ROCKET PHARMACEUTICALS, INC. — Call Transcript 2025

... All right, I think we're ready to get started. Welcome, everyone. I'm Josh Schimmer from the Cantor Biotech Equity Research Team, and very pleased to introduce from Rocket Pharmaceuticals, Gaurav Shah, Chief Executive Officer. Gaurav, great to see you again, as always, and a very recent, very positive update on the Danon Disease program. So give us a quick snapshot of where Rocket is in advancing your gene therapy portfolio, and we'll dive right into Danon after that. Thanks for having us here, Josh. Great to see you and see everyone. And yeah, the Danon hold lift was a big step. I think it showed us both that, the program has value, it's a high unmet need, patients are waiting, and that the FDA is listening and collaborating. We had a lift in record time of less than three months, which we're very happy about, for reasons that made a lot of sense to us and the FDA, and so we're gonna move that program forward. Rocket is a gene therapy company, obviously, and our premise is to go after diseases with truly high unmet need, mostly pediatric in nature, although we're not limited to pediatrics, that are rare and devastating and often fatal. And I think the asset selection itself is half the battle in gene therapy. I think gene therapy is really meant for these sorts of diseases and cannot be seen as a nice-to-have. Secondly, we're trying to find diseases where we can either be first or only in class in some cases. And thirdly, we're looking for diseases that have an increased prevalence so that it makes a business justification long-term. With that in mind, we have started the company, as you know, from a lenti perspective. We started with Fanconi anemia, LAD, and pyruvate kinase deficiency, PKD, and we pivoted to the cardiac portfolio increasingly over time because the cardiac portfolio meets all three of those aspects, right? So I am a big fan of lentiviral-based ex vivo gene therapy. When gene therapy works, it works, and you see that with LAD, FA, and PKD. With the constraint in resources and the need to prioritize and focus, we are definitely shifting our focus to the AAV cardiac portfolio as we move forward, but we will continue getting Kresladi through approval pathway. We're gonna pause a lot of the Fanconi spend. We'll continue to keep it open as either something we pursue in the future or partner soon, and PKD we put on pause for some time, but that's also a partner-worthy opportunity. The three cardiac programs represent three buckets of cardiomyopathy that are of great importance. One is arrhythmogenic, like PKP2, another is hypertrophic, like Danon, and the third is dilated, like BAG3. If you add these three programs together, they represent more than a hundred thousand patients in the U.S. and Europe, so while each disease is rare, rare disease as a whole is not rare. Okay. All right, so maybe then focusing first on the Danon program. You came off clinical hold fairly quickly after the capillary leak syndromes that occurred with the addition of the C3 inhibitor. Have you been able to kind of further establish why that added C3 inhibition component kind of triggered those complications? And I guess, like, you were clearly able to convince the FDA that that was the likely culprit to come off of clinical hold, I'm guessing. So what C3 inhibition did do well is that it prevented TMA for the first week. We saw no complement activation. But based on the lab evaluations that we did, as well as studying this patient carefully, who unfortunately passed away, and a second one who had capillary leak, but has recovered and is doing much better now. Based on the lab data there, it appears that after about a week, there is a paradoxical effect that's not TMA, but it's endothelial damage directly, likely through unencumbered AAV vector. So while C3 itself opsonizes and sequesters AAV, once you have a C3 inhibitor, it takes that pathway away and allows AAV to directly damage endothelial cells, unfortunately, and that's what we saw. The only two patients that we know of in the history of gene therapy who had capillary leak were these two particular patients. So the correlation there is clear. Now, C3, of course, the C3 inhibition, it's a great drug. It works in multiple diseases with high unmet need. I think combining it with the torrential downpour of AAV was just the wrong path to go down. Mm. What we were solving for with C3 was an increased risk of TMA that we saw early in the phase two. We saw two out of four cases of TMA early in the phase two trial. The first one, we think was likely due to an additional gene that was mutated, that's next to the Danon Disease gene, next to LAMP2, and that gene conferred an increased risk of complement activation. We think the first of those two patients was likely because of that extra gene that we've now ruled out moving forward for patients moving forward. We had another TMA in a boy who did not get a very high dose, and the thought was that in Danon Disease, the higher full empties actually portend higher potency, and therefore a higher risk of complement activation. So in the revised trial, what we've done now is we've corrected or recalibrated the dose to rectify or account for that increased full empty ratio by about 40%. That's why you see the new number that is around 4E13. On top of that, there were two patients in the pediatric trial, 108 and 109, who got an effective dose around 4E13 anyway, and if you look carefully, they were the earliest responders and the most profound responders in terms of LV mass index. So putting all this together, one and two, both on full empty correction as well as the pediatric experience, it's likely that the right dose for Danon is within the dose range of phase one, but it's closer to the 4E13. We aligned with FDA on that. But just taking a step back, we saw higher TMA. We tried to correct for it with the C3 inhibitor. That was the wrong path, so what we should have done right from the beginning and then what we are doing now, and we feel very good about, is reducing or recalibrating that dose, removing C3, but also having a lower threshold for C5 inhibition based on the trajectory and kinetics of both platelets and SC5b-9. So, essentially you're saying that the move from four E thirteen to three point eight E. Well, hold on. Getting my numbers a little confused here, but. It would have been- Let's go ... around six to four, around six point seven to four. About a forty- Six point seven to four. Yeah. Okay, so it's like, it's kind of a modest decline. Yeah. Right. What gives you the comfort, though, that that modest decline is sufficient to now in collaboration with a heightened TMA monitoring regimen to get patients through? Right. So the phase one patients who were dosed at six point seven E thirteen, the phase two equivalent dose, based on this recalibration, would've been around four E thirteen. Right? So the whole phase one trial using the... If we had the phase two product, those patients would've been dosed at four E thirteen. So that's what gives us the confidence, because they had a pretty clean safety profile, and remarkable efficacy across every parameter, as we know from the NEJM paper. Okay, and then the TMA monitoring, well, prophylaxis and monitoring protocol. Maybe just give us a sense where it is now and where it's coming from. How has it evolved? I would say the bottom line is that we're going back to the phase one approach. A combination of rituximab, sirolimus, and steroids with a rapid taper. The two minor differences are that the eculizumab, like I said, is gonna be administered with a lower threshold, based on all what we've learned from the trajectory of platelets and other complement factors, right, so we have a better sense of how to see or foresee complement activation very early after a patient gets treated, even on the second day, and the other minor change is that we have, instead of having rituximab administered over two doses, we have it over three doses, and that, based on literature and based on our, in our own hands, leads to a more profound B-cell depletion, which is gonna be beneficial for the complement pathway. When is the Rituxan dose relative to the AAV? So it used to be a week, you know, within the two weeks prior, and now we have three weeks prior. That's the big difference. So, and the- Dosed over three weeks. Dosed over three weeks. Okay. And then to what extent does... You know, if you do start to see complement activation to trigger eculizumab, to what extent does that kind of shut off the complement activation and keep patients protected? If done early, it can be effective. You have to get ahead of the cascade and know exactly what to look for. Others have asked if prophylaxis is the right thing, but given our experience in C3, the complement pathway is tricky. Sometimes you shut down one pathway, and another one pops up. That's what we saw. So given that in phase one, we didn't have to use it for the six patients where we have long-term efficacy, we didn't see clinical complement activation there at all, we would rather do it this way, rather than be married to a particular inhibitor over time and risk additional safety events. What is TMA? How does it present? What do the patients have to get through and deal with? Yeah, it's thrombotic microangiopathy. Essentially, complement activation leads to platelet deposition in kidney and other areas, leading to kidney damage, potentially other organ damage as well. And most patients, even in our lives and, you know, for normal people, when you have high viral activation, even with other viruses like COVID-19, you can get complement activation, and there's a point at which the complement becomes a cascade that you can't stop. Even regular infections will cause an increase in SC5b-9 and a drop in platelets, right? We see that all the time in viral infections in the hospital outside of gene therapy. But with E-15, E-16 level of viral exposure, total viral exposure, you can understand how this can get out of hand. So, spotting early the platelet declines, the complement factor changes, is essential to intervene at the right time, I would say. Okay, got it. Do you have a sense of what % of patients need eculizumab with the new protocol? We didn't need it for any of the six patients that were followed long term. We did use it for one patient in phase one, and I'm talking about phase one. One patient in phase one who got a very high total viral dose, patient 1007, who then went on to transplant, so we don't have long-term follow-up. That patient got a dose of Eculizumab. It was safely tolerated, but otherwise, for the other six, we didn't need it at all. The hope here is that we need it minimally once this product is approved. I don't think we'll ever get to zero risk of TMA in AAV nine. You see it with other AAV nine programs. It's a known risk. It's something that's even part of the label, but we'll mitigate it, we'll minimize it. And what happened in the phase two, what we tried to do is that we tried to make a good product perfect. But given the devastating nature of this disease, a good product is actually great. Now, patients don't come in saying, "My platelets are low." So when they have TMA, what do they experience in that as they're kind of making their way through this? Yeah ... cascade, what needs to be treated? So this is a lab diagnosis largely. Patients can be asymptomatic until they have kidney damage and start having lower urine output. Until then, you're not gonna notice platelet drops, you're not gonna notice complement activation. Patients often feel normal until they're further along. So these patients need to be monitored locally in the hospital for the first two weeks. The patients, however, I'll give you an example, who got that 4E13 dose, 108 and 109, went home around day 10 or 11. Their profile was much more squeaky clean, and also had efficacy that was at or better than the levels we saw for the other patients, which, again, gave us confidence that going back to around that dose would be the right next move for us. Is this permanent loss of renal function, or it's transient? All the patients who have had TMA in our trials have recovered renal function, and potentially may be benefiting from the gene therapy for their heart, too. We don't have the final endpoints now, but the patients are doing well and back to normal. I mean, 'cause, like, in that what may be one of the worst-case scenarios of temporary dialysis, for a patient whose prognosis is otherwise heart transplant and a life of living with a heart transplant, that's not even necessarily a difficult trade-off or risk-benefit to have to work through. I totally agree. One of our patients who had TMA in Germany and was on dialysis for a couple of months, even during that period, their family had said: "You know, we would rather actually prefer a kidney transplant over a heart transplant," because in Germany, heart transplants are so difficult to find, and the mortality is about 50%, right? And that doesn't say that that is a justifiable long-term side effect, but having transient renal failure and then coming back to normal, these kidneys recover naturally. We might see it in some patients. We want to minimize it, mitigate it, make it as near zero as we can, but the benefit-risk, because the disease is so devastating, is still gonna be positive. You'd mentioned that one TMA patient who had a mutation in a complement gene, the risk complement. How common are those, and to what extent have you started to screen for potentially other mutations that could put patients at risk? So that particular mutation is exceedingly rare. It's called CUL4B, but it's now part of a 14-gene panel that we test for. And these 14 genes are thought to be complement-potentiating genes, so we screen them out, and so far, other than that patient, in all the patients that we've screened for phase two, we have not found anybody. Okay. How are the physician and patient communities kind of responding to some of the, these updates and their own interest in potentially being clinical trial candidates? So first of all, when this event happened, with the patient who got the C3 inhibitor, who passed away, it was devastating for us. It was devastating for our team, but mostly it was devastating for, of course, the patient's family and the community. A week after the event, we had a call together with the patient community, and at that point, the general sentiment was that, again, because this is an otherwise fatal disease, that there was an acceptance of even that one patient death without stopping enthusiasm for the trial. No one has dropped out of the trial. All the investigators who have been involved are leaning into when is the trial gonna start up. Very happy about the FDA lifting the clinical hold. This is why, I might have said this before, gene therapy works for devastating rare diseases, but it's not a nice-to-have, right? It. When you really have a disease like Danon, where only DNA replacement is gonna work, there's actually no other approach. You can't. There's no protein, there's no factor that you can give to these patients. The patients and families have been generously supportive. So, the number of identified patients has been obviously a topic of conversation for investors. Speed of enrollment has been an important conversation topic for investors. I think in the most recent press release kind of now gave us an indication, two ped run-ins and a total of six patients treated. I think that's a little less than maybe many of us were thinking. Yeah ... relative to the burden of illness, the unmet need, right? The number of identified patients out there. So maybe talk a little bit about enrollment, logistical challenges, how you've navigated them, and what gives you the, you know, the confidence that there are a number of patients out there still to treat, despite some of the- Yeah, enrollment challenges you might have been having. Going back to the start of the phase two, we had to start with two pediatric patients and then wait a certain number of months. It ended up being about four to six months to get through FDA, IDMC, and site start-up for the full trial, right? It was two pediatrics and then plus ten. Once we got past those two pediatrics, we enrolled the next ten patients in two months and three days, right? The consent and the enrollment happened really rapidly, and with our funnel, we had additional patients that were waiting. ... and then the trial started. That was, I believe, last year, between June and July, that we got the enrollment done. The patients started being treated in August and September, but then that next patient had a TMA event, or the second, the fourth patient, right? So one, two, three, four. The fourth patient had a TMA event, and that paused the trial for another six months while we got the C3 inhibitor on board. And then we started the C3 inhibitor, and then the first two patients had a TMA. But when we mapped out the infusion times this year to finish the trial, it would have been between May and the end of June, right? So really what stopped us is these unfortunate side effects. And if we can get past, I'm feeling good that we can, given everything that we talked about, the next three patients from safety viewpoint, we think we can replicate that same infusion timing over the coming months after that. So how should we be thinking in terms of months to kind of work through this now? It's very helpful to kind of frame the four to six months after the first two patients- Right ... who enrolled. Again, just so we have our expectations appropriately aligned, timelines for kind of the next phase of the pivotal program. So given that for the new patients that will be treated, we still need a three-month troponin run-in. We just got off the hold. We got to go through IDMC, we have to go through IRBs, and get the drug product release, et cetera. We anticipate those three patients being treated in early 2026, and then agreeing with FDA as to what the rest of the trial should look like, which I can talk about in a second. And then once we have those patient identified, the infusions can be lined up without being staggered, so it should be relatively rapid. We can't guide on the exact timing until we talk to the FDA. I think the best-case scenario is that we replace the two C3 inhibitor-treated patients, and therefore we have a total of fourteen, so twelve plus two. We have patients who are already, so it's not a question of finding these patients, it's just getting through them through the vaccinations and the troponin run-ins, which we're going to try to do in parallel between now and when the three patients are treated. And the three run-in patients, are those going to be sequential? So when you say treat in early twenty twenty-six, that's you've worked through all three of them, including- They're a month apart. Okay. And then for the rest of the program, I guess you have to kind of discuss with the FDA the revised protocol, but what are you thinking in terms of kind of where you initially started with around ten or so patients to or ten to twelve patients to where you're likely to wind up now? So the FDA has not asked us to enroll more than 12 patients, right? There's no clear directive for that at all. I think that the right way to really evaluate efficacy is with a somewhat consistent immunomodulation regimen and have at least 12 patients treated with that regimen. So far, we've treated four, so that would leave eight more slots. It could be, though, that with the dose recalibration, the FDA wants us to treat a couple of additional patients. So we have enough patients that we have eyes on to fulfill those needs, and we have enough drug product, but it's just a question of getting that clarified as soon as possible. In terms of the efforts to go identify patients who could benefit from therapy, where are you in that process? So we have both a top-down analysis, and we're going to provide an update on the top-down model in... before the end of the year, actually. And then we have a bottom-up analysis, which is sort of reported patients and looking at actual cases and also looking at claims, right? So, that is likely going to be part of the program update. That's going to be, at this point, some point next year once we get through the first three patients and have clarity on both what the final trial looks like and also how many patients need to be positive to have a positive trial outcome. I'll also mention with the FDA that in our correspondence, not only have they not asked us to treat more patients, but there's been no question on the trial design or the endpoints themselves. So we're moving forward with the assumption that we're in the midst of this pivotal trial, and getting this to a positive read is going to lead to a potential approval. Got it. Are there lessons from the Danon program that you've been applying to the PKP2 program, and if so, what? So most of the Danon lessons were around TMA and C3, plus AAV-related capillary leaks, so neither of those really applied to rh74. With rh74 at higher doses, we've seen liver toxicities. Compared with those doses, we're about half of the viral exposure per kilogram, so hopefully, we don't hit those. We're also applying very stringent criteria as to patient selection. Anyone with any sort of remote liver disease is either excluded or goes through a rigorous hepatology consult to make sure that they're safe. We rule out CMV, so we're learning from other programs to apply more to rh74. I think the Danon learnings are just that protein expression matters. There's many ways to measure protein. Western blot is not always the most effective. In PKP2, we've now figured out how to use immunofluorescence to localize the PKP2 protein to the desmosome, and that's probably a more meaningful outcome than just total Western blot. That's one lesson that we've extrapolated a little bit from Danon. And the other lesson is that Danon, and this is almost a contrarian lesson from Danon, Danon was, in some ways, easy endpoint-wise. It's a disease of big hearts. They grow rapidly. You shrink them rapidly. You can have a big delta between treated and untreated. In PKP2, it's more slowly progressive. There's multiple parameters that are affected, like arrhythmias, and RV function, and how a patient functions and feels. The fingerprint of a composite endpoint for that is something that's more of a discussion and negotiation with the FDA, where we've started that dialogue, and we hope to have some resolution as soon as we can. Are there any similar empty-full capsid ratios for the AAVrh74 program and PKP2s that are in Danon? Like, how do you think about adjusting for that? We started the PKP2 program already with an enhanced full empty profile, similar to Danon. So, while we continuously improve the product, there's not that much room to go. So, the phase two material should be pretty similar to the phase one. How does your empty-to-full ratio, maybe compare to Elevidys or other AAV rh74 programs? Do you know? I think we're in a pretty good place. I will say in Danon, more is not necessarily better, for the reasons that we outlined. We think that an enriched product with higher full-empty could trigger a TLR9-associated complement activation, and therefore earlier TMA than you would see with a lower full-empty ratio. So I think for Danon, we're right where we need to be with the new product. It's gonna lead to better availability of drug product, lower COGS, et cetera. We're gonna have a really good margin. I think for PKP2, we're in a very similar place, but I think being 90%, 95%, 99% is not necessarily always a good thing. Okay. What's the prophylaxis regimen you're using in the PKP2 program? How does that compare? It's basically exactly the same as what we've done with the renewed Danon program. Rituximab spaced out a little bit more, sirolimus, steroids, and a lower threshold for eculizumab. Maybe you can give us an overview of what you've started to see in the phase one-two program, and what we should be expecting from that program in the months ahead? The phase two program. I would say the next time that you'll hear from us about PKP2 is when we achieve alignment with the FDA on the phase two pivotal trial design. Those discussions are early. They're gonna take a little bit of time. We're still developing and reading out some of our natural history efforts to get there. I will say, though, that a single-arm 12-patient trial, like we got alignment on Fanconi with FDA on Danon, may have been a one-off. We know the drug works, although we've only treated three patients. These patients all had improvements in efficacy parameters, and they all feel much better than they did. They're functioning better. Some of them are actually exercising, and they've never actually exercised for years. So we know we have a product that works. The next step is to get to a trial that works, a pivotal trial that works. So it's not always about the smallest trial you can get away with. It's about the right trial design that leads to a positive outcome. And actually, the FDA has been quite collaborative in their dialogue with us, trying to make us think carefully about how to get a positive trial rather than one that just makes us look good. Maybe we can maybe talk a little bit about the milestones then from these programs and kind of the visibility you'll give us into enrollment updates, data updates, either, you know, or across Danon and PKP2 and even BAG3. Danon, I would say the next couple of milestones are when patients are treated safely, and then we have that itself, three patients treated safely, then the alignment on the rest of the trial, and along with that, a program update, how many patients are needed for positive trial and also epidemiology update, right? Those are catalysts for Danon. For PKP2, the big one is FDA alignment and endpoints, and then actually starting the phase two. In BAG3, we're gonna start the phase one. That'll likely be next year as well. I will just put in for BAG3 that it's likely as large or bigger than PKP2 in terms of trial size, patient size, patient population. Also the endpoint there, it's a dilated cardiomyopathy. These patients have dilated hearts, loss of ejection fraction, so the obvious endpoint there is EF. It's an accepted endpoint in other cardiac diseases, and if we can get to that agreement with FDA, that would be a win. Obviously, that would not be until the end of the phase one. But with these three programs together, again, it's a hundred thousand patients, and we have at least two others that are being developed and are undisclosed. For the BAG3 program, what's the capsid, what's the dose, and what's the route of delivery? It's Rh74. It's IV. We did inherit this program from Renovacor, which was an AAV9 localized approach. So we used some of the mouse model data, but we redid a lot of the IND enabling work. And I think we feel, based on our experience already with PKP2 and Danon, that this is the right approach. You said kind of the one of the next updates on PKP2 is FDA alignment. You said it's gonna take some time. Any general frameworks? Is that likely to be a 2026 update or to be determined? I would just say at this point TBD, but as soon as possible. All right. Excellent. Gaurav, thanks so much for joining. Thanks everyone for coming out. Thank you.

Speaker 2: ... All right, I think we're ready to get started. Welcome, everyone. I'm Josh Schimmer from the Cantor Biotech Equity Research Team, and very pleased to introduce from Rocket Pharmaceuticals, Gaurav Shah, Chief Executive Officer. Gaurav, great to see you again, as always, and a very recent, very positive update on the Danon Disease program. So give us a quick snapshot of where Rocket is in advancing your gene therapy portfolio, and we'll dive right into Danon after that. ... all All right, I think we're ready to get started. all right i think we're ready to get started Welcome, everyone. welcome everyone I'm Josh Schimmer from the Cantor Biotech Equity Research Team, and very pleased to introduce from Rocket Pharmaceuticals, Gaurav Shah, Chief Executive Officer. i'm josh schimmer from the cantor biotech equity research team and very pleased to introduce from rocket pharmaceuticals gaurav shah chief executive officer Gaurav, great to see you again, as always, and a very recent, very positive update on the Danon Disease program. gaurav great to see you again as always and a very recent very positive update on the danon disease program So give us a quick snapshot of where Rocket is in advancing your gene therapy portfolio, and we'll dive right into Danon after that. so give us a quick snapshot of where rocket is in advancing your gene therapy portfolio and we'll dive right into danon after that

Speaker 1: Thanks for having us here, Josh. Great to see you and see everyone. And yeah, the Danon hold lift was a big step. I think it showed us both that, the program has value, it's a high unmet need, patients are waiting, and that the FDA is listening and collaborating. We had a lift in record time of less than three months, which we're very happy about, for reasons that made a lot of sense to us and the FDA, and so we're gonna move that program forward. Rocket is a gene therapy company, obviously, and our premise is to go after diseases with truly high unmet need, mostly pediatric in nature, although we're not limited to pediatrics, that are rare and devastating and often fatal. And I think the asset selection itself is half the battle in gene therapy. Thanks for having us here, Josh. thanks for having us here josh Great to see you and see everyone. great to see you and see everyone And yeah, the Danon hold lift was a big step. and yeah the danon hold lift was a big step I think it showed us both that, the program has value, it's a high unmet need, patients are waiting, and that the FDA is listening and collaborating. i think it showed us both that the program has value it's a high unmet need patients are waiting and that the fda is listening and collaborating We had a lift in record time of less than three months, which we're very happy about, for reasons that made a lot of sense to us and the FDA, and so we're gonna move that program forward. we had a lift in record time of less than three months which we're very happy about for reasons that made a lot of sense to us and the fda and so we're gonna move that program forward Rocket is a gene therapy company, obviously, and our premise is to go after diseases with truly high unmet need, mostly pediatric in nature, although we're not limited to pediatrics, that are rare and devastating and often fatal. rocket is a gene therapy company obviously and our premise is to go after diseases with truly high unmet need mostly pediatric in nature although we're not limited to pediatrics that are rare and devastating and often fatal And I think the asset selection itself is half the battle in gene therapy. and i think the asset selection itself is half the battle in gene therapy I think gene therapy is really meant for these sorts of diseases and cannot be seen as a nice-to-have. Secondly, we're trying to find diseases where we can either be first or only in class in some cases. And thirdly, we're looking for diseases that have an increased prevalence so that it makes a business justification long-term. With that in mind, we have started the company, as you know, from a lenti perspective. We started with Fanconi anemia, LAD, and pyruvate kinase deficiency, PKD, and we pivoted to the cardiac portfolio increasingly over time because the cardiac portfolio meets all three of those aspects, right? So I am a big fan of lentiviral-based ex vivo gene therapy. When gene therapy works, it works, and you see that with LAD, FA, and PKD. I think gene therapy is really meant for these sorts of diseases and cannot be seen as a nice-to-have. i think gene therapy is really meant for these sorts of diseases and cannot be seen as a nice-to-have Secondly, we're trying to find diseases where we can either be first or only in class in some cases. secondly we're trying to find diseases where we can either be first or only in class in some cases And thirdly, we're looking for diseases that have an increased prevalence so that it makes a business justification long-term. and thirdly we're looking for diseases that have an increased prevalence so that it makes a business justification long-term With that in mind, we have started the company, as you know, from a lenti perspective. with that in mind we have started the company as you know from a lenti perspective We started with Fanconi anemia, LAD, and pyruvate kinase deficiency, PKD, and we pivoted to the cardiac portfolio increasingly over time because the cardiac portfolio meets all three of those aspects, right? we started with fanconi anemia lad and pyruvate kinase deficiency pkd and we pivoted to the cardiac portfolio increasingly over time because the cardiac portfolio meets all three of those aspects right So I am a big fan of lentiviral-based ex vivo gene therapy. so i am a big fan of lentiviral-based ex vivo gene therapy When gene therapy works, it works, and you see that with LAD, FA, and PKD. when gene therapy works it works and you see that with lad fa and pkd With the constraint in resources and the need to prioritize and focus, we are definitely shifting our focus to the AAV cardiac portfolio as we move forward, but we will continue getting Kresladi through approval pathway. We're gonna pause a lot of the Fanconi spend. We'll continue to keep it open as either something we pursue in the future or partner soon, and PKD we put on pause for some time, but that's also a partner-worthy opportunity. The three cardiac programs represent three buckets of cardiomyopathy that are of great importance. One is arrhythmogenic, like PKP2, another is hypertrophic, like Danon, and the third is dilated, like BAG3. If you add these three programs together, they represent more than a hundred thousand patients in the U.S. and Europe, so while each disease is rare, rare disease as a whole is not rare. With the constraint in resources and the need to prioritize and focus, we are definitely shifting our focus to the AAV cardiac portfolio as we move forward, but we will continue getting Kresladi through approval pathway. with the constraint in resources and the need to prioritize and focus we are definitely shifting our focus to the aav cardiac portfolio as we move forward but we will continue getting kresladi through approval pathway We're gonna pause a lot of the Fanconi spend. we're gonna pause a lot of the fanconi spend We'll continue to keep it open as either something we pursue in the future or partner soon, and PKD we put on pause for some time, but that's also a partner-worthy opportunity. we'll continue to keep it open as either something we pursue in the future or partner soon and pkd we put on pause for some time but that's also a partner-worthy opportunity The three cardiac programs represent three buckets of cardiomyopathy that are of great importance. the three cardiac programs represent three buckets of cardiomyopathy that are of great importance One is arrhythmogenic, like PKP2, another is hypertrophic, like Danon, and the third is dilated, like BAG3. one is arrhythmogenic like pkp2 another is hypertrophic like danon and the third is dilated like bag3 If you add these three programs together, they represent more than a hundred thousand patients in the U.S. and Europe, so while each disease is rare, rare disease as a whole is not rare. if you add these three programs together they represent more than a hundred thousand patients in the u.s and europe so while each disease is rare rare disease as a whole is not rare

Speaker 2: Okay. All right, so maybe then focusing first on the Danon program. You came off clinical hold fairly quickly after the capillary leak syndromes that occurred with the addition of the C3 inhibitor. Have you been able to kind of further establish why that added C3 inhibition component kind of triggered those complications? And I guess, like, you were clearly able to convince the FDA that that was the likely culprit to come off of clinical hold, I'm guessing. Okay. okay All right, so maybe then focusing first on the Danon program. all right so maybe then focusing first on the danon program You came off clinical hold fairly quickly after the capillary leak syndromes that occurred with the addition of the C3 inhibitor. you came off clinical hold fairly quickly after the capillary leak syndromes that occurred with the addition of the c3 inhibitor Have you been able to kind of further establish why that added C3 inhibition component kind of triggered those complications? have you been able to kind of further establish why that added c3 inhibition component kind of triggered those complications And I guess, like, you were clearly able to convince the FDA that that was the likely culprit to come off of clinical hold, I'm guessing. and i guess like you were clearly able to convince the fda that that was the likely culprit to come off of clinical hold i'm guessing

Speaker 1: So what C3 inhibition did do well is that it prevented TMA for the first week. We saw no complement activation. But based on the lab evaluations that we did, as well as studying this patient carefully, who unfortunately passed away, and a second one who had capillary leak, but has recovered and is doing much better now. Based on the lab data there, it appears that after about a week, there is a paradoxical effect that's not TMA, but it's endothelial damage directly, likely through unencumbered AAV vector. So while C3 itself opsonizes and sequesters AAV, once you have a C3 inhibitor, it takes that pathway away and allows AAV to directly damage endothelial cells, unfortunately, and that's what we saw. So what C3 inhibition did do well is that it prevented TMA for the first week. so what c3 inhibition did do well is that it prevented tma for the first week We saw no complement activation. we saw no complement activation But based on the lab evaluations that we did, as well as studying this patient carefully, who unfortunately passed away, and a second one who had capillary leak, but has recovered and is doing much better now. but based on the lab evaluations that we did as well as studying this patient carefully who unfortunately passed away and a second one who had capillary leak but has recovered and is doing much better now Based on the lab data there, it appears that after about a week, there is a paradoxical effect that's not TMA, but it's endothelial damage directly, likely through unencumbered AAV vector. based on the lab data there it appears that after about a week there is a paradoxical effect that's not tma but it's endothelial damage directly likely through unencumbered aav vector So while C3 itself opsonizes and sequesters AAV, once you have a C3 inhibitor, it takes that pathway away and allows AAV to directly damage endothelial cells, unfortunately, and that's what we saw. so while c3 itself opsonizes and sequesters aav once you have a c3 inhibitor it takes that pathway away and allows aav to directly damage endothelial cells unfortunately and that's what we saw The only two patients that we know of in the history of gene therapy who had capillary leak were these two particular patients. So the correlation there is clear. Now, C3, of course, the C3 inhibition, it's a great drug. It works in multiple diseases with high unmet need. I think combining it with the torrential downpour of AAV was just the wrong path to go down. The only two patients that we know of in the history of gene therapy who had capillary leak were these two particular patients. the only two patients that we know of in the history of gene therapy who had capillary leak were these two particular patients So the correlation there is clear. so the correlation there is clear Now, C3, of course, the C3 inhibition, it's a great drug. now c3 of course the c3 inhibition it's a great drug It works in multiple diseases with high unmet need. it works in multiple diseases with high unmet need I think combining it with the torrential downpour of AAV was just the wrong path to go down. i think combining it with the torrential downpour of aav was just the wrong path to go down

Speaker 2: Mm. Mm. mm

Speaker 1: What we were solving for with C3 was an increased risk of TMA that we saw early in the phase two. We saw two out of four cases of TMA early in the phase two trial. The first one, we think was likely due to an additional gene that was mutated, that's next to the Danon Disease gene, next to LAMP2, and that gene conferred an increased risk of complement activation. We think the first of those two patients was likely because of that extra gene that we've now ruled out moving forward for patients moving forward. We had another TMA in a boy who did not get a very high dose, and the thought was that in Danon Disease, the higher full empties actually portend higher potency, and therefore a higher risk of complement activation. What we were solving for with C3 was an increased risk of TMA that we saw early in the phase two. what we were solving for with c3 was an increased risk of tma that we saw early in the phase two We saw two out of four cases of TMA early in the phase two trial. we saw two out of four cases of tma early in the phase two trial The first one, we think was likely due to an additional gene that was mutated, that's next to the Danon Disease gene, next to LAMP2, and that gene conferred an increased risk of complement activation. the first one we think was likely due to an additional gene that was mutated that's next to the danon disease gene next to lamp2 and that gene conferred an increased risk of complement activation We think the first of those two patients was likely because of that extra gene that we've now ruled out moving forward for patients moving forward. we think the first of those two patients was likely because of that extra gene that we've now ruled out moving forward for patients moving forward We had another TMA in a boy who did not get a very high dose, and the thought was that in Danon Disease, the higher full empties actually portend higher potency, and therefore a higher risk of complement activation. we had another tma in a boy who did not get a very high dose and the thought was that in danon disease the higher full empties actually portend higher potency and therefore a higher risk of complement activation So in the revised trial, what we've done now is we've corrected or recalibrated the dose to rectify or account for that increased full empty ratio by about 40%. That's why you see the new number that is around 4E13. On top of that, there were two patients in the pediatric trial, 108 and 109, who got an effective dose around 4E13 anyway, and if you look carefully, they were the earliest responders and the most profound responders in terms of LV mass index. So putting all this together, one and two, both on full empty correction as well as the pediatric experience, it's likely that the right dose for Danon is within the dose range of phase one, but it's closer to the 4E13. We aligned with FDA on that. So in the revised trial, what we've done now is we've corrected or recalibrated the dose to rectify or account for that increased full empty ratio by about 40%. so in the revised trial what we've done now is we've corrected or recalibrated the dose to rectify or account for that increased full empty ratio by about 40% That's why you see the new number that is around 4E13. that's why you see the new number that is around 4e13 On top of that, there were two patients in the pediatric trial, 108 and 109, who got an effective dose around 4E13 anyway, and if you look carefully, they were the earliest responders and the most profound responders in terms of LV mass index. on top of that there were two patients in the pediatric trial 108 and 109 who got an effective dose around 4e13 anyway and if you look carefully they were the earliest responders and the most profound responders in terms of lv mass index So putting all this together, one and two, both on full empty correction as well as the pediatric experience, it's likely that the right dose for Danon is within the dose range of phase one, but it's closer to the 4E13. so putting all this together one and two both on full empty correction as well as the pediatric experience it's likely that the right dose for danon is within the dose range of phase one but it's closer to the 4e13 We aligned with FDA on that. we aligned with fda on that But just taking a step back, we saw higher TMA. We tried to correct for it with the C3 inhibitor. That was the wrong path, so what we should have done right from the beginning and then what we are doing now, and we feel very good about, is reducing or recalibrating that dose, removing C3, but also having a lower threshold for C5 inhibition based on the trajectory and kinetics of both platelets and SC5b-9. But just taking a step back, we saw higher TMA. but just taking a step back we saw higher tma We tried to correct for it with the C3 inhibitor. we tried to correct for it with the c3 inhibitor That was the wrong path, so what we should have done right from the beginning and then what we are doing now, and we feel very good about, is reducing or recalibrating that dose, removing C3, but also having a lower threshold for C5 inhibition based on the trajectory and kinetics of both platelets and SC5b-9. that was the wrong path so what we should have done right from the beginning and then what we are doing now and we feel very good about is reducing or recalibrating that dose removing c3 but also having a lower threshold for c5 inhibition based on the trajectory and kinetics of both platelets and sc5b-9

Speaker 2: So, essentially you're saying that the move from four E thirteen to three point eight E. Well, hold on. Getting my numbers a little confused here, but. So, essentially you're saying that the move from four E thirteen to three point eight E. so essentially you're saying that the move from four e thirteen to three point eight e Well, hold on. well hold on Getting my numbers a little confused here, but. getting my numbers a little confused here but

Speaker 1: It would have been- It would have been- it would have been-

Speaker 2: Let's go Let's go let's go

Speaker 1: ... around six to four, around six point seven to four. About a forty- ... around six to four, around six point seven to four. around six to four around six point seven to four About a forty- about a forty-

Speaker 2: Six point seven to four. Six point seven to four. six point seven to four

Speaker 1: Yeah. Yeah. yeah

Speaker 2: Okay, so it's like, it's kind of a modest decline. Okay, so it's like, it's kind of a modest decline. okay so it's like it's kind of a modest decline

Speaker 1: Yeah. Right. Yeah. yeah Right. right

Speaker 2: What gives you the comfort, though, that that modest decline is sufficient to now in collaboration with a heightened TMA monitoring regimen to get patients through? What gives you the comfort, though, that that modest decline is sufficient to now in collaboration with a heightened TMA monitoring regimen to get patients through? what gives you the comfort though that that modest decline is sufficient to now in collaboration with a heightened tma monitoring regimen to get patients through

Speaker 1: Right. So the phase one patients who were dosed at six point seven E thirteen, the phase two equivalent dose, based on this recalibration, would've been around four E thirteen. Right? So the whole phase one trial using the... If we had the phase two product, those patients would've been dosed at four E thirteen. So that's what gives us the confidence, because they had a pretty clean safety profile, and remarkable efficacy across every parameter, as we know from the NEJM paper. Right. right So the phase one patients who were dosed at six point seven E thirteen, the phase two equivalent dose, based on this recalibration, would've been around four E thirteen. so the phase one patients who were dosed at six point seven e thirteen the phase two equivalent dose based on this recalibration would've been around four e thirteen Right? right So the whole phase one trial using the... so the whole phase one trial using the If we had the phase two product, those patients would've been dosed at four E thirteen. if we had the phase two product those patients would've been dosed at four e thirteen So that's what gives us the confidence, because they had a pretty clean safety profile, and remarkable efficacy across every parameter, as we know from the NEJM paper. so that's what gives us the confidence because they had a pretty clean safety profile and remarkable efficacy across every parameter as we know from the nejm paper

Speaker 2: Okay, and then the TMA monitoring, well, prophylaxis and monitoring protocol. Maybe just give us a sense where it is now and where it's coming from. How has it evolved? Okay, and then the TMA monitoring, well, prophylaxis and monitoring protocol. okay and then the tma monitoring well prophylaxis and monitoring protocol Maybe just give us a sense where it is now and where it's coming from. maybe just give us a sense where it is now and where it's coming from How has it evolved? how has it evolved

Speaker 1: I would say the bottom line is that we're going back to the phase one approach. A combination of rituximab, sirolimus, and steroids with a rapid taper. The two minor differences are that the eculizumab, like I said, is gonna be administered with a lower threshold, based on all what we've learned from the trajectory of platelets and other complement factors, right, so we have a better sense of how to see or foresee complement activation very early after a patient gets treated, even on the second day, and the other minor change is that we have, instead of having rituximab administered over two doses, we have it over three doses, and that, based on literature and based on our, in our own hands, leads to a more profound B-cell depletion, which is gonna be beneficial for the complement pathway. I would say the bottom line is that we're going back to the phase one approach. i would say the bottom line is that we're going back to the phase one approach A combination of rituximab, sirolimus, and steroids with a rapid taper. a combination of rituximab sirolimus and steroids with a rapid taper The two minor differences are that the eculizumab, like I said, is gonna be administered with a lower threshold, based on all what we've learned from the trajectory of platelets and other complement factors, right, so we have a better sense of how to see or foresee complement activation very early after a patient gets treated, even on the second day, and the other minor change is that we have, instead of having rituximab administered over two doses, we have it over three doses, and that, based on literature and based on our, in our own hands, leads to a more profound B-cell depletion, which is gonna be beneficial for the complement pathway. the two minor differences are that the eculizumab like i said is gonna be administered with a lower threshold based on all what we've learned from the trajectory of platelets and other complement factors right so we have a better sense of how to see or foresee complement activation very early after a patient gets treated even on the second day and the other minor change is that we have instead of having rituximab administered over two doses we have it over three doses and that based on literature and based on our in our own hands leads to a more profound b-cell depletion which is gonna be beneficial for the complement pathway

Speaker 2: When is the Rituxan dose relative to the AAV? When is the Rituxan dose relative to the AAV? when is the rituxan dose relative to the aav

Speaker 1: So it used to be a week, you know, within the two weeks prior, and now we have three weeks prior. That's the big difference. So it used to be a week, you know, within the two weeks prior, and now we have three weeks prior. so it used to be a week you know within the two weeks prior and now we have three weeks prior That's the big difference. that's the big difference

Speaker 2: So, and the- So, and the- so and the-

Speaker 1: Dosed over three weeks. Dosed over three weeks. dosed over three weeks

Speaker 2: Dosed over three weeks. Okay. And then to what extent does... You know, if you do start to see complement activation to trigger eculizumab, to what extent does that kind of shut off the complement activation and keep patients protected? Dosed over three weeks. dosed over three weeks Okay. okay And then to what extent does... and then to what extent does You know, if you do start to see complement activation to trigger eculizumab, to what extent does that kind of shut off the complement activation and keep patients protected? you know if you do start to see complement activation to trigger eculizumab to what extent does that kind of shut off the complement activation and keep patients protected

Speaker 1: If done early, it can be effective. You have to get ahead of the cascade and know exactly what to look for. Others have asked if prophylaxis is the right thing, but given our experience in C3, the complement pathway is tricky. Sometimes you shut down one pathway, and another one pops up. That's what we saw. So given that in phase one, we didn't have to use it for the six patients where we have long-term efficacy, we didn't see clinical complement activation there at all, we would rather do it this way, rather than be married to a particular inhibitor over time and risk additional safety events. If done early, it can be effective. if done early it can be effective You have to get ahead of the cascade and know exactly what to look for. you have to get ahead of the cascade and know exactly what to look for Others have asked if prophylaxis is the right thing, but given our experience in C3, the complement pathway is tricky. others have asked if prophylaxis is the right thing but given our experience in c3 the complement pathway is tricky Sometimes you shut down one pathway, and another one pops up. sometimes you shut down one pathway and another one pops up That's what we saw. that's what we saw So given that in phase one, we didn't have to use it for the six patients where we have long-term efficacy, we didn't see clinical complement activation there at all, we would rather do it this way, rather than be married to a particular inhibitor over time and risk additional safety events. so given that in phase one we didn't have to use it for the six patients where we have long-term efficacy we didn't see clinical complement activation there at all we would rather do it this way rather than be married to a particular inhibitor over time and risk additional safety events

Speaker 2: What is TMA? How does it present? What do the patients have to get through and deal with? What is TMA? what is tma How does it present? how does it present What do the patients have to get through and deal with? what do the patients have to get through and deal with

Speaker 1: Yeah, it's thrombotic microangiopathy. Essentially, complement activation leads to platelet deposition in kidney and other areas, leading to kidney damage, potentially other organ damage as well. And most patients, even in our lives and, you know, for normal people, when you have high viral activation, even with other viruses like COVID-19, you can get complement activation, and there's a point at which the complement becomes a cascade that you can't stop. Even regular infections will cause an increase in SC5b-9 and a drop in platelets, right? We see that all the time in viral infections in the hospital outside of gene therapy. But with E-15, E-16 level of viral exposure, total viral exposure, you can understand how this can get out of hand. Yeah, it's thrombotic microangiopathy. yeah it's thrombotic microangiopathy Essentially, complement activation leads to platelet deposition in kidney and other areas, leading to kidney damage, potentially other organ damage as well. essentially complement activation leads to platelet deposition in kidney and other areas leading to kidney damage potentially other organ damage as well And most patients, even in our lives and, you know, for normal people, when you have high viral activation, even with other viruses like COVID-19, you can get complement activation, and there's a point at which the complement becomes a cascade that you can't stop. and most patients even in our lives and you know for normal people when you have high viral activation even with other viruses like covid-19 you can get complement activation and there's a point at which the complement becomes a cascade that you can't stop Even regular infections will cause an increase in SC5b-9 and a drop in platelets, right? even regular infections will cause an increase in sc5b-9 and a drop in platelets right We see that all the time in viral infections in the hospital outside of gene therapy. we see that all the time in viral infections in the hospital outside of gene therapy But with E-15, E-16 level of viral exposure, total viral exposure, you can understand how this can get out of hand. but with e-15 e-16 level of viral exposure total viral exposure you can understand how this can get out of hand So, spotting early the platelet declines, the complement factor changes, is essential to intervene at the right time, I would say. So, spotting early the platelet declines, the complement factor changes, is essential to intervene at the right time, I would say. so spotting early the platelet declines the complement factor changes is essential to intervene at the right time i would say

Speaker 2: Okay, got it. Do you have a sense of what % of patients need eculizumab with the new protocol? Okay, got it. okay got it Do you have a sense of what % of patients need eculizumab with the new protocol? do you have a sense of what % of patients need eculizumab with the new protocol

Speaker 1: We didn't need it for any of the six patients that were followed long term. We did use it for one patient in phase one, and I'm talking about phase one. One patient in phase one who got a very high total viral dose, patient 1007, who then went on to transplant, so we don't have long-term follow-up. That patient got a dose of Eculizumab. It was safely tolerated, but otherwise, for the other six, we didn't need it at all. The hope here is that we need it minimally once this product is approved. I don't think we'll ever get to zero risk of TMA in AAV nine. You see it with other AAV nine programs. It's a known risk. It's something that's even part of the label, but we'll mitigate it, we'll minimize it. We didn't need it for any of the six patients that were followed long term. we didn't need it for any of the six patients that were followed long term We did use it for one patient in phase one, and I'm talking about phase one. we did use it for one patient in phase one and i'm talking about phase one One patient in phase one who got a very high total viral dose, patient 1007, who then went on to transplant, so we don't have long-term follow-up. one patient in phase one who got a very high total viral dose patient 1007 who then went on to transplant so we don't have long-term follow-up That patient got a dose of Eculizumab. that patient got a dose of eculizumab It was safely tolerated, but otherwise, for the other six, we didn't need it at all. it was safely tolerated but otherwise for the other six we didn't need it at all The hope here is that we need it minimally once this product is approved. the hope here is that we need it minimally once this product is approved I don't think we'll ever get to zero risk of TMA in AAV nine. i don't think we'll ever get to zero risk of tma in aav nine You see it with other AAV nine programs. you see it with other aav nine programs It's a known risk. it's a known risk It's something that's even part of the label, but we'll mitigate it, we'll minimize it. it's something that's even part of the label but we'll mitigate it we'll minimize it And what happened in the phase two, what we tried to do is that we tried to make a good product perfect. But given the devastating nature of this disease, a good product is actually great. And what happened in the phase two, what we tried to do is that we tried to make a good product perfect. and what happened in the phase two what we tried to do is that we tried to make a good product perfect But given the devastating nature of this disease, a good product is actually great. but given the devastating nature of this disease a good product is actually great

Speaker 2: Now, patients don't come in saying, "My platelets are low." So when they have TMA, what do they experience in that as they're kind of making their way through this? Now, patients don't come in saying, "My platelets are low." So when they have TMA, what do they experience in that as they're kind of making their way through this? now patients don't come in saying "my platelets are low." so when they have tma what do they experience in that as they're kind of making their way through this Yeah Yeah yeah ... cascade, what needs to be treated? ... cascade, what needs to be treated? cascade what needs to be treated

Speaker 1: So this is a lab diagnosis largely. Patients can be asymptomatic until they have kidney damage and start having lower urine output. Until then, you're not gonna notice platelet drops, you're not gonna notice complement activation. Patients often feel normal until they're further along. So these patients need to be monitored locally in the hospital for the first two weeks. The patients, however, I'll give you an example, who got that 4E13 dose, 108 and 109, went home around day 10 or 11. Their profile was much more squeaky clean, and also had efficacy that was at or better than the levels we saw for the other patients, which, again, gave us confidence that going back to around that dose would be the right next move for us. So this is a lab diagnosis largely. so this is a lab diagnosis largely Patients can be asymptomatic until they have kidney damage and start having lower urine output. patients can be asymptomatic until they have kidney damage and start having lower urine output Until then, you're not gonna notice platelet drops, you're not gonna notice complement activation. until then you're not gonna notice platelet drops you're not gonna notice complement activation Patients often feel normal until they're further along. patients often feel normal until they're further along So these patients need to be monitored locally in the hospital for the first two weeks. so these patients need to be monitored locally in the hospital for the first two weeks The patients, however, I'll give you an example, who got that 4E13 dose, 108 and 109, went home around day 10 or 11. the patients however i'll give you an example who got that 4e13 dose 108 and 109 went home around day 10 or 11 Their profile was much more squeaky clean, and also had efficacy that was at or better than the levels we saw for the other patients, which, again, gave us confidence that going back to around that dose would be the right next move for us. their profile was much more squeaky clean and also had efficacy that was at or better than the levels we saw for the other patients which again gave us confidence that going back to around that dose would be the right next move for us

Speaker 2: Is this permanent loss of renal function, or it's transient? Is this permanent loss of renal function, or it's transient? is this permanent loss of renal function or it's transient

Speaker 1: All the patients who have had TMA in our trials have recovered renal function, and potentially may be benefiting from the gene therapy for their heart, too. We don't have the final endpoints now, but the patients are doing well and back to normal. All the patients who have had TMA in our trials have recovered renal function, and potentially may be benefiting from the gene therapy for their heart, too. all the patients who have had tma in our trials have recovered renal function and potentially may be benefiting from the gene therapy for their heart too We don't have the final endpoints now, but the patients are doing well and back to normal. we don't have the final endpoints now but the patients are doing well and back to normal

Speaker 2: I mean, 'cause, like, in that what may be one of the worst-case scenarios of temporary dialysis, for a patient whose prognosis is otherwise heart transplant and a life of living with a heart transplant, that's not even necessarily a difficult trade-off or risk-benefit to have to work through. I mean, 'cause, like, in that what may be one of the worst-case scenarios of temporary dialysis, for a patient whose prognosis is otherwise heart transplant and a life of living with a heart transplant, that's not even necessarily a difficult trade-off or risk-benefit to have to work through. i mean 'cause like in that what may be one of the worst-case scenarios of temporary dialysis for a patient whose prognosis is otherwise heart transplant and a life of living with a heart transplant that's not even necessarily a difficult trade-off or risk-benefit to have to work through

Speaker 1: I totally agree. One of our patients who had TMA in Germany and was on dialysis for a couple of months, even during that period, their family had said: "You know, we would rather actually prefer a kidney transplant over a heart transplant," because in Germany, heart transplants are so difficult to find, and the mortality is about 50%, right? And that doesn't say that that is a justifiable long-term side effect, but having transient renal failure and then coming back to normal, these kidneys recover naturally. We might see it in some patients. We want to minimize it, mitigate it, make it as near zero as we can, but the benefit-risk, because the disease is so devastating, is still gonna be positive. I totally agree. i totally agree One of our patients who had TMA in Germany and was on dialysis for a couple of months, even during that period, their family had said: "You know, we would rather actually prefer a kidney transplant over a heart transplant," because in Germany, heart transplants are so difficult to find, and the mortality is about 50%, right? one of our patients who had tma in germany and was on dialysis for a couple of months even during that period their family had said "you know we would rather actually prefer a kidney transplant over a heart transplant," because in germany heart transplants are so difficult to find and the mortality is about 50% right And that doesn't say that that is a justifiable long-term side effect, but having transient renal failure and then coming back to normal, these kidneys recover naturally. and that doesn't say that that is a justifiable long-term side effect but having transient renal failure and then coming back to normal these kidneys recover naturally We might see it in some patients. we might see it in some patients We want to minimize it, mitigate it, make it as near zero as we can, but the benefit-risk, because the disease is so devastating, is still gonna be positive. we want to minimize it mitigate it make it as near zero as we can but the benefit-risk because the disease is so devastating is still gonna be positive

Speaker 2: You'd mentioned that one TMA patient who had a mutation in a complement gene, the risk complement. How common are those, and to what extent have you started to screen for potentially other mutations that could put patients at risk? You'd mentioned that one TMA patient who had a mutation in a complement gene, the risk complement. you'd mentioned that one tma patient who had a mutation in a complement gene the risk complement How common are those, and to what extent have you started to screen for potentially other mutations that could put patients at risk? how common are those and to what extent have you started to screen for potentially other mutations that could put patients at risk

Speaker 1: So that particular mutation is exceedingly rare. It's called CUL4B, but it's now part of a 14-gene panel that we test for. And these 14 genes are thought to be complement-potentiating genes, so we screen them out, and so far, other than that patient, in all the patients that we've screened for phase two, we have not found anybody. So that particular mutation is exceedingly rare. so that particular mutation is exceedingly rare It's called CUL4B, but it's now part of a 14-gene panel that we test for. it's called cul4b but it's now part of a 14-gene panel that we test for And these 14 genes are thought to be complement-potentiating genes, so we screen them out, and so far, other than that patient, in all the patients that we've screened for phase two, we have not found anybody. and these 14 genes are thought to be complement-potentiating genes so we screen them out and so far other than that patient in all the patients that we've screened for phase two we have not found anybody

Speaker 2: Okay. How are the physician and patient communities kind of responding to some of the, these updates and their own interest in potentially being clinical trial candidates? Okay. okay How are the physician and patient communities kind of responding to some of the, these updates and their own interest in potentially being clinical trial candidates? how are the physician and patient communities kind of responding to some of the these updates and their own interest in potentially being clinical trial candidates

Speaker 1: So first of all, when this event happened, with the patient who got the C3 inhibitor, who passed away, it was devastating for us. It was devastating for our team, but mostly it was devastating for, of course, the patient's family and the community. A week after the event, we had a call together with the patient community, and at that point, the general sentiment was that, again, because this is an otherwise fatal disease, that there was an acceptance of even that one patient death without stopping enthusiasm for the trial. No one has dropped out of the trial. All the investigators who have been involved are leaning into when is the trial gonna start up. Very happy about the FDA lifting the clinical hold. So first of all, when this event happened, with the patient who got the C3 inhibitor, who passed away, it was devastating for us. so first of all when this event happened with the patient who got the c3 inhibitor who passed away it was devastating for us It was devastating for our team, but mostly it was devastating for, of course, the patient's family and the community. it was devastating for our team but mostly it was devastating for of course the patient's family and the community A week after the event, we had a call together with the patient community, and at that point, the general sentiment was that, again, because this is an otherwise fatal disease, that there was an acceptance of even that one patient death without stopping enthusiasm for the trial. a week after the event we had a call together with the patient community and at that point the general sentiment was that again because this is an otherwise fatal disease that there was an acceptance of even that one patient death without stopping enthusiasm for the trial No one has dropped out of the trial. no one has dropped out of the trial All the investigators who have been involved are leaning into when is the trial gonna start up. all the investigators who have been involved are leaning into when is the trial gonna start up Very happy about the FDA lifting the clinical hold. very happy about the fda lifting the clinical hold This is why, I might have said this before, gene therapy works for devastating rare diseases, but it's not a nice-to-have, right? It. When you really have a disease like Danon, where only DNA replacement is gonna work, there's actually no other approach. You can't. There's no protein, there's no factor that you can give to these patients. The patients and families have been generously supportive. This is why, I might have said this before, gene therapy works for devastating rare diseases, but it's not a nice-to-have, right? this is why i might have said this before gene therapy works for devastating rare diseases but it's not a nice-to-have right It. it When you really have a disease like Danon, where only DNA replacement is gonna work, there's actually no other approach. when you really have a disease like danon where only dna replacement is gonna work there's actually no other approach You can't. you can't There's no protein, there's no factor that you can give to these patients. there's no protein there's no factor that you can give to these patients The patients and families have been generously supportive. the patients and families have been generously supportive

Speaker 2: So, the number of identified patients has been obviously a topic of conversation for investors. Speed of enrollment has been an important conversation topic for investors. I think in the most recent press release kind of now gave us an indication, two ped run-ins and a total of six patients treated. I think that's a little less than maybe many of us were thinking. So, the number of identified patients has been obviously a topic of conversation for investors. so the number of identified patients has been obviously a topic of conversation for investors Speed of enrollment has been an important conversation topic for investors. speed of enrollment has been an important conversation topic for investors I think in the most recent press release kind of now gave us an indication, two ped run-ins and a total of six patients treated. i think in the most recent press release kind of now gave us an indication two ped run-ins and a total of six patients treated I think that's a little less than maybe many of us were thinking. i think that's a little less than maybe many of us were thinking

Speaker 1: Yeah Yeah yeah

Speaker 2: ... relative to the burden of illness, the unmet need, right? The number of identified patients out there. So maybe talk a little bit about enrollment, logistical challenges, how you've navigated them, and what gives you the, you know, the confidence that there are a number of patients out there still to treat, despite some of the- ... relative to the burden of illness, the unmet need, right? relative to the burden of illness the unmet need right The number of identified patients out there. the number of identified patients out there So maybe talk a little bit about enrollment, logistical challenges, how you've navigated them, and what gives you the, you know, the confidence that there are a number of patients out there still to treat, despite some of the- so maybe talk a little bit about enrollment logistical challenges how you've navigated them and what gives you the you know the confidence that there are a number of patients out there still to treat despite some of the- Yeah, enrollment challenges you might have been having. Yeah, enrollment challenges you might have been having. yeah enrollment challenges you might have been having

Speaker 1: Going back to the start of the phase two, we had to start with two pediatric patients and then wait a certain number of months. It ended up being about four to six months to get through FDA, IDMC, and site start-up for the full trial, right? It was two pediatrics and then plus ten. Once we got past those two pediatrics, we enrolled the next ten patients in two months and three days, right? The consent and the enrollment happened really rapidly, and with our funnel, we had additional patients that were waiting. Going back to the start of the phase two, we had to start with two pediatric patients and then wait a certain number of months. going back to the start of the phase two we had to start with two pediatric patients and then wait a certain number of months It ended up being about four to six months to get through FDA, IDMC, and site start-up for the full trial, right? it ended up being about four to six months to get through fda idmc and site start-up for the full trial right It was two pediatrics and then plus ten. it was two pediatrics and then plus ten Once we got past those two pediatrics, we enrolled the next ten patients in two months and three days, right? once we got past those two pediatrics we enrolled the next ten patients in two months and three days right The consent and the enrollment happened really rapidly, and with our funnel, we had additional patients that were waiting. the consent and the enrollment happened really rapidly and with our funnel we had additional patients that were waiting ... and then the trial started. That was, I believe, last year, between June and July, that we got the enrollment done. The patients started being treated in August and September, but then that next patient had a TMA event, or the second, the fourth patient, right? So one, two, three, four. The fourth patient had a TMA event, and that paused the trial for another six months while we got the C3 inhibitor on board. And then we started the C3 inhibitor, and then the first two patients had a TMA. But when we mapped out the infusion times this year to finish the trial, it would have been between May and the end of June, right? So really what stopped us is these unfortunate side effects. ... and then the trial started. and then the trial started That was, I believe, last year, between June and July, that we got the enrollment done. that was i believe last year between june and july that we got the enrollment done The patients started being treated in August and September, but then that next patient had a TMA event, or the second, the fourth patient, right? the patients started being treated in august and september but then that next patient had a tma event or the second the fourth patient right So one, two, three, four. so one two three four The fourth patient had a TMA event, and that paused the trial for another six months while we got the C3 inhibitor on board. the fourth patient had a tma event and that paused the trial for another six months while we got the c3 inhibitor on board And then we started the C3 inhibitor, and then the first two patients had a TMA. and then we started the c3 inhibitor and then the first two patients had a tma But when we mapped out the infusion times this year to finish the trial, it would have been between May and the end of June, right? but when we mapped out the infusion times this year to finish the trial it would have been between may and the end of june right So really what stopped us is these unfortunate side effects. so really what stopped us is these unfortunate side effects And if we can get past, I'm feeling good that we can, given everything that we talked about, the next three patients from safety viewpoint, we think we can replicate that same infusion timing over the coming months after that. And if we can get past, I'm feeling good that we can, given everything that we talked about, the next three patients from safety viewpoint, we think we can replicate that same infusion timing over the coming months after that. and if we can get past i'm feeling good that we can given everything that we talked about the next three patients from safety viewpoint we think we can replicate that same infusion timing over the coming months after that

Speaker 2: So how should we be thinking in terms of months to kind of work through this now? It's very helpful to kind of frame the four to six months after the first two patients- So how should we be thinking in terms of months to kind of work through this now? so how should we be thinking in terms of months to kind of work through this now It's very helpful to kind of frame the four to six months after the first two patients- it's very helpful to kind of frame the four to six months after the first two patients- Right Right right ... who enrolled. Again, just so we have our expectations appropriately aligned, timelines for kind of the next phase of the pivotal program. ... who enrolled. who enrolled Again, just so we have our expectations appropriately aligned, timelines for kind of the next phase of the pivotal program. again just so we have our expectations appropriately aligned timelines for kind of the next phase of the pivotal program

Speaker 1: So given that for the new patients that will be treated, we still need a three-month troponin run-in. We just got off the hold. We got to go through IDMC, we have to go through IRBs, and get the drug product release, et cetera. We anticipate those three patients being treated in early 2026, and then agreeing with FDA as to what the rest of the trial should look like, which I can talk about in a second. And then once we have those patient identified, the infusions can be lined up without being staggered, so it should be relatively rapid. We can't guide on the exact timing until we talk to the FDA. I think the best-case scenario is that we replace the two C3 inhibitor-treated patients, and therefore we have a total of fourteen, so twelve plus two. So given that for the new patients that will be treated, we still need a three-month troponin run-in. so given that for the new patients that will be treated we still need a three-month troponin run-in We just got off the hold. we just got off the hold We got to go through IDMC, we have to go through IRBs, and get the drug product release, et cetera. we got to go through idmc we have to go through irbs and get the drug product release et cetera We anticipate those three patients being treated in early 2026, and then agreeing with FDA as to what the rest of the trial should look like, which I can talk about in a second. we anticipate those three patients being treated in early 2026 and then agreeing with fda as to what the rest of the trial should look like which i can talk about in a second And then once we have those patient identified, the infusions can be lined up without being staggered, so it should be relatively rapid. and then once we have those patient identified the infusions can be lined up without being staggered so it should be relatively rapid We can't guide on the exact timing until we talk to the FDA. we can't guide on the exact timing until we talk to the fda I think the best-case scenario is that we replace the two C3 inhibitor-treated patients, and therefore we have a total of fourteen, so twelve plus two. i think the best-case scenario is that we replace the two c3 inhibitor-treated patients and therefore we have a total of fourteen so twelve plus two We have patients who are already, so it's not a question of finding these patients, it's just getting through them through the vaccinations and the troponin run-ins, which we're going to try to do in parallel between now and when the three patients are treated. We have patients who are already, so it's not a question of finding these patients, it's just getting through them through the vaccinations and the troponin run-ins, which we're going to try to do in parallel between now and when the three patients are treated. we have patients who are already so it's not a question of finding these patients it's just getting through them through the vaccinations and the troponin run-ins which we're going to try to do in parallel between now and when the three patients are treated

Speaker 2: And the three run-in patients, are those going to be sequential? So when you say treat in early twenty twenty-six, that's you've worked through all three of them, including- And the three run-in patients, are those going to be sequential? and the three run-in patients are those going to be sequential So when you say treat in early twenty twenty-six, that's you've worked through all three of them, including- so when you say treat in early twenty twenty-six that's you've worked through all three of them including-

Speaker 1: They're a month apart. They're a month apart. they're a month apart

Speaker 2: Okay. And then for the rest of the program, I guess you have to kind of discuss with the FDA the revised protocol, but what are you thinking in terms of kind of where you initially started with around ten or so patients to or ten to twelve patients to where you're likely to wind up now? Okay. okay And then for the rest of the program, I guess you have to kind of discuss with the FDA the revised protocol, but what are you thinking in terms of kind of where you initially started with around ten or so patients to or ten to twelve patients to where you're likely to wind up now? and then for the rest of the program i guess you have to kind of discuss with the fda the revised protocol but what are you thinking in terms of kind of where you initially started with around ten or so patients to or ten to twelve patients to where you're likely to wind up now

Speaker 1: So the FDA has not asked us to enroll more than 12 patients, right? There's no clear directive for that at all. I think that the right way to really evaluate efficacy is with a somewhat consistent immunomodulation regimen and have at least 12 patients treated with that regimen. So far, we've treated four, so that would leave eight more slots. It could be, though, that with the dose recalibration, the FDA wants us to treat a couple of additional patients. So we have enough patients that we have eyes on to fulfill those needs, and we have enough drug product, but it's just a question of getting that clarified as soon as possible. So the FDA has not asked us to enroll more than 12 patients, right? so the fda has not asked us to enroll more than 12 patients right There's no clear directive for that at all. there's no clear directive for that at all I think that the right way to really evaluate efficacy is with a somewhat consistent immunomodulation regimen and have at least 12 patients treated with that regimen. i think that the right way to really evaluate efficacy is with a somewhat consistent immunomodulation regimen and have at least 12 patients treated with that regimen So far, we've treated four, so that would leave eight more slots. so far we've treated four so that would leave eight more slots It could be, though, that with the dose recalibration, the FDA wants us to treat a couple of additional patients. it could be though that with the dose recalibration the fda wants us to treat a couple of additional patients So we have enough patients that we have eyes on to fulfill those needs, and we have enough drug product, but it's just a question of getting that clarified as soon as possible. so we have enough patients that we have eyes on to fulfill those needs and we have enough drug product but it's just a question of getting that clarified as soon as possible

Speaker 2: In terms of the efforts to go identify patients who could benefit from therapy, where are you in that process? In terms of the efforts to go identify patients who could benefit from therapy, where are you in that process? in terms of the efforts to go identify patients who could benefit from therapy where are you in that process

Speaker 1: So we have both a top-down analysis, and we're going to provide an update on the top-down model in... before the end of the year, actually. And then we have a bottom-up analysis, which is sort of reported patients and looking at actual cases and also looking at claims, right? So, that is likely going to be part of the program update. That's going to be, at this point, some point next year once we get through the first three patients and have clarity on both what the final trial looks like and also how many patients need to be positive to have a positive trial outcome. I'll also mention with the FDA that in our correspondence, not only have they not asked us to treat more patients, but there's been no question on the trial design or the endpoints themselves. So we have both a top-down analysis, and we're going to provide an update on the top-down model in... before the end of the year, actually. so we have both a top-down analysis and we're going to provide an update on the top-down model in before the end of the year actually And then we have a bottom-up analysis, which is sort of reported patients and looking at actual cases and also looking at claims, right? and then we have a bottom-up analysis which is sort of reported patients and looking at actual cases and also looking at claims right So, that is likely going to be part of the program update. so that is likely going to be part of the program update That's going to be, at this point, some point next year once we get through the first three patients and have clarity on both what the final trial looks like and also how many patients need to be positive to have a positive trial outcome. that's going to be at this point some point next year once we get through the first three patients and have clarity on both what the final trial looks like and also how many patients need to be positive to have a positive trial outcome I'll also mention with the FDA that in our correspondence, not only have they not asked us to treat more patients, but there's been no question on the trial design or the endpoints themselves. i'll also mention with the fda that in our correspondence not only have they not asked us to treat more patients but there's been no question on the trial design or the endpoints themselves So we're moving forward with the assumption that we're in the midst of this pivotal trial, and getting this to a positive read is going to lead to a potential approval. So we're moving forward with the assumption that we're in the midst of this pivotal trial, and getting this to a positive read is going to lead to a potential approval. so we're moving forward with the assumption that we're in the midst of this pivotal trial and getting this to a positive read is going to lead to a potential approval

Speaker 2: Got it. Are there lessons from the Danon program that you've been applying to the PKP2 program, and if so, what? Got it. got it Are there lessons from the Danon program that you've been applying to the PKP2 program, and if so, what? are there lessons from the danon program that you've been applying to the pkp2 program and if so what

Speaker 1: So most of the Danon lessons were around TMA and C3, plus AAV-related capillary leaks, so neither of those really applied to rh74. With rh74 at higher doses, we've seen liver toxicities. Compared with those doses, we're about half of the viral exposure per kilogram, so hopefully, we don't hit those. We're also applying very stringent criteria as to patient selection. Anyone with any sort of remote liver disease is either excluded or goes through a rigorous hepatology consult to make sure that they're safe. We rule out CMV, so we're learning from other programs to apply more to rh74. I think the Danon learnings are just that protein expression matters. There's many ways to measure protein. Western blot is not always the most effective. So most of the Danon lessons were around TMA and C3, plus AAV-related capillary leaks, so neither of those really applied to rh74. so most of the danon lessons were around tma and c3 plus aav-related capillary leaks so neither of those really applied to rh74 With rh74 at higher doses, we've seen liver toxicities. with rh74 at higher doses we've seen liver toxicities Compared with those doses, we're about half of the viral exposure per kilogram, so hopefully, we don't hit those. compared with those doses we're about half of the viral exposure per kilogram so hopefully we don't hit those We're also applying very stringent criteria as to patient selection. we're also applying very stringent criteria as to patient selection Anyone with any sort of remote liver disease is either excluded or goes through a rigorous hepatology consult to make sure that they're safe. anyone with any sort of remote liver disease is either excluded or goes through a rigorous hepatology consult to make sure that they're safe We rule out CMV, so we're learning from other programs to apply more to rh74. we rule out cmv so we're learning from other programs to apply more to rh74 I think the Danon learnings are just that protein expression matters. i think the danon learnings are just that protein expression matters There's many ways to measure protein. there's many ways to measure protein Western blot is not always the most effective. western blot is not always the most effective In PKP2, we've now figured out how to use immunofluorescence to localize the PKP2 protein to the desmosome, and that's probably a more meaningful outcome than just total Western blot. That's one lesson that we've extrapolated a little bit from Danon. And the other lesson is that Danon, and this is almost a contrarian lesson from Danon, Danon was, in some ways, easy endpoint-wise. It's a disease of big hearts. They grow rapidly. You shrink them rapidly. You can have a big delta between treated and untreated. In PKP2, it's more slowly progressive. There's multiple parameters that are affected, like arrhythmias, and RV function, and how a patient functions and feels. In PKP2, we've now figured out how to use immunofluorescence to localize the PKP2 protein to the desmosome, and that's probably a more meaningful outcome than just total Western blot. in pkp2 we've now figured out how to use immunofluorescence to localize the pkp2 protein to the desmosome and that's probably a more meaningful outcome than just total western blot That's one lesson that we've extrapolated a little bit from Danon. that's one lesson that we've extrapolated a little bit from danon And the other lesson is that Danon, and this is almost a contrarian lesson from Danon, Danon was, in some ways, easy endpoint-wise. and the other lesson is that danon and this is almost a contrarian lesson from danon danon was in some ways easy endpoint-wise It's a disease of big hearts. it's a disease of big hearts They grow rapidly. they grow rapidly You shrink them rapidly. you shrink them rapidly You can have a big delta between treated and untreated. you can have a big delta between treated and untreated In PKP2, it's more slowly progressive. in pkp2 it's more slowly progressive There's multiple parameters that are affected, like arrhythmias, and RV function, and how a patient functions and feels. there's multiple parameters that are affected like arrhythmias and rv function and how a patient functions and feels The fingerprint of a composite endpoint for that is something that's more of a discussion and negotiation with the FDA, where we've started that dialogue, and we hope to have some resolution as soon as we can. The fingerprint of a composite endpoint for that is something that's more of a discussion and negotiation with the FDA, where we've started that dialogue, and we hope to have some resolution as soon as we can. the fingerprint of a composite endpoint for that is something that's more of a discussion and negotiation with the fda where we've started that dialogue and we hope to have some resolution as soon as we can

Speaker 2: Are there any similar empty-full capsid ratios for the AAVrh74 program and PKP2s that are in Danon? Like, how do you think about adjusting for that? Are there any similar empty-full capsid ratios for the AAVrh74 program and PKP2s that are in Danon? are there any similar empty-full capsid ratios for the aavrh74 program and pkp2s that are in danon Like, how do you think about adjusting for that? like how do you think about adjusting for that

Speaker 1: We started the PKP2 program already with an enhanced full empty profile, similar to Danon. So, while we continuously improve the product, there's not that much room to go. So, the phase two material should be pretty similar to the phase one. We started the PKP2 program already with an enhanced full empty profile, similar to Danon. we started the pkp2 program already with an enhanced full empty profile similar to danon So, while we continuously improve the product, there's not that much room to go. so while we continuously improve the product there's not that much room to go So, the phase two material should be pretty similar to the phase one. so the phase two material should be pretty similar to the phase one

Speaker 2: How does your empty-to-full ratio, maybe compare to Elevidys or other AAV rh74 programs? Do you know? How does your empty-to-full ratio, maybe compare to Elevidys or other AAV rh74 programs? how does your empty-to-full ratio maybe compare to elevidys or other aav rh74 programs Do you know? do you know

Speaker 1: I think we're in a pretty good place. I will say in Danon, more is not necessarily better, for the reasons that we outlined. We think that an enriched product with higher full-empty could trigger a TLR9-associated complement activation, and therefore earlier TMA than you would see with a lower full-empty ratio. So I think for Danon, we're right where we need to be with the new product. It's gonna lead to better availability of drug product, lower COGS, et cetera. We're gonna have a really good margin. I think for PKP2, we're in a very similar place, but I think being 90%, 95%, 99% is not necessarily always a good thing. I think we're in a pretty good place. i think we're in a pretty good place I will say in Danon, more is not necessarily better, for the reasons that we outlined. i will say in danon more is not necessarily better for the reasons that we outlined We think that an enriched product with higher full-empty could trigger a TLR9-associated complement activation, and therefore earlier TMA than you would see with a lower full-empty ratio. we think that an enriched product with higher full-empty could trigger a tlr9-associated complement activation and therefore earlier tma than you would see with a lower full-empty ratio So I think for Danon, we're right where we need to be with the new product. so i think for danon we're right where we need to be with the new product It's gonna lead to better availability of drug product, lower COGS, et cetera. it's gonna lead to better availability of drug product lower cogs et cetera We're gonna have a really good margin. we're gonna have a really good margin I think for PKP2, we're in a very similar place, but I think being 90%, 95%, 99% is not necessarily always a good thing. i think for pkp2 we're in a very similar place but i think being 90% 95% 99% is not necessarily always a good thing

Speaker 2: Okay. What's the prophylaxis regimen you're using in the PKP2 program? How does that compare? Okay. okay What's the prophylaxis regimen you're using in the PKP2 program? what's the prophylaxis regimen you're using in the pkp2 program How does that compare? how does that compare

Speaker 1: It's basically exactly the same as what we've done with the renewed Danon program. Rituximab spaced out a little bit more, sirolimus, steroids, and a lower threshold for eculizumab. It's basically exactly the same as what we've done with the renewed Danon program. it's basically exactly the same as what we've done with the renewed danon program Rituximab spaced out a little bit more, sirolimus, steroids, and a lower threshold for eculizumab. rituximab spaced out a little bit more sirolimus steroids and a lower threshold for eculizumab

Speaker 2: Maybe you can give us an overview of what you've started to see in the phase one-two program, and what we should be expecting from that program in the months ahead? Maybe you can give us an overview of what you've started to see in the phase one-two program, and what we should be expecting from that program in the months ahead? maybe you can give us an overview of what you've started to see in the phase one-two program and what we should be expecting from that program in the months ahead

Speaker 1: The phase two program. I would say the next time that you'll hear from us about PKP2 is when we achieve alignment with the FDA on the phase two pivotal trial design. Those discussions are early. They're gonna take a little bit of time. We're still developing and reading out some of our natural history efforts to get there. I will say, though, that a single-arm 12-patient trial, like we got alignment on Fanconi with FDA on Danon, may have been a one-off. We know the drug works, although we've only treated three patients. These patients all had improvements in efficacy parameters, and they all feel much better than they did. They're functioning better. Some of them are actually exercising, and they've never actually exercised for years. So we know we have a product that works. The phase two program. the phase two program I would say the next time that you'll hear from us about PKP2 is when we achieve alignment with the FDA on the phase two pivotal trial design. i would say the next time that you'll hear from us about pkp2 is when we achieve alignment with the fda on the phase two pivotal trial design Those discussions are early. those discussions are early They're gonna take a little bit of time. they're gonna take a little bit of time We're still developing and reading out some of our natural history efforts to get there. we're still developing and reading out some of our natural history efforts to get there I will say, though, that a single-arm 12-patient trial, like we got alignment on Fanconi with FDA on Danon, may have been a one-off. i will say though that a single-arm 12-patient trial like we got alignment on fanconi with fda on danon may have been a one-off We know the drug works, although we've only treated three patients. we know the drug works although we've only treated three patients These patients all had improvements in efficacy parameters, and they all feel much better than they did. these patients all had improvements in efficacy parameters and they all feel much better than they did They're functioning better. they're functioning better Some of them are actually exercising, and they've never actually exercised for years. some of them are actually exercising and they've never actually exercised for years So we know we have a product that works. so we know we have a product that works The next step is to get to a trial that works, a pivotal trial that works. So it's not always about the smallest trial you can get away with. It's about the right trial design that leads to a positive outcome. And actually, the FDA has been quite collaborative in their dialogue with us, trying to make us think carefully about how to get a positive trial rather than one that just makes us look good. The next step is to get to a trial that works, a pivotal trial that works. the next step is to get to a trial that works a pivotal trial that works So it's not always about the smallest trial you can get away with. so it's not always about the smallest trial you can get away with It's about the right trial design that leads to a positive outcome. it's about the right trial design that leads to a positive outcome And actually, the FDA has been quite collaborative in their dialogue with us, trying to make us think carefully about how to get a positive trial rather than one that just makes us look good. and actually the fda has been quite collaborative in their dialogue with us trying to make us think carefully about how to get a positive trial rather than one that just makes us look good

Speaker 2: Maybe we can maybe talk a little bit about the milestones then from these programs and kind of the visibility you'll give us into enrollment updates, data updates, either, you know, or across Danon and PKP2 and even BAG3. Maybe we can maybe talk a little bit about the milestones then from these programs and kind of the visibility you'll give us into enrollment updates, data updates, either, you know, or across Danon and PKP2 and even BAG3. maybe we can maybe talk a little bit about the milestones then from these programs and kind of the visibility you'll give us into enrollment updates data updates either you know or across danon and pkp2 and even bag3

Speaker 1: Danon, I would say the next couple of milestones are when patients are treated safely, and then we have that itself, three patients treated safely, then the alignment on the rest of the trial, and along with that, a program update, how many patients are needed for positive trial and also epidemiology update, right? Those are catalysts for Danon. For PKP2, the big one is FDA alignment and endpoints, and then actually starting the phase two. In BAG3, we're gonna start the phase one. That'll likely be next year as well. I will just put in for BAG3 that it's likely as large or bigger than PKP2 in terms of trial size, patient size, patient population. Also the endpoint there, it's a dilated cardiomyopathy. These patients have dilated hearts, loss of ejection fraction, so the obvious endpoint there is EF. Danon, I would say the next couple of milestones are when patients are treated safely, and then we have that itself, three patients treated safely, then the alignment on the rest of the trial, and along with that, a program update, how many patients are needed for positive trial and also epidemiology update, right? danon i would say the next couple of milestones are when patients are treated safely and then we have that itself three patients treated safely then the alignment on the rest of the trial and along with that a program update how many patients are needed for positive trial and also epidemiology update right Those are catalysts for Danon. those are catalysts for danon For PKP2, the big one is FDA alignment and endpoints, and then actually starting the phase two. for pkp2 the big one is fda alignment and endpoints and then actually starting the phase two In BAG3, we're gonna start the phase one. in bag3 we're gonna start the phase one That'll likely be next year as well. that'll likely be next year as well I will just put in for BAG3 that it's likely as large or bigger than PKP2 in terms of trial size, patient size, patient population. i will just put in for bag3 that it's likely as large or bigger than pkp2 in terms of trial size patient size patient population Also the endpoint there, it's a dilated cardiomyopathy. also the endpoint there it's a dilated cardiomyopathy These patients have dilated hearts, loss of ejection fraction, so the obvious endpoint there is EF. these patients have dilated hearts loss of ejection fraction so the obvious endpoint there is ef It's an accepted endpoint in other cardiac diseases, and if we can get to that agreement with FDA, that would be a win. Obviously, that would not be until the end of the phase one. But with these three programs together, again, it's a hundred thousand patients, and we have at least two others that are being developed and are undisclosed. It's an accepted endpoint in other cardiac diseases, and if we can get to that agreement with FDA, that would be a win. it's an accepted endpoint in other cardiac diseases and if we can get to that agreement with fda that would be a win Obviously, that would not be until the end of the phase one. obviously that would not be until the end of the phase one But with these three programs together, again, it's a hundred thousand patients, and we have at least two others that are being developed and are undisclosed. but with these three programs together again it's a hundred thousand patients and we have at least two others that are being developed and are undisclosed

Speaker 2: For the BAG3 program, what's the capsid, what's the dose, and what's the route of delivery? For the BAG3 program, what's the capsid, what's the dose, and what's the route of delivery? for the bag3 program what's the capsid what's the dose and what's the route of delivery

Speaker 1: It's Rh74. It's IV. We did inherit this program from Renovacor, which was an AAV9 localized approach. So we used some of the mouse model data, but we redid a lot of the IND enabling work. And I think we feel, based on our experience already with PKP2 and Danon, that this is the right approach. It's Rh74. it's rh74 It's IV. it's iv We did inherit this program from Renovacor, which was an AAV9 localized approach. we did inherit this program from renovacor which was an aav9 localized approach So we used some of the mouse model data, but we redid a lot of the IND enabling work. so we used some of the mouse model data but we redid a lot of the ind enabling work And I think we feel, based on our experience already with PKP2 and Danon, that this is the right approach. and i think we feel based on our experience already with pkp2 and danon that this is the right approach

Speaker 2: You said kind of the one of the next updates on PKP2 is FDA alignment. You said it's gonna take some time. Any general frameworks? Is that likely to be a 2026 update or to be determined? You said kind of the one of the next updates on PKP2 is FDA alignment. you said kind of the one of the next updates on pkp2 is fda alignment You said it's gonna take some time. you said it's gonna take some time Any general frameworks? any general frameworks Is that likely to be a 2026 update or to be determined? is that likely to be a 2026 update or to be determined

Speaker 1: I would just say at this point TBD, but as soon as possible. I would just say at this point TBD, but as soon as possible. i would just say at this point tbd but as soon as possible

Speaker 2: All right. Excellent. Gaurav, thanks so much for joining. Thanks everyone for coming out. All right. all right Excellent. excellent Gaurav, thanks so much for joining. gaurav thanks so much for joining Thanks everyone for coming out. thanks everyone for coming out

Speaker 1: Thank you. Thank you. thank you