robust and meaningful dystrophin data set that has been produced to date. It is the only placebo-controlled study looking at dystrophin and where we had pre and post-treatment biopsies that led to this analysis. It also -- the other program that was not exon skipping was PTC's program looking at atalurin. They showed very low levels, very modest levels of dystrophin increase that were nowhere near the levels of dystrophin positive fibers that we've seen here. So we are very encouraged by this. We think that it will translate, we believe, to clinical benefit. It is just a matter of how long will it take and how would we select the right patient population to show that effect in a clinical study.

Excellent. I appreciate the update. Great data.

Thanks, Ted.

Your next question comes from the line of Bill Tanner with Lazard Capital Markets.

Thanks for taking the question. For you, Chris. Just on understanding the number of positive staining fibers, what's the heterogeneity, I guess the intrapatient heterogeneity, either intermuscle or intramuscle, just in terms of if you looked at a cross section or whatever. I think you understand the question.

Bill, yes, I know. That's a question we get as well. I think the answer we got from this study which was most impressive to us was the consistency that we saw across the patients but also across the samples in the patients. So first let me describe in animal models where we're able to look at all of the musculature in both the diseased mouse and diseased dog model of Duchenne, which both of these species get Duchenne naturally. When we look at earlier time points, we tend to see spottier patches of dystrophin and it is not well-distributed or diffused across all of the musculature in the same way.

However, and particularly in mouse models. have demonstrated longer term dosing. We start to see the achievement of steady stage and better-distributed, more well-distributed diffuse dystrophin throughout the musculature and what the mouse model would suggest is that you need at least 24 weeks of treatment to achieve that steady state. And this is exactly the hypothesis that we were testing in our study, based on a lot of that literature. Now, in humans, we don't have the ability to take multiple biopsies of different muscle groups. This was a surgical biopsy but a single sample.

We used alternating bicep muscles to look at the dystrophin. However, we did take that piece of muscle, we cut it into two blocks. We sliced that further into the 12 pieces of muscle tissue for staining and we got values for each of those samples so we had 24 values pre and 24 values post or 48 values that were averaged to get our novel dystrophin production within each patient. And then we saw that fairly consistent across the four patients in 24 weeks.

So we only have that one sample to go by. However, it suggests that we may have achieved better distributed and more diffused dystrophin throughout the musculature by taking this random bicep sample and seeing that consistency within the patient and across the patient, lead us to believe that this should translate to better muscle function and improvement of clinical outcomes if that's the case. We won't, unfortunately, be able to look at every muscle group and we have to use these biopsies of the proxies for what's happening in the rest of the musculature of the patient.

So there is no plan to -- or contemplation to look at it in leg muscles? Obviously that would be important for a six-minute walk. So basically these are bicep biopsies.

Yes. Well, we did that for a reason. First of all, the third biopsy, we wanted to ensure that it wasn't taken from the same surgical place that was taking the first biopsy. So we've allowed quadriceps to be one of those muscles that the third biopsy can be taken from.

But we actually purposely discouraged it and one of the reasons we picked the biceps was because we think it is a large extremity muscle group that would be akin to the quadriceps and we do think that we didn't want to interfere with surgery on a quadricep muscle that could impede or interfere with exactly what you're describing, the walking test and the test of ambulation where we want to make sure that we're not disrupting their ability, pain, et cetera, any complication that would be associated with surgery, et cetera, in their legs which is what we're testing above all.

Okay. Fair enough. Then, as it relates, I think you mentioned there were a couple of patients that actually -- their disease progressed faster than one might expect. How do you guard against that as you do these -- for future trials because obviously that's something that is going to not help out with your detecting of reasonable signal or real signal, I guess.

This is why we do clinical studies. We get a data set. We learn from it. And we can shape a better design moving forward. In selecting patients. There are a few ways that we could potentially achieve that and we're evaluating all of those different ways. We want to wait for the 48-week data to have a more robust data set to inform that decision. We want to have a discussion with the FDA to get their feeling after we have the 48-week data to talk about these issues. But there are a few different ways that we can protect against that from happening.

One way is if you can craft a lead-in phase where patients are on a drug for 16 to 24 weeks before they would be qualifying on the inclusion criteria where you know that you're producing meaningful levels of dystrophin in that treated group opposed to a placebo, for example. You could stratify the population by six-minute walk either above or below a threshold, let's say 300 meters or something like that. to make sure that you had a good balanced portion in each group and see how that progression is blunted in terms of treatment effect.

You could do some type of a responder analysis where you predefine who would or wouldn't be included in the final analysis. There are a few different ways we can learn from these rapid progressors where a treatment effect isn't able to take hold before they progress. That's something we continue to discuss and we hope to have a discussion with regulatory authorities as well.

And then I guess the last question is -- I've not heard you mention and I would suspect it has been thought about, like a subpart H, if it is something that -- I mean this would seem to be -- if you're producing dystrophin, not only one would think that clinically things would get better and if there is a time frame, it is actually fairly long before you can actually see that. I mean have you talked to the FDA about potentially pursuing subpart H? Or any reason why they would not?

Yes, well I don't want to -- it is a difficult thing when approaching the FDA. They can easily be turned off by an overly aggressive approach from industry. I already know that the advocacy groups out there would definitely like to see the FDA show some flexibility to accept a biochemical marker for the basis of approval like dystrophin where we know that that's the essential protein that's lacking and we're restoring it to very high levels. So we believe we're in a better position to make that argument after we have a fuller data set.

So we'll look at the 48 week data and see if that clinical outcome benefit is more robust and more meaningful. I do know that the FDA has approved drugs in rare diseases where a subset of patients have responded, where you don't have all of the patients respond and if we could have -- there are even products where a third of patients responded on a surrogate marker and gained approval and others where half the patients respond. So I'm not turned away from the potential of an accelerated approval because a subset of patients might show good response. But I think we want to gather more data before we ask that question of the FDA. And again, as I say, we'll have a meeting with the FDA planned for later this year after we get a chance to see the 48 week data set.

Okay. All right. Thanks very much.

All right.

Your next question comes from the line of Reni Benjamin with Rodman.

Hi, good afternoon, thanks for taking the questions. Chris, can you just let me know or just remind us about the genetic tests that were performed, the sequencing analyses that were performed to get into the trial. Were all these patients who came in, do they have uniform mutations that could be addressed by the exon skipping technology and did they have sequencing that was performed on let's say the RNA from their biopsies after dosing?

Yes. So let me answer your last question first. So the biopsy samples were run by RT-PCR to show the evidence of the protein. In other words, that we did skip efficiently and that those patients actually were showing exon skipping of the target exon and actually translating to produce that protein. Basically, we look for the exon that would be reading -- be red after the skip of exon 51. So in most of these patients, it's at exon 52 depending on the mutation. And so if that's read out, then it means that reading frame is translating to produce the protein.

So that was done to show that evidence. In terms of the inclusion criteria, there are about 70 patients that would be amenable to an exon 51 skipping drug. We had all of those patients represented in our study. There were three genotypes that were represented in the 30 milligram cohort where we did see a 24-week robust dystrophin production. and importantly, none of those patients had an exon 49-50 deletion. And the reason I highlight that is because there was some suggestion in the previous study that we saw a little bit of an outside response in patients who had an exon 49-50.

That could have been random. People were wondering is this the only genotype that this drug is going to work in? Is there something about the 49-50 genotype that is unique? Well, this study basically addressed that. We had, again, three genotypes, four patients, that did not have that that showed higher levels for the most part than we saw in the previous study. And we have exon 49-50 deletion in the other cohorts where the third biopsy again will be important because we will have evidence of dystrophin production across all of these genotypes in that 48-week biopsy.

So the inclusion criteria were based on a genetic test or genetic investigation of exactly what genotype they had that would qualify them for the study and again, this is a commercially available test that can be ordered in any local institution or lab. So we're very confident that these were Duchenne patients based on the outer frame deletions that were captured via the genetic investigation. And then we had further evidence that we achieved that exon skipping in the muscle biopsies in those treated patients that produced that -- those high levels of dystrophin.

And I guess when we look forward and think about the next data set that's coming and the longer term exposure, how should we be thinking about the data? And I guess what I'm trying to get at here is it already seems like a win. Like you should be able to go to the agency, talk about the potential benefit here, the improvement in the six-minute walk. It was a small trial so you couldn't expect statistical significance. Why go even longer? Why not start talking with the agency right now and then when you do go longer, what are your no-go decision metrics? So for example if the six-minute walk test is still the same, do you decide not to move forward with it? Or do you decide that either which way, you're moving forward and talking with the agency? How should we be thinking about those results?

Yes. So, Ren, that's a great question. I do think we have enough now that suggests that this program should move forward into pivotal studies. There are three main questions that we wanted to answer. Number one was the production of dystrophin and we believe that that question was answered in this 24-week cohort and will only further be answered in the 48-week data where we only had four patients dosed and biopsied after 24 weeks of treatment.

At the 48-week time point, we're going to have all 12 who have received either 24 weeks of treatment or 48 weeks of treatment and so we may have on our hands 12 out of 12 patients who show around or more than 15% or hopefully an average of 20% across all of those patients, of dystrophin in the muscle biopsy. So that's the first question. I think that is pretty derisked in terms of the answer we're expecting. The second one is safety. This is a life-long, chronic disease that's going to require long-term therapy and we want to have a safety profile, particularly when we're dosing children and these boys, I'm sure the parents will want to start providing therapy as early as possible. We think safety is important.

And the fact that we saw no treatment-related adverse events, no treatment-related lab abnormalities, if we have that at 48 weeks, and we'll have more than 48 weeks when we have the 48-week biopsy data, it is open label. We should have a few more weeks of safety beyond that to go into the FDA meeting with. I think that's another important element to underscore with the FDA that we're -- it doesn't appear that we're doing any harm in terms of that risk benefit ratio. The third question is around the clinical benefits.

As I mention, there are some who believe this is enough to suggest that the drug should be available to patients who need it, in this very rapid progressing, high mortality disease. But the FDA will likely want to see [inaudible - technical difficulty] signal of clinical outcome. Now we think the six-minute walk test I described, albeit on a subset of the patients, started to show a signal of benefit here versus the placebo patient. We will have to look at the 48-week data to see if that's enhanced and if that becomes a compelling data set for the FDA in those discussions. But we wanted to wait until we had a stronger data set and argument to go to the FDA. And we think that 48-week data set could be the answer to that question.

Fair enough. Just one other question regarding the burn going forward for the rest of the year. I know that the first quarter was maybe abnormally high. Could you just give us some guidance as to what we should -- how should we be modeling this for the rest of the year given that the study is extending quite a bit?

Yes, you're absolutely right. We knew going into this year that we had more burn in the first half of the year than the second half of the year. And you're right. The first quarter was higher than average as we look across the rest of the year. Also remember we instituted the reduction in force in December of last year. We had some severance in a lot of those employees, we started cutting a lot of nonessential activities.

And we didn't feel the full benefit of those changes in the first quarter but we will throughout the rest of the year. We've also curtailed. Obviously when the stock become more depressed in recent weeks, we started to be more sensitive to cash conservation and we have made some other adjustments to make sure that our cash runway goes longer. We just obviously put a 10Q out that highlighted that we have a year of cash that we communicated so we're comfortable that we have a year of cash on the balance sheet. And again, we have a lot of other activities that can be taking place. I mentioned we could foresee a partnership before the 48-week data that could bring in nondilutive cash.

We have a couple proposals that we submitted to the government and continue to evaluate for our infectious disease programs, other grants that could bring in additional funding. And so we think there are other ways to shore up our balance sheet and as we always communicate we continue to look to make sure we have enough cash to continue operations and we always explore varying financing vehicles. It is a function of where the stock price is. What terms, what the demand is to come into the stock and we continue to evaluate that.

Great. Thanks for taking the questions and good luck.

All right. Thanks, Ren. And operator, I just want to say everyone at AVI is very excited about the progress we made in the first part of this year across our lead program. And we look forward to the continued data set that we can generate from our extension study with eteplirsen with 48-week data due later this year and thank you all for calling in and participating in this earnings call.

Ladies and gentlemen, that concludes today's presentation. Thank you for dialing in. Have a wonderful day.