Rocket Pharmaceuticals, Inc. (RCKT) Earnings Call Transcript & Summary

Thank you for standing by, and welcome to the Rocket Pharma Investor Conference Call. As a reminder, today's conference is being recorded. I would now like to hand the conference over to your host, Meg Dodge, Head of Investor Relations and Corporate Communications. Please begin.

Hello, and thank you for joining today's webinar. Joining from Rocket is Chief Executive Officer, Dr. Gaurav Shah. On the line with me also to the Q&A session at the end of the webinar is Dr. Kinnari Patel, President of R&D and COO of Rocket; and Dr. Jonathan Schwartz, our Chief Medical and Gene Therapy Officer. As we begin, I'd like to briefly discuss the use of our forward-looking statements on this conference call. Statements made during today's webinar and our responses during the Q&A may include forward-looking statements, and these forward-looking statements are subject to known and unknown risks and uncertainties that may cause actual results to differ materially from the statements made. Factors that could cause actual results to differ are described in the disclaimer and our annual filings with the U.S. Securities and Exchange Commission including the Risk Factors section of our annual report on the Form 10-K filed with the SEC. As a reminder, this call is being recorded. In the press release and slide presentation regarding today's results is available on the Rocket Pharmaceuticals website. On today's call, we'll be sharing an overview of Rocket's data presented earlier today at the American Heart Association 2024 Conference during the late-breaking scientific sessions as well as data published in the New England Journal of Medicine, followed by Q&A. With that, I'll now turn the call over to Gaurav.

Thank you, Meg, and thanks, everybody, for joining today's webinar. On the heels of an exciting presentation earlier this morning at AHA by one of our principal investigators, Dr. Joe Rossano, for the RP-A501 Phase I trial. I'm also extremely excited to share that the data from this Phase I study was published today in the New England Journal of Medicine. Today's data shows the lasting impact of this treatment, and it has been about 2 years since we last provided any significant update on these patients. So I'm thrilled to share longer-term data from RP-A501 in this webinar. Now the long-term safety and efficacy results from the Phase I study showed that RP-A501 was generally well tolerated and all evaluable Danon disease patients demonstrated LAMP2 protein expression at 12 months and beyond. Today, I actually want to make a further and exciting update that the first patient who was treated in this trial back in 2019, just had a recent biopsy at the 5-year mark, and there is preliminary evidence of robust protein expression. The overall evidence of RP-A501 clinical efficacy included cardiac biomarkers, structural and symptomatic improvements each of which were observed in all 6 evaluable patients over 24 to 54 months of follow-up now. Now as we begin, I'd like to refamiliarize everyone briefly with Danon disease. Danon disease is a rare X-linked disorder characterized by severe cardiomyopathy and neuromuscular deficits. It's caused by the LAMP2 gene mutation. The LAMP2 protein is important for autophagy, which is like the recycling center of the cell. Deficits in autophagy caused accumulation of vacuoles and also lead to myofibrillar disarray and fibrosis and heart failure. For affected males, the median age of cardiovascular symptom onset is 13 years, the cardiac hypertrophy then progresses rapidly into early heart failure and eventually mortality. It's also worth noting that females are affected, but they are heterozygous and present a little bit later but also have frequent mortality in their 30s or 40s, sometimes earlier. The reality for patients is that a prognosis with Danon disease is poor. For males, progressive heart failure leads to death or transplant at a median age of 20 years, and medical therapy does not alter the course of disease. Transplant is the only effective therapy but is not curative and is associated with significant mortality as well as complications and the need for second transplant often. As shown here on the right, there's a time window when stabilization of cardiac function potentially with gene therapy may avert progression into advanced heart failure, after which it's too late. Rocket's investigational therapy, RP-A501, consists of an AAV9 capsid encoding the full-length, wild-type LAMP2B protein. AAV9 is cardiotropic AAV9 loves the heart. Systemic AAV gene therapy has been associated with immunologic toxicities, including complement-mediated thrombotic microangiopathy and hepatotoxicity. Danon disease skeletal myopathy may also be exacerbated by glucocorticoids, which are included as part of the immunomodulatory regimen in this program. Now as you can see here, the RP-A501 Phase I clinical trial was designed to assess safety and preliminary efficacy in male patients with Danon disease. The eligibility criteria shown on the left, included males age 8 or greater with disease causing LAMP2 variants, evidence of cardiac hypertrophy and symptoms of heart failure. The presence of neutralizing antibodies against AAV9 was an exclusion criteria. The study was conducted in 3 doses: one, a low-dose 6.7e13 vector genomes per kilogram in adult and adolescents who are 15 years or greater in age; a high dose at 1.1e14 in adolescents and adults; and the third cohort, receiving a low dose of 6.7e13 vector genomes per kilogram in pediatric subjects who are less than 15 years old. Now all these patients received an immunomodulatory regimen that included steroids, tacrolimus or sirolimus and/or rituximab used to mitigate the potential immune-related toxicities mentioned previously. Patient 1007, who was second patient dosed in the high-dose adult adolescent cohort as seen in the middle chart here was the only patient who had decreased LV ejection fraction at baseline of 32% and had disease progression requiring a heart transplant 5 months after therapy. Now although this patient's data contributes to the safety analysis, this patient is not considered invaluable for long-term efficacy. Looking at baseline characteristics for the patients in the trial, severe LV hypertrophy was present as indicated by increased wall thickness and LV mass index elevated BNP and cardiac troponin are shown here. All patients were on NYHA Class II at baseline indicating the presence of heart failure symptoms. As already noted in the prior slide, patient 1007 experienced progressive heart failure requiring transplant, again, this patient had low EF at baseline, had decompensated heart failure at baseline and was likely past the point of no return at which therapy would not have helped. This patient is currently stable more than 3 years post heart transplant. Regarding safety, I want to point out that there are no new updates with regard to the tolerability and toxicity profile of RP-A501 in the Phase I trial. All SAEs were observed within the initial 2 to 4 months following dosing and were reversible with supportive care, no additional SAEs have been identified after these post-treatment intervals. SAE is determined to be related to RP-A501 included AST/ALT elevation, pyrexia and nausea/vomiting, all seen in the low-dose adult patients. These were self-limited and resolved without incident. Patient 1007 in the high-dose cohort experienced complement-mediated TMA, thrombocytopenia and acute kidney injury requiring dialysis. This patient completely recovered platelets and renal function within 4 weeks. Steroid and/or immunomodulatory related SAEs included 3 events of Grade 3 skeletal myopathy, that were considered due to steroid-induced exacerbation of underlying Danon disease myopathy. These resolved with corticosteroid discontinuation. An additional instances of Salmonella sepsis and Grade 2 DVT were also associated with the steroid or immunomodulatory regimen. Notably, there were no treatment-related SAEs identified in the pediatric cohort at the 6.7e13 dose level. And this dose level was determined to be optimal for further investigation and is currently underway in our ongoing pivotal Phase II trial. Endomyocardial biopsy assessment showed durable LAMP2 protein expression by immunohistochemistry staining. The grading system measures the percent of cardiomyocytes that are positive for LAMP2. Expression was first observed at 6 to 12 months post dosing and sustained to the most recent visit for all evaluable patients. In fact, the preliminary assessment of patient 1001's biopsy, as I mentioned earlier, at its 5-year visit, chose robust actually Grade 3 expression. As an example, the right panel shows representative IHC staining from the patients that received the low dose at time points through 36 and 24 months, respectively. Positive immunostaining is indicative of higher levels of lab proteins. With the positive protein expression, we also see morphologic changes in cardiomyocytes. Danon disease results in the accumulation of large vacuoles containing cell debris and metabolites. These representative images show that vacuoles and cardiomyocytes are dramatically reduced as seen on H&E staining and electron microscopy. So on a cellular level, we see that protein is not just present, but actually working. This is the key slide. Here, we show the key efficacy assessments represented as the change from baseline to most recent follow-up visit, ranging from 24 months to 54 months. Now the first thing I'd like to point out is the ages of the adult and adolescent cohort patients. All of these patients are now between 22 and 25 years of age, at most recent follow-up. Remember, this is past to age where they would typically decompensate and need either a heart transplant or unfortunately pass away. These patients are not only alive, but we also know anecdotally that they are thriving and living much improved lives from before. Imaging assessments show stable LVEF in all patients at the most recent visit. Now recall that these patients did have preserved LVEF at baseline, so we expect to see stable LVEF here. Measures of hypertrophy show that all patients had reduction in heart size sustained out to the most recent visit. The LV mass index which, as a reminder, is also a component of our primary endpoint in the ongoing pivotal Phase II trial is a measure of left ventricular mass as measured by echo or MRI. This is indexed to the patient's overall body size, and it's done. We do this to adjust for normal or expected growth as younger patients grow up. The LV mass index decreased in all patients with a median reduction of about 23%. This is clear evidence of tissue remodeling in the heart, and we'll discuss this further in the next slide. Moving on to biomarkers. Patients demonstrated substantial reductions in BNP and cardiac troponin with mean reductions of about 50% and about 80%, respectively, further supporting the improvements in heart function. In terms of functional assessments, all patients moved from NYHA Class II to NYHA Class I. NYHA class is a commonly used standardized assessment that classifies the severity of heart failure in terms of the patient's symptoms. NYHA Class I corresponds to an absence of symptoms or limitations due to heart failure. So it's truly remarkable to see a reversal in symptomatology, especially in such an aggressive and rapidly progressive disease. And finally, quality of life metrics show all patients reporting, feeling better. Now a 5-point change in the KCCQ score is considered meaningful and actually has been associated with heart failure outcomes that are positive in other clinical studies. All patients here are above this threshold, and in fact, the mean improvement in KCCQ score is 26 points. Now I'd like to focus on the structural changes we see in the heart, specifically the reduction in hypertrophy as measured by LV mass index, measurements of LV mass shown here were conducted using either MRI when it was available, or echo in patients for whom MRI was not possible. MRI tends to be the more accurate method of generating images for structural measurements. However, some patients were not able to go under MRI, undergo MRI because of implantable cardiac devices. Now on the chart on the left, we show each patient's change from baseline over time. The dotted green line on the chart that's horizontal represents the 10% decreased threshold that we've identified for our Phase II pivotal study. The majority of patients do show reductions in LV mass index as early as 6 months, as you can see here and all patients sustained these reductions at all subsequent time points. On the upper right side of the slide, we show the percent change from baseline at 12 months, which is when we plan to assess our primary endpoint in the Phase II pivotal trial. And as you can see, all patients -- this is the first time we're reporting this, all patients had a 10% or greater reduction in LV mass index at the 12-month point -- 12-month time point. And remember, this is in conjunction with positive protein expression at 12 months that's been sustained. Moving to the bottom right. These LV mass index reductions were also sustained through the most recent visit for all patients with reductions ranging from 7% to 48%. Now in some cases, out 4.5 years from treatment. So we are truly seeing lasting structural remodeling and reversal of hypertrophy with this therapy. And lastly, just like to take a second to cover the improvement in biomarkers, specifically the troponins. Troponin levels are assessed by blood test and are an indicator of cardiac injury. Troponin levels are a key secondary endpoint in the Phase II pivotal study. As you can see here, all patients showed decreases in circulating troponin levels that are also sustained to the most recent visit. In fact, our 2 patients in the low-dose adult cohort, the longest follow-up are approaching normal limits. Now before we call the Q&A session to order. I'd like to reiterate what I've shared before, which is that when gene therapy works, it really works. When we're able to get the correct gene and protein into the right cell population prior to irreversible disease damage the effects can be transformative. We spent a lot of time designing the Phase I study, and it paid off because we were able to expeditiously align with the FDA on a trial design for our Phase II study with RP-A501. These data, along with the simultaneous publication of the Phase I data today in the New England Journal Medicine represents a critical milestone for cardiac gene therapy demonstrating for the first time long-term AAV conferred efficacy in a cardiac indication. We are so enthusiastic about the path to head for cardiac gene therapy programs like RP-A501, and I really want to thank our teams in Cranbury, New York and elsewhere. I want to thank our scientific advisers, our investigators and most importantly, the patients that we work with for their commitment to this program to advance the potentially life-changing treatment option for Danon patients. Importantly, with the rapid enrollment of the Phase II study and the ongoing dosing of patients in that study, we look forward to presenting a broader program update on epidemiology and prevalence in 2025 after dosing is complete for this trial. With that, operator, let's open the call up to Q&A.

[Operator Instructions] Your first question is coming from Cory Jubenvill from LifeSci Capital.

Can you hear me?

Yes.

This is Thibaut Pardo. I'm stepping in for Cory. So my first -- my question would be what information is being precluded by using different imaging techniques, for example, the fibrosis. And will this have an impact when aggregating the data as a whole or making any statements on the benefits of RP-A501 in the heart?

Great question. I'm going to hand this over to Jonathan.

Thanks. So we utilized both cardiac magnetic resonance imaging or CMR as well as echocardiography when imaging the patient's heart on the studies. The MR is a preferred imaging modality. However, in some of the institutions, patients -- Danon patients who have implanted devices, ICDs may not be permitted to undergo a magnetic resonance imaging. So when we have longitudinal MR available, especially when it's reviewed in a blinded, centralized manner, we will utilize those images as opposed to the echo. Echo is nonetheless very good. And we utilized echocardiograms whenever possible in a centralized blinded manner as well and in settings where patients have ICDs and institutional policy does not permit MR imaging than the echo is utilized. MR in general, provides a more consistent point-to-point precision for many of the cardiac parameters and also does allow assessment of late gadolinium enhancement LGE, which may indicate fibrosis. Echo nonetheless, is highly valuable and is an important resource as well. I hope I've addressed your question.

Your next question is coming from Greg Harrison from Scotiabank.

Congrats on the update. Looks really good. First, I wanted to ask about patient 1001, and if you've identified any reasons why the patient didn't have any expression detected at month 30 and 36 even though it appears patient is doing well and has expression now. And then if you could provide any additional color on patient 5 and the grade 4 adverse events seen with him, that would be great.

Sure. So Greg, thanks for the question. So on 1001, we saw ongoing evidence of vector copy numbers and RNA in those samples at month 30 and 36 this is also delineated in the NEJM article. So we actually never thought the patient completely lost protein expression. I think sometimes the autophagy system is regulated in a way that allows for maximum cleanup of cells when it's needed and its sort of -- and for that reason, it could be modulated over time by the cells themselves. So seeing it long term is definitely reassuring. 5-year point as far as I know, the longest time point anyone's ever seen. And I think it reemphasizes the -- and validate the thesis that episomal expression in the heart is going to be long-lasting. Cardiomyocytes do not turn over, as we've said multiple times. So I think the 5-year time point here was highly reassuring for all of us. So thanks for the question. On patient #5, this is nothing new. This is a patient that was treated quite a while ago, more than 3 years ago, and was treated with a low ejection fraction also at a high dose, got the highest viral particles that we ever delivered on the trial, did have a transient TMA event and acute kidney injury was on transient dialysis for a couple of weeks, and we've reported this previously, even at our first presentation back in 2020 or 2021. So nothing new here.

Your next question is coming from Tyler Van Buren from TD Cowen.

Thanks for the presentation. Great to see the long-term evidence and maintenance of these improvements in these patients. So expression increases up to 36 months in some patients, but LV mass index improvement seems to be largely stable beyond 12 months, which I suppose is good confirmation of the 12-month endpoint for the ongoing pivotal. But curious to get your thoughts on a couple of things. So first, just on the relationship of expression to LV mass index improvements and if you would expect further improvements in some of these patients beyond 12 months that maybe aren't at beyond a year, 3 or beyond yet? And then second, if you believe it makes sense to wait to report the pivotal data until all patients have past 12 months, or if 6 to 9 months could make sense as we're seeing improvements in most patients by that time range?

Yes. So in terms of LV mass index improving and/or stabilizing, I think it's important to note that some of these patients actually end up near normal. So there's not much point to continue to decrease LV mass, right? The really thick heart and just looking at the slide itself, if I'm, for example, looking at patient #2, who reduced from 260 to 135 an LV mass index with 48% and for patient 6 who reduced from 141 to 88, 38%, that's pretty meaningful. And once you're down to 80, 70, improving further doesn't really confer that much more benefit, right? It's already near normal. The patients who reduced less are -- were already near normal. So I think that what we're seeing here is a reduction in normalization or near normalization of LV mass index. And I think that's about as good as outcome that anyone could hope for. And then in terms of -- sorry, the second question was?

It was just on the pivitol data, if you think you need to wait for the 12-month primary endpoint to report it or if you -- 6 to 9 months could make sense to report it as a lot of these improvements in those patients are being observed by that time range.

I'll hand this to Kinnari.

That's a really good question. Because this is a single-arm study, what we want to do is really preserve the pivotal nature of it to make registration enabling with FDA and EMA. So we'll likely -- if we see positive turns in data 6, 9 months, et cetera, our goal #1 is to really talk to the health authority. And ideally, we use the 1-year 12-patient data cutoff in order to really have the publicly available and disclose data by our principal investigator at one of the academic or medical conferences.

Your next question is coming from Mani Foroohar from Leerink.

Thanks for all the questions and for the update, very remarkable long-term follow-up data. Certainly for the longest that we've seen in gene therapy coverage. So I have a little bit of a different question, although similar in some ways to Tyler's. So -- it's very reasonable to think the positively releasing data prior to the 12-month defined endpoint could be premature. I hear you, Kinnari. But if you see a number of patients who reached 12 months, cross the defined threshold, which is greater than the number of the patients you need in the study to have a positive outcome, i.e., 7 versus required -- 7 required, for example, whatever the number is. Could you then potentially engage with regulators proceed with a rolling submission? Would that be an interim analysis? If you have enough responders that a positive result is statistically inevitable. Does it not make sense then to stop the study early, given that there's no risk of unblinding because it's not a blinded study.

Yes. Mani, good operational question, great operational question. So I think we haven't disclosed the SAP, the statistical analysis plan. And because it's not blinded, we do have reserved the possibility of approaching regulators whenever we feel that we've hit top line and also we can share that publicly. I can't give any specific guidance for Danon at the moment, but I can refer you back to the way that we did for fanconi anemia where we hit top line after a certain number of patients met the primary endpoint. And so that's the closest reference I can do here, Mani. But I can't quite give guidance on Danon, and we'll figure things out as we go.

That makes sense to me. I'm going to quickly slide a second 1 in here. I know that I'm sort of overstaying my welcome a little bit on the Q&A. So you brought up fanconi, I think one of the debates that we have in kind of the current uncertain regulatory environment is, obviously, those companies that are more well capitalized and less subject to capital markets risk tend to do better. And I've had a lot of discussions with people around what is the value of a PRV and how -- on what time horizon you at Rocket may receive one or more PRVs. So could you give us a little bit of an update of where you guys are in terms of addressing LAD-I, progress towards potential PRV eligibility for eventual Fanconi approval, et cetera? Like what are the time lines for those programs? And how should we think about PRV award and your views on that end market for those assets?

Yes. I mean PRV prices are definitely fluctuating recently upward, which is reassuring. And we have been engaged in discussions for LAD-I with an undisclosed partner. So we feel pretty good about the ability to capitalize on these PRVs at the right time. We -- I do anticipate approval starting in 2025 with LAD-I and the PRV could apply to LAD-I, Fanconi and Danon, right? So that's future source of nondilutive capital that keeps us sleeping well at night.

Congrats again.

[Operator Instructions] your next question is coming from Mike Ulz from Morgan Stanley.

Congrats on the long-term update as well. Maybe just a quick one on the LV mass reduction, in particular, for patient 1006 looks like they met the threshold that I think it was 12 months and continued to improve over the longer period, but then sort of reversed a little bit. Anything unique with that patient that you can call out or explain that?

Yes. The only thing I would call out there is, this is with the high-dose patient. And when we decided to move forward with the low dose, it was keeping in mind that the low dose, we were already probably reaching peak efficacy already at the low dose and there was no reason to introduce more risk with the absence of additional efficacy. And factor 1006, you can see he's the 1 patient who was higher on LV mass index at month 6, and that's likely because of the higher dose you required more steroids. So I'm not surprised that this trajectory is a little bit different, but all the low-dose patients here, as you can see, remain below 10% long term. Jonathan?

And very importantly, at recent time points and at the most recent follow-up, this patient continues to show multilevel signs of profound improvement. This is a patient who resides in Europe. He's in adult, he's living independently, working the job. And by and large, really, really the overwhelming set of parameters for this patient indicate a strong and sustained benefit. And I think when looking at all these things, it's really important to evaluate each patient in totality and to evaluate the data points, not just point by point, but really the overall trend as opposed to any points that vary slightly relative to the trend, especially for echo, there will be some variations in assessments from time point to time point and this is really why having the overall picture over time is so valuable.

Your next question is coming from Eric Joseph from JPMorgan.

Thanks for updating us, this term follow-up. Maybe I just had a question on the pivotal and the treatment of change in LVMI as part of a co-primary endpoint. Just in calling out to -- trying see a mean of greater than a 10% decline in this study. Can you just talk about sort of how that's being calculated or how your status plan treats that? Are you, just wondering how sort of accommodates for any kind of outsized size performing patients on LV mass decline and whether a responder analysis is also part of that assessment.

So that aspect of the primary endpoint is not being evaluated in aggregate or as a median or mean. We're seeking that a specific group of patients meet the primary endpoint and have at least 10% reduction in LV mass index from baseline at 12 months. We haven't provided precise guidance on what that percentage of patients need to be, but because the no hypothesis is so stark that these patients don't remodel their [indiscernible] protein by themselves. We don't need to see each and every patient meet the primary endpoint for the study to be successful and likely a modest majority would be -- patients who have that degree of reduction would fulfill the primary endpoint.

Your next question is coming from Ha Dae Gon from Stifel.

I'll add my congrats on the long-term update looks robust. Maybe a question -- a follow-up question and maybe a short clarification. Following up on the earlier question, Jonathan, when it comes to cardiac MR and echo has it been clearly defined with the FDA. I guess, how much of a wiggle room there is between some patients who might be measured with an echo versus cardiac MR. And maybe if you can expand on the sensitivity of these 2 assessments, understanding that ICD is what's going to move the decision play between using either of these metrics. And then a clarification is with the Phase II fully enrolled, I just wanted to get your latest thoughts on when the late -- the completion of dosing could happen.

Gaurav here. So the FDA has agreed that we could use either echo or MRI, but MRI is preferable. It's just more accurate and that's what we're going to intend to do in the Phase II. In terms of the completion of dosing, we don't have any specific guidance, but I can tell you that, it's an active trial. We're dosing patients as soon as possible. And as you know, there is this 3-month troponin run-in that some patients have to get through, but we'll give further updates as they come.

Your next question is coming from Rich Law from Goldman Sachs.

Congrats on the data. Gaurav, you guys presented the data in a few places today, including AHA, this webinar and also publication at the New England Journal of Medicine. Can you highlight in contrast any differences or additional insights of [indiscernible] presentation? And then I have a couple of follow-ups.

Yes. So the one big difference to NEJM versus what we showed today was the 5-year biopsy for patient 1001, that was a great news. It's just new. It just came out recently. So that's why it wasn't in there. And the other difference, so we -- what we presented on this webinar is the same as what Dr. Rossano presented at AHA. The one difference on the NEJM paper was that for one of the patients 1001, we actually used echo in the NAM because we were required to have the same central reviewer and the same central reviewer was only present for echo and not this patient's MRI. But again, we had accurate reads on MRI in our database and MRI is preferable to echo. So because we had MRI in AHA and in our presentation, we showed MRI changes over here. That's the only difference. And again, to reiterate, that Slide 12 that shows that all 6 of 6 patients reduced their LVEF by more than 10% at 12 months using best available either echo or MRI. So those are the 2 differences.

I got it. And then for the LAMP2 expression, since the band within each grade are pretty wide, can you discuss like how the LAMP2 expression trended over time within each of the grade? Or I don't know if you can provide like numerical values. I think especially for like say, patient 2 and 3 that drop from 9 months to the later months. And also what is the standard deviation or variability in LV mass reduction or LAMP2 expression in these measurements.

Yes. I can't comment on LV mass variability at the moment. I think it's probably less variable than protein expression. I will say on protein expression that there's some waxing and waning depending on the needs, autophagic needs of the cells, right? There are times, even with fasting, there's more or less autophagy. With heavy meals, there's more autophagy. So there's day-to-day variations that's going to drive up some protein expression some days and down someday. So I wouldn't read much into that. I think the bottom line is that as long as patients have a grade 1 improvement or more, all patients have been associated with long-term benefit as you can see here, even patients like 1006 who had Grade 1 for quite a while in patient 1001, who have low protein expression for a while. When you move to Slide 11, both of these patients have remarkable benefits over time. So while we haven't quantified more specifically, what level of Grade 1 or Grade 2 or Grade 3, I think it's important to note that a little LAMP goes a long way in this disease. And just, again, the old analogy just turning on the switch of the vacuum cleaner you just need to let it go, and over time, it works.

I see. Got it. And then just 1 last question. Can you discuss any screening efforts that you have implemented so far? And also what other screening programs are you planning in the pediatric or newborn space?

Yes, I'll hand this to Kinnari.

Yes. A couple of things that we put in an effort for first of all, last year, we announced that we do have an ICD-10 code, which helps us to understand where the patient population is. The other component is we're working on a mission genome, which really working with Invitae and other organizations to have a grounds up genetic testing availability for patients with cardiac gene therapy, including LAMP2 mutation.

Your next question is coming from Jason Zemansky from Bank of America.

Congratulations on the data. I wanted to circle back on 1 of your comments earlier regarding LAMP2 expression. I appreciate there's a level of variability here given a lot of parameters. But after 5 years, do you have a sense of ultimately how long protein expression is likely to be sustained, especially given that myocyte turnover is low. I guess, fundamentally, ultimately, what level of LAMP do you think is necessary to provide some of these longer-term benefits to kind of maintain them maybe decades into the future.

Thanks, Jason. That's a great question and a little bit philosophical, which I like. I think the bottom line is that these patients who might have passed away or needed a heart transplant in the late teens, early 20s seem to be thriving. Some of them are working full-time jobs and going to university. We know that all of us are basically born with the same heart cells that we still have. There's a little bit of attrition, but there are no use cells that come from some cells or otherwise into the heart over decades. So we anticipate potentially that we could have long-term durable benefit. Obviously, we can't guarantee it. But given how these patients are doing 5 years out now, I think we're very hopeful that hopefully, these patients avert heart transplant and death for quite some time.

And I think it's also worthwhile to add that at present now there is data in hemophilia, both in [ anon ] and clinical settings of durability of episomal AAV transduction out to 7 to 10 years. And that's in the liver, which is an organ where there is more cell turnover and cell division relative to the heart. So although it's really hard to do any hard extrapolation, it would be logical that the durability of benefit that we'll see could last for many years and potentially multiple decades.

I guess to kind of layer on another question. Is it not necessarily the extent of production per cell, but overall, the number of myocytes that have been transduced?

I think the more myocyte better transduced, yes, the more longevity. But having said that, again, the data speak for themselves, even when we have less than 25% expression, we're seeing long-term benefit and durability. So it really is remarkable that a little LAMP goes a long way.

Your next question is coming from Gil Blum from Needham & Company.

Allow me to add my congratulations, a very impressive long-term follow-up here. So just a couple from us. Specifically as it relates to the high-dose patient, that appears to not have any dose dependence, which supports the use of the lower dose. Any thoughts as to why it kind of seems like a overall response is a little lower? Does this have to do with the patient's baseline? And I have a follow-up.

Yes. It's hard to know. I can tell you that the patient who was transplanted, we have an explanted heart. And we know that, that patient has full thickness LAMP2 expression in the explanted heart at a high dose. 1006 responded a little bit differently in the early days, but you can see over time, he's improved his protein expression to 3 plus as well. So I do think that there's variability, it could be that has greater benefit long term than you did in the early days. But I do think the bottom line is that once you've hit efficacy, there's no need to risk further safety if you already have full efficacy at the low dose, which is what we've done.

Yes. And very importantly also, I think, I mean, the extent of response in patients, patient 1006 has really been pretty substantial across the many of the parameters, obviously, there's been less of a reduction in left ventricular mass index relative to some of the other patients. Bear in mind that, that was a patient who was 21 years of age at the time of treatment. And that -- the remodeling of the heart is going to be dependent on a number of different factors, including age and the extensive fibrosis that's there. We'll learn more about that as we have a larger data set from the Phase II and we take a deeper dive into things like the extensive fibrosis on MR in each and every patient that we're able to study, especially as we get a larger Phase II data set.

And maybe a closely related question. So in your view, is there a patient baseline dependent ceiling effect for left ventricular mass reduction.

I think the only really critical parameter at baseline that we identified in this Phase I study was the patients who have diminished ejection fraction, LVEF, it's low, below 40% or even below 50%, likely have extensive fibrosis, more advanced cardiomyopathy and advanced heart failure and are less likely to derive benefit as was the case with patient 1007 or patient 5 And that's why the eligibility criteria with respect to preserved LVEF was implemented prior to the pediatric cohort in the Phase I that has continued into the Phase II.

Your next question is coming from Whitney Ijem from Canaccord.

Congrats on the positive data. This is Joohwan on for Whitney Ijem and maybe 2 slightly different Qs cues from us. First, given the great longer-term data shown today, what's your latest thinking around a female Danon trial? And secondly, you touched on this a little bit before, but can you speak on any read-through you might have from these data and durability to the PKP2 program despite the different capsids?

Kinnari, will do the female trial, and I'll talk about PKP2.

So we realize that the Danon disease impacts the female and honestly, they don't make it past the mid 30s and 40s. So it is a severe disease. We remain committed to the fact that upon completion of all of the patients dosed in the male study, we will be starting the female studies, especially in the severe final population that demonstrate unfortunate clinical outcomes similar to those of males.

And then on the PKP2 question, I don't know if there's specific read-through. I think except to say that we've learned a lot about how to leverage appropriate biomarkers in the Danon trial that we can try to apply to PKP2, so that's all I can say at the moment, but each trial is different, each disease is different, each vector is different, and we'll learn a lot from the Phase I for PKP2 that will apply into a pivotal trial design.

And our last question is coming from Sami Corwin from William Blair.

Congrats on the long-term data. I know it's a bit early to speculating about what the label might look like. But do you think that the label could potentially exclude patients with reduced EF? And what percentage of patients do you think have reduced ejection fraction? And then given that you announced a couple of months ago, the completion of enrollment in the pivotal trial. I guess, what are the current bottlenecks in terms of treating those patients?

Yes, no problem. So I think the EF question in the label, we can't anticipate. I can say, though, that we always try to go for as broad label as possible. But patient safety is first and paramount. So we'll have those discussions at the right time with FDA and EMA. In terms of what's gating for the dosing, it's -- there's -- these patients need to come in, get 3 months of troponin at baseline, they need to get cardiac biopsies and other things to be fully eligible. So all of that is going on, and we're dosing patients as rapidly as possible now.

Thank you. Ladies and gentlemen, this concludes today's conference. Thank you all for participating. You may now disconnect. Have a great day.