Good morning and welcome to Sarepta's conference call to discuss the safety update for Elevidys and steps to strengthen safety in non-ambulatory individuals with Duchenne. As a reminder, today's program is being recorded. At this time, I'll turn the call over to Doug Ingram, President and CEO. Please go ahead.
Thank you, Michelle. Let's move to slide three, please. Before I begin, I just want to remind you that we'll be making some forward-looking statements today. Please refer to our various public filings for the risks and uncertainties that come with making predictions about the future. Let's move to slide four. Thank you, everyone, for joining Sarepta's call today to update you on important steps we are taking to enhance the safety of Elevidys treatment for non-ambulatory individuals. It is with great sadness that I must report that a non-ambulatory patient dosed with Elevidys has passed away from acute liver failure. We have by now dosed over 900 patients with Elevidys across a broad range of ages and weights and ambulatory status and spanning over seven years of infusion experience.
While liver injury is a known risk with the use of any AAV-mediated gene therapy, historically, we have not had a signal that would lead our safety committee to conclude additional measures were necessary or appropriate. However, following this second tragic event, we have immediately taken steps with the goal of enhancing further the safety profile of Elevidys in the non-ambulatory patient population. You will hear shortly from our Head of R&D, Dr. Louise Rodino-Klapac, who will provide the preclinical results of a study conducted by Sarepta on the use of sirolimus. The data from these studies suggest that an immunosuppression regimen employing sirolimus could significantly mitigate the risk of elevated liver biomarkers and therefore ALF in connection with dosing of an AAV-mediated gene therapy. With that in mind, we have taken the following steps.
We immediately took the decision to pause our non-ambulatory study ENVISION or Study 303 while we seek a protocol amendment to add the prophylactic use of sirolimus in connection with future infusions. We have temporarily suspended commercial shipping of Elevidys for non-ambulatory patient infusions until such time as we have completed the following two activities. We have called an expert panel to share the data and align on the use of sirolimus and its protocol in connection with future infusions. Second, we have had an opportunity to take feedback from the FDA on the recommendation of additional immunosuppression as a prophylactic addition to the treatment protocol for Elevidys in the non-ambulatory patient population. Our goal is to complete both activities as rapidly as possible as we know that non-ambulatory patients are waiting for treatment and, as with all DMD patients, time is not on their side.
Let me now turn the call over to Dr. Louise Rodino-Klapac, who will provide more detail on the preclinical data that support our proposed enhanced immunosuppressive regimen and will explain how this data underpins our confidence that this approach can effectively mitigate the risk that we have observed. Louise.
Thanks, Doug. Our mission at Sarepta is to support those living with Duchenne. With over 900 individuals treated with Elevidys, patient safety is and always will be our absolute top priority. In light of today's heartbreaking news, we are acting swiftly and decisively. Our immediate actions, as Doug just outlined, are directly informed and supported by robust preclinical data, which I'll now outline for you. Next slide, please. Our current understanding is that the safety events we've observed are likely related to the AAV vector in the liver, which triggers a T-cell-mediated immune response. This response then causes inflammation, which in severe cases can lead to acute liver injury and, in very rare cases, acute liver failure. We believe sirolimus can mitigate this risk because it's a potent inhibitor of T-cells.
This mechanism of action is crucial as it helps suppress the activation of T-cells, thereby mitigating the immune-mediated liver inflammation that can lead to liver injury. Our proposed regimen, which includes sirolimus, is therefore designed to address the underlying immune response, which we believe may be responsible for these events. Next slide, please. Next slide. We performed a study in human primates to test the effect of sirolimus on antibody formation and immune response to AAV874 and transgenes. Animals were monitored for approximately 12 weeks. The significance of this study includes that the data highlights the effects of sirolimus on the immune system, specifically its ability to lower T-cells. As shown on the left of the slide, when AAV874 was administered along with mTOR, which is just sirolimus delivered via a lipid nanoparticle, we observed a clear suppression of the immune response to AAV.
The data on the right further confirms its effectiveness in suppressing the immune response to the transgene. Next slide, please. I'd like to turn your attention to this slide, which provides evidence of how sirolimus impacts liver health in our preclinical studies. Here we are tracking key liver biomarkers: ALT, AST, and bilirubin. Elevated levels of ALT and AST are common signals of liver cell stress or injury, while high bilirubin can indicate problems with liver function. The results demonstrate that across all of these vital measures, sirolimus effectively moderates or significantly reduces these liver enzyme elevations in non-human primates. Next slide, please. It's also important to evaluate how adding sirolimus for safety reasons might impact Elevidys expression. The data from these charts clearly demonstrate that expression is not negatively impacted by including sirolimus in the regimen.
The chart on the left shows strong protein expression in the heart and skeletal muscle measured via an ELISA assay. The chart on the right further illustrates robust expression in the heart, diaphragm, and skeletal muscle through immunofluorescence or IF. These findings collectively confirm that the addition of sirolimus maintains the desired expression across key tissues. Next slide, please. Next slide. To summarize, our preclinical data provides a critical foundation for these next steps. As data demonstrated that our proposed enhanced immunosuppressive regimen with the addition of sirolimus was effective at suppressing liver enzyme elevations. This finding gives a strong rationale for its potential to help mitigate liver-related safety events in patients and has informed the actions we have announced today. In summary, our commitment to patients and patient safety is unwavering. As we learn more, we will update the community and others thoroughly and with expediency.
I'll now turn the call back to Doug for any final remarks and Q&A. Doug?
Excuse me, Doug, you're on mute.
Apologies, everyone. I was on mute. Thank you, Louise. Let me reiterate that our goal is to implement this enhanced risk mitigation plan as rapidly as possible as we know that time is muscle for all patients living with Duchenne, and that certainly includes our non-ambulatory patients. Of course, we do not yet have visibility into the exact timeline to resume dosing in the non-ambulatory population, and we are going to need more time to assess its impact. Thus, we were required to suspend our revenue guidance. We plan to provide an update on guidance in our second quarter results call. As we look at 2025 performance, we will assess the impact on revenue, and then we are going to take a careful look at our cost structure to ensure that we remain financially disciplined. With that, Michelle, let's open the call to questions.
Thank you. If you'd like to ask a question, please press star one one. If your question has been answered and you'd like to remove yourself from the queue, please press star one one again. We ask that you please limit yourself to one question. Our first question comes from Brian Abrahams with RBC Capital Markets. Your line is open.
Hi there. Thank you so much for taking the question, and sorry to hear the news here. Is there anything more you can say about this particular case in terms of whether this was somebody who was receiving Elevidys in the commercial setting or in the ENVISION study? Anything you could say about dosing and weight? I know in the prior case, the management and mitigation measures were done to very high standards. Was this the same thing here where the monitoring—I guess maybe talk a little bit about what the course was like and how the patient was managed. Thanks.
Brian, thank you. I'll just make one comment before I turn this over to Louise, and that is that this patient was cared for at an absolutely stellar site by an absolutely stellar physician, and they received very good care. With that, Louise, perhaps you want to comment?
Sure. This particular patient was a non-ambulatory patient in our ENVISION study, so it was in a clinical trial setting. As Doug mentioned, received the best care possible. This was an individual that was 15 years old. There were similarities to the previous case that we have. We are not going to provide too many details on the exact case just for privacy reasons, but there were similarities in the first case, and there were some differences as well. This patient was well cared for. We are currently evaluating this case in the context of this case alone, and then in comparison to the previous case, we have not identified a single risk factor, but we are working expeditiously to identify anything that we can potentially point to. In the absence of that, we have obviously talked about our intention to include immunosuppression.
As I mentioned, sirolimus will limit liver enzyme elevations, which will then limit the ALI signal.
Thank you. Our next question comes from Tazeen Ahmad with Bank of America Securities. Your line is open.
Hey, guys. Good morning. This is Daniel Ong for Tazeen. Thanks for taking our question. I was just wondering if you could maybe help us understand what gives you confidence that this is not going to happen with younger patients and what's giving you confidence that you can maintain the same kind of immunosuppressive regimen for those patients and you only need to adopt it for the non-ambulatory ones. Thank you.
Louise, would you like to take this question?
What we could say right now is the safety signal was seen in non-ambulatory individuals. As you know, ambulatory status is really a surrogate for the severity of disease progression. We have only seen the signal in this non-ambulatory population. It is certainly something that we will evaluate as we go on and continue to evaluate in this population. We have not seen it in the ambulatory population, but it is certainly something that we will continue to evaluate, the immunosuppression in the non-ambulatory population, and certainly continue to look at it more broadly as well.
Thank you. Our next question comes from Ry Forseth with Guggenheim . Your line is open.
Good morning. Given the potential implications of the two deaths and what they may have on the overall Elevidys brand reputation, do you anticipate that younger ambulant patients will want to wait for next-gen gene therapy technology rather than dosing with Elevidys?
Look, I'm not going to speculate on the near-term impact of this announcement other than to note, to the best of my knowledge, there is no obvious next-gen gene therapy that's coming right around the corner. Please remember that this issue that we have now identified and seen a signal for relates to liver stress, which is a known risk of any AAV-mediated gene therapy. We're not aware of a single development stage non-AAV gene therapy that's currently in existence.
Thank you. Our next question comes from Gena Wang with Barclays. Your line is open.
Thank you for taking my questions, and I'm very sorry for this unfortunate event. My question is, I know you presented the preclinical data, but we do know that Regenxbio is also actually using sirolimus in their Prophy regimen. Will you be able to use some of the clinical data, the human data? I think FDA has all these data as well. Sorry. Bottom line, the question is, what kind of human data you need to run a study, and how many patients, what kind of data that will be sufficient for FDA to consider this regimen will be safe, and how long follow-up that you need to have in order for FDA to think this regimen will be safe?
I will turn this over to Louise to comment. Your points are a very good one, Gena, which is that there are other gene therapies that have employed the use of sirolimus because it's a—anyways, in the patient setting, I think, as you mentioned, there's one gene therapy from Regenxbio that uses a cocktail of immunosuppressive and other complement suppressive pretreatments. Of course, there's also a gene therapy for GAN that existed that used this as well. Given the amount of that data, one might consider that to some extent anecdotal, but it certainly provides additional conviction that the use of sirolimus could greatly mitigate the stress on the liver and elevated liver biomarkers and therefore greatly reduce the risk of ALF in these patients.
Our goal is to meet rapidly with the FDA to discuss this and to put this in place now, first as a protocol for our Study 303, our non-ambulatory study, as well as in the commercial setting. We have not yet had the opportunity to have those discussions with the FDA. We want to have them as rapidly as possible. We want to have an expert panel as absolutely rapidly as possible to nail that protocol and then to put it in place. One thing I will say is that the FDA has proactively asked us if we have considered the use of additional immunosuppression, and I believe, and Louise will correct me if I'm wrong, actually mentioned sirolimus itself.
Our hope is that we're going to have a very constructive discussion with the FDA about getting this in place right now to mitigate the risk in the non-ambulatory patient population. Louise, feel free to add anything or correct me if I've made a mistake.
You've covered most of it. The only other thing I'll add is, and as Doug mentioned, you mentioned a few, but there are several clinical programs that have used sirolimus, and it's been used pretty commonly in gene therapy. There are slightly different protocols, so one of the things that we'll be confirming with the expert panel that we meet with is the exact regimen. Sirolimus is not without any risk. There is some effect on the immune system, so we want to make sure that we're being thoughtful about the balance between suppressing the liver toxicity but also not making any of them susceptible to more infections than needed. The protocol typically will start shortly before dosing and then continue for several months, and we'll be confirming that exact regimen and the dosing with both the panel and then with the FDA.
Thank you. Our next question comes from Andrew Tsai with Jefferies. Your line is open.
Hey, good morning. Sorry about the tragic news. As we think about the outlook ahead, why should investors feel confident ALF will only be limited to the non-ambulatory population? Are you aware of any other patients being hospitalized for serious cases of liver injury right now? Thank you.
What we can say is that the signal for ALF is obviously exceptionally rare and has only emerged in the non-ambulatory patient population right now. To remind you, we have dosed well over 900 patients. We've been dosing for seven years. At the time of our first approval and our broader approval, we had no signal of this serious ALF concept. We had elevated liver enzymes, and a minority of patients, they responded very rapidly to modest increases in steroids. We're following the available objective evidence that we have right now. Obviously, as Louise mentioned, the ambulatory status is very likely a surrogate for disease progression.
Certainly, once we have developed this protocol and we're able to implement it with the non-ambulatory patient population, physicians can use their judgment to determine the circumstances in which they see it as a valuable additional prophylactic for other patients as well in their medical judgment. That is where we are right now. Is there anything I've missed in that, Louise?
No. Got it.
Thank you. Our next question comes from Mike Oles with Morgan Stanley. Your line is open.
Good morning. Thanks for taking the question, and sorry about the news as well. Maybe just a quick follow-up on one of the prior questions regarding dosing, and if you're willing to share, just curious if the second patient might have been on a higher dose versus the first patient. Thanks.
Louise?
No. No, the dose was the same between the patients. We dosed per kilogram. Yep.
Yeah. Just to add on to Louise's point, the dose is always the same for patients. It's weight-based dosing. The first patient was 70 kg. The second patient was 50 kg. So obviously, you've got a lower dose overall, but obviously, all the patients get the same dose based on their weight.
Thank you. Our next question comes from Louise Chen with Scotiabank. Your line is open.
Hi. This is Hannah Luan for Louise Chen. Thanks for taking our question. We wanted to ask, since your March safety update, it looks like you dosed an additional approximately 100 patients. What was the feedback like from those patients and their physicians, and why did they feel comfortable going ahead with treatment despite the known safety risk? Thanks.
I'm not going to comment on the number of patients we've dosed. Obviously, we'll update you on all of that in our second-quarter conference call. I will note that versus our second-quarter guidance, we were modestly tracking at the time before this event to exceeding that. I think that at least based on the discussions we've had with physicians and families regarding this therapy, folks understood the risk-benefit. They understood the potential value of Elevidys. The patients who, I would remind you, are suffering from a devastating degenerative disease that invariably results in death understood the risk profile and the number of patients that had been dosed and the signal. That's what we've heard so far.
Thank you. Our next question comes from Kostas Biliouris with BMO Capital Markets. Your line is open.
Good morning. This is Dale Allen for Costis Villores, thank you for taking our question and sorry for the tragic news. Our question is about the ratio between the ambulatory and the non-ambulatory commercial patients you have treated so far. Also, what is the expected contribution of the non-ambulatory patients to the latest 2025 guidance? Thank you.
Yeah. On the latter half, I'm obviously going to—I’m going to refrain from answering that question. We'll do more work, and then we'll talk to what our guidance—what impact this will have on our 2025 guidance, which we're suspending right now. We'll discuss that. Hopefully, at the second-quarter conference call, we'll have some update on that. I can just give you the broadest of strokes epidemiologically and otherwise with respect to ambulatory and non-ambulatory. Broadly speaking, if you look epidemiologically, it's 50% ambulatory, 50% non-ambulatory. If you look at the number of patients treated with Elevidys since our initial launch, it's more like 85% ambulatory, 15% non-ambulatory. If you looked at just narrowly this year, we were tracking to more like 70% ambulatory, 30% non-ambulatory. There was a greater percentage with the broader label, obviously, this year than before. Again, we will do the work.
We'll do all the analytics, both on the guidance and as well on our cost structure, and then we'll provide an update to everyone when we're able to do that. Hopefully, we'll have some update at the second-quarter conference call.
Thank you. Our next question comes from Ritu Baral with TD Cowen. Your line is open.
Hi. Good morning. This is Joshua Fleischmann on the line for Ritu. Thanks for taking our questions. Curious, what is the window of suspicion after Elevidys treatment for these severe adverse reactions to occur, and what % of the 140 dosed non-ambulatory patients are currently in this window of suspicion? You have indicated that the safety signal has only been identified in non-ambulatory patients, but we believe it has been seen in younger patients too. Should the enhanced regimen also be a discussion point for those younger patients? If so, why not? Thank you.
Yeah. We haven't seen a signal in ambulatory patients as we sit here today, but nonetheless, Joshua, to your point, I think once a protocol is in place for the use of sirolimus for the non-ambulatory patient population, I would imagine that physicians are going to reflect on that and then make some risk-based decisions about whether it makes sense in other cases, late ambulatory or other risk factors where they decide that the use of sirolimus might make sense even for ambulatory patients. With that, I'll turn the remainder of your question over to Dr. Louise Rodino-Klapac.
Yeah. The question was around the timing of when we might see these events. Typically, with any liver enzyme elevation, they typically occur within the first 90 days, as most of our AEs do. That is typically the window that we would be looking at as far as % of patients. I do not have a % to provide you as far as how many patients are currently in that window.
Thank you. Our next question comes from Brian Skorney with Baird. Your line is open.
Hey, good morning. I'm very sorry to hear about the tragic death of this young man. I know all our thoughts are with his family. I guess to push a little more on the question of liver safety differential between ambulatory and non-ambulatory, if you don't expect sirolimus use to impact expression, why not add it in the ambulatory setting as well? I understand acute liver failure has only been seen in non-ambulatory patients, but these are really small numbers. In the past, you had indicated that you had not seen any difference in LFTs based on HR weight, which would imply that potentially the acute liver failure risk is functionally the same. Why shouldn't risk mitigation be the same?
I'm just wondering, do you have any additional analysis for people who have been in ALT broken out by ambulatory and non-ambulatory, and can you provide that to us?
Brian, to your very good point, look, the ambulatory status is very likely a surrogate for disease progression. We are required to follow the evidence. Right now, the signal that we've seen is ALF in the non-ambulatory patient population. To your very point, once a protocol is in place, it will be available for physicians to consider the use of sirolimus in other patients, including ambulatory patients. We are going to be, with respect to the non-ambulatory patient population, more prescriptive, assuming that we get through this expert panel and the FDA confers in our view. That does not foreclose the ability to use sirolimus in connection with even ambulatory patients as the protocol is published. We would leave that to physicians, and we'll provide them with all of the evidence that we have available to us that can help guide those decisions.
Thank you. Our next question comes from Gil Blum with Needham & Company. Your line is open.
Good morning, and my condolences to the family here. Following up on something that was asked previously, I just want to clarify this point. What additional clinical development would be required to add sirolimus to your protocol? Thank you.
Our goal is to add it now and then to additionally have a protocol amendment for Study 303 or ENVISION to put it in place for ENVISION as well. Our goal is to implement it as a risk mitigation plan now. We have not had formal discussions or even informal live discussions with the FDA yet to take their input on that. I would note, however, that the FDA proactively asked us about whether we were considering the use of additional immunosuppression, including the use of sirolimus, to risk mitigate elevated liver enzymes and therefore signal of ALF.
While I can't say in advance how those discussions will proceed, we are hopeful, given that this is also on the mind of the FDA, that those discussions could be very constructive and that we could add this as a risk mitigation strategy right now for our non-ambulatory patients who are waiting. That is important to us because remember, for all Duchenne patients, as we often say, time is muscle. They lose muscle they cannot get back on a daily, weekly, monthly, and yearly basis. That is no less true. In fact, muscle is even in some regards more precious for these non-ambulatory patients who have already lost an enormous amount of muscle. We will have that dialogue with the FDA. Our goal is to have it as soon as reasonably possible, and then we'll provide updates on those discussions once they have concluded.
Thank you. Our next question comes from Jo Schwartz with Leerink Partners. Your line is open.
Thanks very much. Please accept our condolences as well. Given the PPMD meeting is later this week, it seems like it could be a very important venue to interact with parents, patients, and the community. Can you talk a little bit about your strategy heading into this meeting and how you plan to rebuild the trust of the community? What will be your main messages, and how do you plan to assuage concerns?
Yeah, we're still obviously, there is an opportunity at the PPMD conference this week to have discussions with the patient community and provide information to the patient community. We're looking at that and looking at other mechanisms to engage. Our number one strategy is to provide accurate and, to the fullest extent possible, complete information on the risk-benefit, both the risk and the efficacy benefits of Elevidys, first and foremost to treating physicians and then referring physicians so they are armed with good information, to have thoughtful discussions with the community, and of course, also to directly dialogue to the extent possible and compliant with the patient community itself to ensure that they have their questions answered as they are reflecting on these important treatment decisions. We are going to take the opportunity.
There'll be a number of individuals and representatives at PPMD to provide accurate and complete information to the extent we have it to PPMD folks that will be in attendance.
Thank you. Our next question comes from Salveen Richter with Goldman Sachs. Your line is open.
Thank you for taking my question. Maybe just stepping back here in the context of this news, what are your steps and just overall strategy here for the company holistically, thoughts about diversifying the pipeline as well as just the underlying base exon skipping business, just confidence in that kind of providing support here on the forward?
Let me start with the acute issues in front of us. Our first goal is to ensure that we do the right thing by patients now. While some might have seen our approach as a conservative one, we do not because we think it is the right answer for the patient community right now. That is why, even though this signal is still in the context of well over 900 patients dosed, a very rare one, we think we are doing the right thing, which is pausing dosing in 303, getting a protocol amendment to add a thoughtful protocol for the pretreatment with sirolimus. Given the data we have today, we have a lot of conviction that that is going to greatly reduce the risk, not only of ALF, but even of elevated liver biomarkers.
We then pause commercial shipments of Elevidys for the non-ambulatory patient population, as painful as that is, because there were non-ambulatory patients waiting for that therapy, but we need to do that for them. Pause it, and as rapidly as we can, get a risk mitigation strategy with sirolimus in place so that those patients can have the opportunity to consider the use of Elevidys in the context of this devastating and deadly disease that they are currently living with. The next thing we have to do, of course, acutely is look carefully at our guidance for the year. First, our revenue guidance for the year. What is the impact on this? Again, we are prioritizing the patients first. Then we will prioritize looking at the revenue guidance and figuring out what impact that has on our revenue for the year.
Of course, we're going to have to look at our cost structure to make sure that we remain financially disciplined in the context of this. Beyond that, we will drive forward the rest of our plans. We are a very mission-driven company. We have a lot of programs to hopefully bring a better life to patients across an array of other diseases, as you will know, in addition to our gene therapies. We have some limb-girdle programs that are moving forward right now. We have this siRNA platform, and we're driving that as well. That's a lot of unmet need inside of those programs. As you know, we have a DM1 and FSHD readout for proof of concept, proof of biology later this year. We have IPF. We have Huntington's disease.
We have BISCAS and a number of other things in addition to our gene therapy. We have a lot of really exciting platforms and pipeline programs that we're focusing on. Our focus right now today is first to ensure that we rapidly do the right thing for our patients, which required us to pause both the 303 and the shipments for non-ambulatory, get the risk mitigation in place, and then think about what that means from a revenue perspective and a cost structure perspective, get all that done. Our R&D colleagues will continue to drive those other platform programs and pipeline programs forward at the same time.
Thank you. Our next question comes from Yanan Zhu with Wells Fargo Securities. Your line is open.
Great. Thanks for taking our questions, and sorry to hear this news. Based on your dialogue with FDA, could there be any regulatory actions on the ambulatory patients or any indications of such actions? Also, any thoughts on why this signal only started emerging after you've treated 100-plus non-ambulatory patients? Any changes in manufacturing or any other factors that you could think of? It feels quite unusual to not have seen this in 100-plus patients now within three months, two patients. Thanks.
Okay. I can only speak to what we know now. First, with respect to the ambulatory patient population and the non-ambulatory patient population, I think that as painful as this is, and I think that I'm very proud of the team for having made what is, I think, a very swift and very appropriate but potentially conservative set of actions, including immediately pausing Study 303, pausing the commercial shipments for non-ambulatory, and working as rapidly as possible to put in place a protocol for the use of sirolimus to mitigate risk. I think with all that said, I think this is very appropriate, and I'm hoping the FDA will agree with us.
I think that there would be no obvious reason why someone would want to go further than what we're already doing, which I think is appropriate and definitely focused first and foremost on patient safety, patient well-being. On the fact that we haven't seen this before, first, I will note on manufacturing, my tech ops team has looked carefully at all of this. We've seen no signals that there's anything in manufacturing that would explain this. Very likely, this is the result of the fact that this signal is a very, very rare one. We have dosed, I said, 900. It's well over 900 patients by now. This has only emerged very recently. Even if you look just down at the non-ambulatory patient population, we've dosed just about 150 non-ambulatory patients. Obviously, even inside of the non-ambulatory patient population, it is a very rare signal.
It is no greater signal, I should note, than other full-body gene therapy infusions that are commercially available today. This may very well just be a reflection of the rarity of this. To your point, we have been dosing patients since January of 2018, and it was only in these last two cases that we have seen this sort of signal that has required us to take these actions that we are announcing today. Thank you for your question.
Thank you. Our next question comes from Anupam Rama with JPMorgan. Your line is open.
Hey, guys. Thanks for taking the question. So sorry about the news. Doug, I know you guys are still working through the guidance and the revenue trajectory here, but just wondering if you could comment on how you plan on managing the 2027 convert and repayment there. Thanks so much.
Sure. I'll have Yanan comment on that.
Sure. Thanks, Anupam. Yeah, managing our liabilities is something that we're always focused on. I think you know that 2027 notes become due in September, so we still have a little over two years to manage them. We have multiple pathways available to us to address it. Doug touched upon it, but in the context of the convert specifically, we're proactively managing our expenses, and we're going to prioritize our portfolio in a way only to focus on the programs that have the highest probability of success and can reach the greatest number of patients. The ambulant population alone supports profitability for us. If our EBITDA ratios, therefore, support access to our $600 million revolver, we remain in a very strong financial position, and we have multiple ways to address the convert.
Thank you. Our next question comes from Biren Amin with Piper Sandler. Your line is open.
Yeah. Thanks for taking my questions. Sorry to hear about this latest event. Have you considered lowering the weight-based dose or the max dose on the non-ambulatory side to reduce the risk of ALF?
The signal that we've seen doesn't look like it would relate specifically to the weight or the total. Half, we've dosed patients significantly heavier than the patients at issue as one example. With that, I'll turn it over to Louise who can provide more color on that.
Yeah. I mean, you basically covered it. We've seen no correlation with total dose in terms of the ALI signal, which is prior to progressing to ALF. We haven't seen any correlation with the total dose. We would not change the dose at this point based on that.
Thank you. Our next question comes from David Hoang with Deutsche Bank. Your line is open.
Hi. Thanks for the update and taking my questions. I wanted to ask, I know there was a plan to, I think, dose patients under the age of four and maybe have a discussion with the FDA on that topic. What is the status of the plan to treat those younger, age two to four? Would you consider risk mitigation with sirolimus for your LGMD gene therapy programs? Thank you.
Comment. Yeah. I'll handle the under four question. Real quick, we are going to have discussions with the FDA on the patients under four. We haven't had it yet, so I guess to answer that question. It is upcoming. When we have more information, it might be more than one meeting. We'll provide an update on that. I will note we're very excited about the potential opportunity to be able to bring this therapy to kids under four. The data that supports it, the expression data that we saw was absolutely fabulous. With that said, we'll continue working on that. When we have an update on that, we'll provide it. With respect to sirolimus and its use in connection with the LGMD population, I will leave that to Dr. Louise Rodino-Klapac.
Yeah. For LGMD, I think it's important to remind that the disease progression is different and unique in LGMD as compared to DMD. We have not seen a signal of ALF in this population. We have seen elevated liver enzymes. Another difference is that there is an overall lower dose in the limb-girdle programs versus DMD as well. With all that said, it's certainly something that we will consider as we implement the immunosuppression with sirolimus in the DMD population. We will consider it for limb-girdle, but it would be a data-driven decision if we decide to go there.
Thank you. Our next question comes from Oiir with Mizuho. Your line is open.
Hey, guys. I'm also sorry to hear about the tragic event. Doug, you mentioned a couple of times that the FDA has asked you to perhaps consider additional immunosuppression regimens. Could you maybe just help us understand when was this, how long ago? Also, are there any either examples outside or within, I guess, gene therapy where you present maybe sort of preclinical data and the FDA allows for a change in, I guess, administration protocol of some sort? Just wanted to get a sense of what could be the hurdle in terms of getting the protocol agreed by the FDA. Thanks.
Yeah. The answer to your first question is very, very recently. They were asked about it. I mean, second of all, just the actual attitude of the FDA and the view of the FDA on these risk mitigation strategies will be known with certainty once we've had live discussions with the FDA, and we'll provide that update once we've done it, as I've said before. Our goal is to rapidly both have an expert panel to provide a protocol. Again, this has been done practically in connection with other gene therapies. While there are some nuances to what that exact protocol ought to look like, and we'll take some advice on that, generally speaking, there's a good path forward to know exactly how one would put a protocol like this in place and do so very rapidly.
The second thing is we need to have that dialogue with the FDA and take their views. Then we can have a better view on how fast we can bring this to the non-ambulatory patient population, which, as I've told you, are waiting for this therapy. We will do that as rapidly as we can.
Thank you. Our next question comes from Eliana Merle with UBS. Your line is open.
Hi. This is Tate Hassan for Ali. Thanks for taking our question and our condolences for this tragic event. I know there's been a lot of discussion about weight. Can you just remind us of the weight range in ambulatory patients versus non-ambulatory patients? And maybe what percentage of patients are getting that max dose in ambulatory versus non-ambulatory? Thanks.
Luis, do you have that data available to you?
I don't have the data. The average weight, I'd say for ambulatory, 35 kg, I think no one's hitting max dose in the ambulatory status. It would be a non-ambulatory where we're hitting the weight cap of the 70 kg. Now you could correct me or Doug, but based on that, there's no weight cap in the ambulatory population because those are all under the max dose.
Thank you. Our next question comes from Mitchell Kapoor with HC Wainwright & Company. Your line is open.
Good morning. This is Danon from Mitchell. Thanks for taking our questions and our condolences for the situation as well. We were curious, what percent of non-ambulatory patients have you seen signs in ALF versus what percent typically experience elevated liver enzymes? This is specifically non-ambulatory patients. Thank you.
We have not seen an elevated liver enzymes, I think it's about the same across all patients. So I don't know, Louise, do you have any more information than I've just provided?
No. It's about 30% of patients have elevated liver enzymes across the board.
Thank you. Our next question comes from Sami Corwin with William Blair. Your line is open.
Hey, this is Caleb Wong for Sami. Thanks for taking our question. Thanks for the update. From the preclinical data, we sort of had a question on the liver enzymes. I think you guys are showing that those nine levels were elevated between days 20 and 50. We were sort of wondering how good these NHP models are for evaluating ALF in humans, which happens a little bit more rapidly. Thanks.
Luis?
The non-ambulatory model is relatively good in terms of the timing and duration. ALF follows an ALI signal, so it's not any quicker than you would see ALI. I think that was the question.
Thank you. There are no further questions at this time. I'd like to turn the call back over to Doug Ingram for closing remarks.
Thank you very much, Michelle. Thank you all for your questions today as we announced this very difficult, but I believe appropriate set of actions to address this issue. I will reiterate again, our goal is to move as rapidly as possible to implement a risk mitigation strategy, which would allow us both to safely commence study 303 and continue to provide what I believe to be a life-enhancing therapy to boys and young men who have Duchenne muscular dystrophy in the United States. We will continue to work on this. As we have updates that are material and appropriate, we'll provide updates to the investment community as we also provide it, more importantly, to our physician and patient community. Thank you all very much.
Thank you for your participation. This does conclude the program, and you may now disconnect. Everyone, have a great day.