Operator
Good morning, and welcome to Sarepta's conference call to host analyst Q&A regarding the LGMD program. As a reminder, today's program is being recorded.
Thank you very much. Thank you all for joining us today for this quick update to address some questions that have arisen in the last 24 hours. We'll be making some forward-looking statements today, so please refer to our public filings for the risks and uncertainties that are associated with making predictions about the future.
In a moment, we will take Q&A and our President, R&D and Tech Ops, Dr. Louise Rodino-Klapac is available to answer your questions. But first, let me make a few clarifying comments.
We understand that there's been some questions regarding a fatal serious adverse event in a trial for SRP-9004, an investigational candidate to treat LGMD type 2D. Now we did not discuss this matter in our call on Wednesday because it was neither material nor central to the topics at hand on Wednesday. This event occurred in a trial that was otherwise completed with all dosing and for a therapy for which we determined independent of this not to proceed. Our usual practice is to share these types of findings in the context of a complete study and its results at an appropriate medical meeting, and we intend to do this when the full data set is available.
Let me also clarify a few points. The difficult decision to proceed with our most advanced LGMD program, SRP-9003 for limb-girdle type 2E, but to discontinue the remainder of our LGMD programs and to look to partner or out-license them did not relate to a safety event in any of the LGMD trials or because of general signals of ALF and ALI and AAV-mediated full infusions of later-stage and more debilitated patients. As we discussed yesterday -- or I'm sorry, on Friday, we've had to largely deprioritize our gene therapy portfolio in favor of our siRNA platform based on their relative risk-adjusted NPVs and the need to focus our pipeline and to cut our expenses to manage our liabilities in the context of conservative estimates of performance.
Second, let me address whether this changes the approach to ELEVIDYS. The event occurred in a late-stage nonambulatory 51-year-old patient with another therapy. As we know and as has been communicated to the patient community, to the physician community and to the FDA, there is a rare risk of ALI becoming a fatal acute liver failure in more debilitated nonambulatory patients receiving ELEVIDYS. This signal is not changed by an event in a late-stage nonambulant patient receiving a different AAV-mediated gene therapy. Indeed, as you are aware, in light of the signal that we've seen, we have taken a very conservative decision already to pause all shipments of ELEVIDYS for dosing in the non-ambulant population while we develop a protocol for and obtain data regarding the use of sirolimus as a prophylactic immunosuppression in that patient population.
Insofar as we have already paused dosing in the non-ambulant patients for ELEVIDYS and this event creates no new or changed signal, we do not believe that the position of the FDA regarding the ELEVIDYS label would change. And in fact, this event occurred about a month ago. FDA has had all of this information for weeks, and we have received no change from the FDA in their position.
With that, we will open up the call to questions.
[Operator Instructions] Our first question comes from the line of Anupam Rama with JPMorgan.
Guys, you just hosted a conference call on Wednesday outlining the strategic initiatives and restructuring of the company. You talked about how the limb-girdle patient death has been known for about a month or so. Can you outline the thinking and considerations around the disclosure strategy here?
Sure. Thank you very much for that question, Anupam. The normal approach to discussing clinical trial results would be in the context of all of the data. We don't have that data yet. As it relates to Wednesday, this wasn't salient to our discussions on Wednesday, and let me sort of explain why.
First and foremost, one might wonder about the decision to stop all the limb-girdle 2E program with SRP-9003. That decision related to the risk-adjusted NPVs of the various programs. It was a painful decision because we think much of our limb-girdle gene therapies, our goal is to out-license or partner those therapies. But it did not relate to any safety event that we've seen. And of course, looking at these programs requires that one look across both the safety and efficacy of these programs.
Second, as it relates to ELEVIDYS, this doesn't change in any way either the safety signal for ELEVIDYS or the approach that we're taking with ELEVIDYS as we previously discussed both with the physician community, with patients and with the investors and with the FDA, we have seen a very rare but serious signal of elevated liver enzymes becoming acute liver failure that it's fatal in non-ambulatory later-stage patients. Nothing about this therapy and seeing it in a 51-year-old nonambulant patient would in any way change that signal. And more than that, one should -- I'm sure you all remember, we actually took a very conservative approach with respect to ELEVIDYS, and we determined after our second event to pause all dosing of non-ambulant patients while we develop the protocol, which we have done for sirolimus and then gather the appropriate information about the use of that before we consider beginning to ship ELEVIDYS for the treatment of nonambulatory patients.
So as it relates to the Wednesday event, it simply was neither material nor relevant. And of course, it's a separate therapy. It's a separate disease state. It's a separate construct and even a different manufacturing process. But thank you very much for your question, Anupam.
Our next question is going to come from the line of Brian Skorney with Baird.
Obviously, sensitive for the last few months to evolving into a bit of a Fubar situation that's difficult to navigate from a management perspective. But it seems very clearly that this was a material event, especially in the context of shutting down the LGMD programs, even if you aren't explicitly taking that into account in the NPV calculation. And my colleague even asked specifically about the safety of LGMD on the call the other day.
So I guess the question is where do you kind of view materiality of safety events right now? And I would just kind of say, if there was an ambulatory death in the DMD setting, I would just want to reiterate that I think this would be a materially -- highly material event for you and you need to be transparent with that immediately.
But in terms of questions, can you give any other context around this patient specifically? It seems like maybe one of the more older patients that have been dosed with AAV, 51-year-old, and just thoughts on dosing older patients with either the 14. And how many patients have been dosed in this 2D study? And was the FDA formally advised of this patient death before the correspondence indicating that a black box update to the ELEVIDYS label is sufficient to address the ambulatory population?
Thank you very much, Brian. I'll leave much of those questions to Louise. Let me answer the materiality. Again, I want to be very clear. The decision to cease the limb-girdle programs didn't relate to this or another event. They related to the risk-adjusted NPVs in the context of our ability to meet our liabilities and remain a viable organization. They were very difficult decisions, but they were the right decisions to make for the organization going forward.
As it relates to materiality, certainly, if there was a material change in the safety signal of one of our marketed therapies, we would disclose that publicly. I think we have a, I believe, a very laudable history of being extraordinarily transparent, not only with the physician and patient community, but with our investor base as well.
This is -- this event occurred in the context of a clinical trial for a program that for independent reasons, was -- we ceased it was -- there was no additional dosing to be had in this trial. The discussion of this event should occur normally in the context of the entire study results at an appropriate medical meeting, which is our plan. And again, there really was no read-through or change in the safety signal of a marketed product from the results of this study, and that kind of explains our thinking. We had a lot to discuss on Wednesday, obviously.
Louise, you might want to answer some of the other questions that Brian has asked.
Sure. The question was around the -- a little bit more detail around this case. This was a 51-year-old non-ambulatory LGMD2D patient. This event occurred about a month ago, which is about 11 -- approximately 11 weeks after dosing. He was in a 4-patient Phase I trial for this study. The dose was 7.41 to 13, so high to the 13 range. This is a 69-kilogram patient and the course in terms of the ALF was similar to what we have seen in the previous two cases with DMD.
And just on the FDA being formally advised of the patients.
Yes. So the FDA was informed first about this case in terms of a life-threatening event and then followed up with the death. So the FDA was properly informed along the way of this case.
Our next question comes from the line of Tazeen Ahmad with BofA.
Doug, I just maybe want to backtrack a little bit to ELEVIDYS and sort of perception among parents as sort of more news flow happens and today's update is not about ELEVIDYS, it's about limb-girdle. But I'm just curious about how the company is thinking about the processes that you would use going forward in order to get parents comfortable with like making an appointment or continuing on with the appointment that's being made for dosing.
So in relation to that, can you just clarify again if there's been any liver enzyme elevations seen in the ambulatory population that's been dosed so far? Or has anyone needed hospitalization post treatment in the ambulatory setting?
We certainly -- we see elevated liver enzymes in the ambulant and the non-ambulant patient population. And in the commercial setting, while we don't have the exact numbers, there may have been hospitalizations, I'm not currently aware of the exact number. We have not seen in the ambulant populations, the serious event that we're talking about with respect to the two prior events of this event.
As it relates to the way we communicate, the goal in our communication with physicians and patients is to arm them with appropriate and factually accurate and balanced information so that physicians and their patients can make intelligent risk-based decisions about this therapy.
And our next question is going to come from the line of Gena Wang with Barclays.
So just wondering, when the FDA gave you the technology platform designation, did they see the limb-girdle death? Or like were they aware of this?
And then second, I know we already asked on Wednesday, but in the case of another, say, unfortunate event in the ambulatory patient, what is your expectation for the label part?
Yes, we -- it's very difficult to speculate on the latter part of your question other than to note that we have agreed with a black box warning that applies more generally than it applies to ambulant certainly, which is that we have seen cases of ALI and we've seen serious cases of acute liver failure resulting in death. So that is all warned in the box label that will come out when we supplement the label with the FDA. And of course, we've gotten that information out to the physician community in advance.
Louise, do you want to touch on the platform designation?
Sure. The platform designation that we received was specifically for LGMD2E or 9003, and that's specific to the manufacturing process, which is the adherent manufacturing process. And so it's very specific to manufacturing in 9003.
Our next question comes from the line of Salveen Richter with Goldman Sachs.
This is Mark on for Salveen. A couple from us. Have there been any other patient deaths on any other of your AAV gene therapy programs? And also regarding the manufacturing process for the LGMD drug here, is the process similar to process B for ELEVIDYS?
And also, were any of the LGMD patients on a background therapy like corticosteroids, if you could speak to that, please?
Yes. I'll answer this, and Louise, you correct me. I think I got all of them. I think the first question was, are there any other fatalities associated with our -- any of our other gene therapy trials associated with the therapy itself? And the answer to that is no.
On the manufacturing side, it's a different manufacturing process for 9004. That's a suspension process. ELEVIDYS is an adherent process.
And then I apologize, Louise, do you recall the third question?
The last question was on -- was limb-girdle patient on background of steroids. So typically, limb-girdle patients are not on standard of care steroids, and that was the case here, but then they do receive our standard protocol of starting prednisone prior to treatment and then continuing for 60 days. So that's the -- it is the protocol that we use with delivery of after infusion.
Our next question comes from the line of Mike Ulz with Morgan Stanley.
I guess appreciating that this recent event was not in a patient on ELEVIDYS, just curious if you've been able to identify other risk factors in these three deaths so far.
Louise?
Yes. We've continued to analyze all three cases, in all three cases, as you know and as we've noted, these are nonambulatory, more progressed patients. There's obviously differences in the pathology between DMD and LGMD. But in both cases, we have patients that are more advanced in their disease and are not unable to recover from the liver injury as a younger patient would be able to. Nothing more specific in terms of very specific single risk factors that we can point to at this point.
Our next question comes from the line of Brian Abrahams with RBC Capital Markets.
This is Kevin on for Brian. Sorry to hear this news today. So we just had a question on 2E. Can you talk about whether you believe you might need additional data at this point to support your BLA for that program, maybe using sirolimus or something alike?
And then maybe do you expect additional feedback from the FDA before filing on that particular LGMD program?
I'll turn this call to Louise.
Yes. So on the -- for LGMD2E, we've conducted three clinical trials in that space. So Phase I, our initial dose-finding study, and then we conducted VOYAGENE, which is in older and nonambulatory patients, and then EMERGENE, which was 17 patients. We did not -- we use our standard steroid protocol and do not use sirolimus in those studies. This is something that we'll continue to evaluate as we submit the BLA in terms of the use of any recommendation for potential use of sirolimus.
Our next question is going to come from the line of Ellie Merle with UBS.
I guess just based on the clinical experience of ELEVIDYS in ambulatory patients, what would you expect for the rate of patients being hospitalized for LFTs and ambulatory patients in the real-world setting?
And I guess what would constitute a deviation from this rate?
And then just lastly, I know a couple of people asked about this, but I just want to confirm that there are no other additional patient deaths that we aren't aware of currently across either the clinical trials or the real-world setting.
Yes. I can turn the first part of the question over to Louise, and I can confirm the second part of the question. Louise?
Yes. So a few comments on the incidence of liver enzyme elevation. We've talked that this is approximately 30% to 40%.
Just to clarify in terms of clinical trials versus the real-world setting. So in clinical trials, we obviously have in-depth visibility into all of adverse events. In general, across the board, whether it's commercial or clinically, we act with vigilance in terms of monitoring patients. In the commercial setting, reporting is given to us, and we follow up immediately. So approximately 30% to 40% of elevated liver enzyme, a subset of them require the infusion of higher doses of IV steroids, for example, and they will be hospitalized for that.
So I don't have the exact numbers on the commercial side, but we certainly want them to go to the hospital to get increased steroids in that case. So we are extremely diligent, whether it's commercial or whether it's clinical, but we're looking for in the upcoming sirolimus trials, a reduction in that percentage or that number of acute liver injury number, which is 30% to 40%.
Our next question comes from the line of Biren Amin with Piper Sandler.
So I understand this is an unfortunate event with LGMD, and it wasn't related to the business update. However, do you believe it had a relevant read-through to ELEVIDYS in the non-ambulatory setting, given it is the same vector across both programs, and therefore, that information should have been shared.
And did your expert committee that evaluated the non-ambulatory side for ELEVIDYS, did they evaluate this event when they were making that recommendation for an enhanced immunosuppression regimen?
And then last question, with this event, how do you think this will shape your discussion with FDA on the non-ambulatory side of things with ELEVIDYS.
I would say I don't believe there's read-through to ELEVIDYS for a number of reasons. I mean, one, of course, a different therapy, different construct, different dosing, different manufacturing process. But also even if it did have read-through, it would be read through to a signal that we've already fully appreciated and disclosed and know about, which is this rare risk of ALI becoming a fatal ALF. So I don't see it as having read-through to ELEVIDYS, properly contextualized. And then as it relates to the approach to ELEVIDYS and the immunosuppression regimen, I don't think this changes because it is a similar signal.
So what we've done here, and I think it's appropriate, but very conservative, we've chosen not to ship ELEVIDYS for the use in the non-ambulatory patient population until we explore the use of sirolimus as a prophylactic immunosuppression. We have very good preclinical data and some anecdotal clinical data that would suggest that this could significantly reduce the risk, and we'll proceed with that. And our hope is to have conversations with the FDA about gathering that data as soon as possible.
One other thing I do want to remind everyone is that this risk both of acute liver enzyme elevations and the risk, very rare risk of elevated liver enzymes going on to become acute liver failure is a class -- an AAV class-related risk that there is associated with the use of AAV, which obviously is significantly present in the liver, a risk of liver stress that can become something more serious in rare cases.
And our next question comes from the line of Yanan Zhu with Wells Fargo.
Great. Could you give us a sense of how many LGMD patients across all genotypes have been dosed and how many are ambulatory versus nonambulatory. I was wondering the rate here appears to be higher than the DMD non-ambulatory cohort that you have treated. So wondering whether the liver enzyme signal is more prominent in this disease in general, which therefore, could explain the higher rate? Or any thoughts on any disease-specific reason to see -- to believe that DMD could be a little different -- could be different than LGMD?
Yes. I'll turn this over to Louise. But before I do, I'll just comment that it is very difficult and probably suspect to draw signals based on a single event.
But with that said, Louise, do you have thoughts on this?
Yes. So in terms of patients dosed across the LGMDs, it's I don't have the exact number, but between 35 and 40 patients dosed across our trials. In terms of ambulatory status, approximately, I would say, 50-50, maybe favoring slightly the ambulatory patients that have across these trials. So it was a wide spectrum of patients dosed.
In terms of numbers, I agree with Doug, this is a rare signal. And so with small numbers like that, it's difficult to make an assessment of a percentage in that small number of cases. We do know that this is a rare event, and you can just point to the DMD population for that.
Our next question comes from the line of David Hoang with Deutsche Bank.
So I just wanted to ask about -- could you just refresh us a little bit on the market opportunity that you perceive around LGMD2E for 9003 and just in terms of the progression of the disease and the level of receptivity and demand you would expect for a gene therapy product there?
Yes. I am not prepared right now to provide sort of a market update other than to say that it is an ultra-rare disease, but it is a disease that's a very serious neuromuscular disease that doesn't have options.
The choice that we've made to proceed with limb-girdle type 2E and SRP-9003 relates most significantly to the fact that we feel a duty to these patients to continue given how the late stage of this particular development.
The decision to cease the other limb-girdles, again, was based on the fact that the risk-adjusted NPVs for all of the limb-girdles, including, frankly, 2E, is not as high and is quite low relative to the pipeline that we've now decided to focus our attention on.
Our next question is going to be from the line of Kristen Kluska with Cantor Fitzgerald.
Can you give us a sense of whether there have been any other life-threatening events observed either clinically or commercially beyond the three that resulted in fatalities?
Louise, do you have a comment on that?
We are not. We do not have any or are unaware of any.
And our next question is going to come from the line of Andy Chen with Wolfe Research.
Another question about ELEVIDYS. Can you please remind us of how the recent events in the past two months or so would affect your collaboration with Roche? Are there terms or conditions in your agreement, for example, milestones that will be affected by the recent events? Or are they all based on quantitative sales?
They're quantitative, and I don't envision that it has an effect on any of the contractual terms of the agreement.
Our next question is going to come from the line of Sami Corwin with William Blair.
I was curious if you think that these recent do they all occurred in non-ambulatory patients could impact the label for 9003 and if that may be restricted to only ambulatory patients.
And then as you're conducting your risk-adjusted NPV to determine the prioritization of your pipeline assets going forward, were you assuming you would be able to commercialize 9003 in ambulatory and nonambulatory patients?
Yes. As to the second question, the answer to that is yes. Yes, the NPVs that we performed across our limb-girdles made that assumption that we'd be able to make them available, both ambulatory and nonambulatory.
Louise, do you have any thoughts on the first part of the question, sort of restrictions in the label potentially?
Yes. As I mentioned, we've dosed a wide range of patient ages and weights across 2E. And as we submit the BLA, we're evaluating whether we make any recommendations on sirolimus, but none of our clinical trial patients were on sirolimus at the time.
Our next question comes from the line of Kostas Biliouris with BMO Capital Markets.
Sorry to hear the news today. Would you expect the third death to increase physician hesitancy with ELEVIDYS? And do you see any impact from today's update on the $500 million floor that you have set for ELEVIDYS?
The answer to both of those questions is no, properly contextualized. Again, this event tragic for the family involved related to a different therapy related to a very debilitated 51-year-old non-ambulatory patients, even if there was read-through to ELEVIDYS and there are lots of caveats to that, given that it's a different therapy, different manufacturing process, different constructs, different dosing regimen, very different patients. This is a 51-year-old patient. You don't see that with Duchenne. It still would not affect the change in the signal. We know there's a signal, a very rare ALI becoming a fatal ALF with ELEVIDYS, and that's well understood.
So it should affect neither properly contextualize ELEVIDYS ambulatory patients and their considerations nor does it affect our stress test, the $500 million stress test.
Our next question comes from the line of Ritu Baral with TD Cowen. Ritu, you line might be on mute.
It was. Apologies. I want to rip through a couple pretty quickly here. Dr. Louise, you mentioned that this patient was on a background medicine, but it wasn't a steroid. Can you elaborate on what background meds this patient was on?
And then as you think about this hypothesis that we discussed last time, which was the issue of liver fat, liver fat levels, et cetera, contributing, are there data points that contribute to this given the patient's age? And then I've got one more follow-up.
Louise, do you want to take both?
Yes. So just quickly on that. I think there was a misunderstanding there. So this patient was not on -- previously on any background meds in terms of steroids. So they started steroids right before dosing and they continued for 60 days and then were adjusted there and after. So there was no background previous [indiscernible]...
I meant backgrounds. I meant backgrounds other than steroids that could...
Okay. [indiscernible] No.
And then the liver fat?
Yes. I mean we're still evaluating specific things that we can point to. All we can say at this point is that it occurs in these -- or has occurred in nonambulatory patients that are more severe and certainly may have more -- less resilience in terms of the liver being able to recover, but we don't have specifics that we can point to yet.
And then the issue of what you are tracking to measure risk, is there something -- is there a better idea with the third case that -- of what to track? Is it the standard definition of Hy's law? Is it like Hy's law with GGT? Is it something established? Or is there a unique profile that is emerging in the liver function test, the liver enzyme parameters? And how long are you monitoring this for, given this is 11 weeks and the others, I believe, were earlier stages. Is there an amendment -- a protocol amendment to monitor all trial patients, clinical patients now out to like three months, four months? How should we be thinking of the panels and the timing?
Yes. So the monitoring occurs throughout. So even though the death occurred, liver enzyme elevations start to occur earlier before that, but certainly, patients are monitored continuously and our physicians are diligent about that.
In terms of what to monitor, all liver enzymes are elevated, GGT and bilirubin are the most reliable in terms of monitoring because AST and ALT are already elevated in both DMD and limb-girdle. But all of them are monitored consistently and usually rise together. So it's a collection of those liver enzymes. Bilirubin obviously, is a strong marker in terms of showing whether or not it's progressing to ALI and ALF.
So is monitoring Hy's law useful in this case?
I mean we certainly -- Hy's law is monitor, but that's just part of the calculation from the liver enzyme. So we're looking at all of it. And we don't look at a single biomarker. We're looking at all of them.
Our next question comes from the line of Mitchell Kapoor with H.C. Wainwright.
Since you're using the same vector across the pipeline, how confident are you that we won't see additional deaths due to ELEVIDYS or the LGMD2E products?
And what would be the time line and process of disclosure of events going forward now that we know what we know on time lines?
And could you expand on how this would differ in the clinical trial setting versus the real-world setting?
There is a known rare risk of elevated liver enzymes becoming acute liver failure fatally in more debilitated patients. And so far, it's always been in the non-ambulatory patient. If that signal changed, we would certainly communicate any change in that signal.
And again, I want to just point out again, I think this is an AAV class risk generally. We've seen this across not just our program, but other programs. One knows that with respect to AAV-mediated gene therapies, particularly in the full body infusion situation, there's always a very rare risk of this that we've now seen emerge this year with ELEVIDYS.
Our next question is going to come from the line of Joe Schwartz with Leerink.
I'm going to ask a question which is similar to the one we asked on Wednesday, and that is, if you could please help us understand the overall numerical extent of hospitalizations due to ALI and ALF and their pattern over time for the company overall. It would be extremely helpful to have some color on what the denominator looks like in terms of the patients who have been hospitalized for ALI and ALF and have been discharged as well as those who haven't, and how these things have been trending, even if it's just qualitative, since hospitalization definitely seems like a leading indicator, and we're all trying to gauge where we are in terms of the mortality trend and whether it has peaked yet or if not, when we might be on the backside of this unfortunate trend?
Louise, do you want to touch on this?
Yes. So I just want to come back to the difference in monitoring in the clinical trial setting versus commercial setting. So we're diligent across the board in terms of clinical and commercial. Clinical, we have more insight into SAEs as they are brought in commercial. We certainly look at reports and we follow up and make sure that we are following up extensively.
In terms of the numbers of hospitalizations. I think it's important to note that we encourage patients and physicians to hospitalize with increases in liver enzymes so that they can get the proper increased steroids, et cetera, for that.
We know that of the -- 30% to 40% have elevated liver enzymes, a subset or a lesser subset of those have ALI and then a very small percentage, somewhere less than 10%, approximately 5% may require hospitalization. So in terms of percentages, that's the information that we have.
Our next question is going to come from the line of Gil Blum with Needham & Company.
Just -- I don't remember if we discussed the time frame in which the ELEVIDYS events unfolded. But just given the time frame here of 11 weeks, does this change your thinking around the study that's being designed with sirolimus here?
Louise?
No, this is consistent -- these cases with our design of the trial. Experts had access to all three cases and took that into consideration. And so there's no change in our design, and it's consistent with potentially preventing what we've seen in these cases and preventing ALI generally. And this is based on experience of many across the field in terms of preventing the elevation of liver enzymes, and we have confidence that we'll do so.
Sorry, just the confusion is the death was seen at 11 weeks, not the course of the increase in liver enzymes that followed the same course as the other cases. And so I just want to make it clear because I think that that's where the misunderstanding is coming from that you're thinking that you're seeing this post that. We're saying the death occurred at 11 weeks.
And our next question comes from the line of Andrew Tsai with Jefferies.
Just to reconfirm, you mentioned FDA had the information for weeks. There's no change in the position. And just to reconfirm, it was before or after the FDA had agreed to a black box warning for ELEVIDYS in ambulatory DMD, just gauging the FDA's level of comfort with these stats.
Louise?
Yes. FDA was made aware of the case as a life-threatening case and then followed up with the notification of the death. So they have been aware of this throughout our conversations with -- about the label.
Our next question is going to come from the line of Louise Chen with Scotiabank.
I wanted to ask you, I know it's a different disease, but have you received any physician feedback on the headlines related to limb-girdle?
And then also, do you plan to just give a general safety update to all the physicians that are currently prescribing ELEVIDYS in regards to LGMD?
Again, this does not affect the new safety signal. We have already provided to physicians the fact that there is a rare but serious risk of elevated liver enzymes becoming a fatal ALF. We've seen it in two cases with ELEVIDYS. But more important than that, perhaps is the fact that we have chosen not to ship for the non-ambulatory patient until we get more clarity on the use of sirolimus and we get data on the use of sirolimus and we can evaluate that risk benefit in the context of the use of sirolimus.
And I'll just add in terms of communication on this case, as mentioned, we've communicated with FDA and that we have communicated with the physicians in these trials on this case, prioritizing communication with our physicians conducting these trials.
And our last question is going to come from the line of Gavin Clark-Gartner with Evercore ISI.
Yes. So Doug, you noted earlier that you would disclose a material change in the ambulatory ELEVIDYS safety profile to the investor community. I'm just curious how this materiality threshold is decided and who determines that?
Well, it's decided based on facts and circumstances, obviously, but we don't -- we are, I think, historically a very transparent organization. If there was a change in the risk profile of ELEVIDYS, we would first and foremost share with physicians and patients. And then, of course, we would share it with investors.
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