Thank you for standing by, and welcome to the Rocket Pharmaceuticals 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 for 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, and 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. Joseph 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 two 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 five-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 six evaluable patients over 24-54 months of follow-up now. Now, as we begin, I'd like to re-familiarize 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 a cell. Deficits in autophagy cause accumulation of vacuoles and also lead to myofibrillar disarray, 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 it's not curative and is associated with significant mortality as well as complications and a 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 eight 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 criterion. The study was conducted in three doses: one, a low dose 6.7 E13 vector genomes per kilogram in adults and adolescents who are 15 years or greater in age; a high dose at 1.1 E14 in adolescents and adults; and a third cohort receiving a low dose of 6.7 E13 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 the 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 five months after therapy.
Now, although this patient's data contributes to the safety analyses, this patient is not considered evaluable 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 at 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 three 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 two to four months following dosing and were reversible with supportive care. No additional SAEs have been identified after these post-treatment intervals. SAEs 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 four weeks. Steroid and/or immunomodulatory-related SAEs included three events of grade 3 skeletal myopathy that were considered due to steroid-induced exacerbation of underlying Danon disease myopathy. These resolved with corticosteroid discontinuation.
In 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 6.7 E13 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 % of cardiomyocytes that are positive for LAMP2. Expression was first observed at six 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 his five-year visit, shows 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 LAMP protein. 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 the 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 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 on the next slide. Moving on with 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.
It's truly remarkable to see a reversal in symptomatology, especially in such an aggressive and rapidly progressive disease. Finally, quality of life metrics show all patients reporting feeling better. Now, a five-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 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% decrease 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 six 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, and 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 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%-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, I'd 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 show decreases in circulating troponin levels that are also sustained to the most recent visit.
In fact, our two 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 of Medicine, represent 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 ahead 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 advisors, 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.
Certainly. Everyone at this time will be conducting a question-and-answer session. If you have any questions or comments, please press Star 1 on your phone at this time.
We do ask that while posing your question, please pick up your handset if you're listening on speakerphone to provide optimum sound quality. Once again, if you have any questions or comments, please press Star 1 on your phone. Your first question is coming from Cory Jubinville from LifeSci Capital. Your line is live.
Hi, can you hear me? Can you hear me? Hi, Corey. Yes. Yes. Hi, Cory. Hi. Hi. This is Teo Walter. I'm stepping in for Corey. Thank you for taking my question. So 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 th e heart? Thank you.
Great question. I'm going to hand this over to Jonathan. Thanks.
We utilize both cardiac magnetic resonance imaging, 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, Danon patients who have implanted devices, ICDs, may not be permitted to undergo 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 utilize 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, then 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.
Yes. Thank you.
Thank you. Your next question is coming from Greg Harrison from Scotiabank. Your line is live.
Hey, good afternoon, guys. Congrats on the update. Looks really good. And thanks for taking the question. 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 the patient's doing well and has expression now. And then if you could provide any additional color on patient five and the grade four adverse events seen with him, that would be great. Thanks so much.
Sure. So hi, Greg. Thanks for the question.
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. We actually never thought the patient completely lost protein expression. I think sometimes the autophagy system is regulated in a way that allows for maximal cleanup of cells when it's needed, and for that reason, it can be modulated over time by the cells themselves. Seeing it long-term is definitely reassuring. Five-year point is, as far as I know, the longest time point anyone's ever seen, and I think it reemphasizes and validates 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. I think the five-year time point here was highly reassuring for all of us. Thanks for that question.
On patient number five, this is nothing new. This is a patient that was treated quite a while ago, more than three 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.
Great. Thanks so much.
Yeah.
Thank you. Your next question is coming from Tyler Van Buren from TD Cowen. Your line is live.
Hey, guys. Thanks for the presentation. Great to see the long-term evidence of maintenance of these improvements in these patients.
Expression increases after 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. 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 three or beyond yet. And then second, if you believe it makes sense to wait to report the pivotal data until all patients have passed 12 months, or if six to nine months could make sense as we're seeing improvements in most patients by that time range. Yeah.
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 hearts, and just looking at the slide itself, if I'm, for example, looking at patient number two who reduced from 260 to 135 on LV mass index with 48%, or patient six who reduced from 141 to 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 were already near normal. So I think that what we're seeing here is a reduction and 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. Yeah. It was just on the pivotal data. If you think you need to wait for the 12-month primary endpoint to report it, or if six to nine months could make sense to report it, as a lot of these improvements in most patients are being observed by that time range. I'll hand this to Kinnari.
Hi. 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 and make it registrational enabling with FDA and EMA, so we'll likely, if we see positive trends in data at six, nine months, etc., our goal number one is to really talk to the health authority.
And ideally, we use the one-year 12-patient data cutoff in order to really have the publicly available and disclosed data by our principal investigator at one of the academic or medical conferences.
Thank you.
Thank you. Your next question is coming from Mani Foroohar from Leerink. Your line is live.
Hey. Thanks for the question and for the update. Very remarkable long-term follow-up data. Certainly some of the longest that we've seen in gene therapy coverage. I have a little bit of a different question, although similar in some ways to Tyler's. So it's very reasonable to think that plausibly 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've 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., seven versus 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?
Yeah. Hi, 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 reserve the possibility of approaching regulators whenever we feel that we've hit top line.
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 Fanconi anemia where we hit top line after a certain number of patients met the primary endpoint. So that's the closest reference I can do here, Matthew, but I can't quite give guidance on Danon. We'll figure things out as we go.
That makes sense to me. I'm going to quickly slide a second one in here. I know that I'm sort of overstaying my welcome a little bit on the Q&A. 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.
I've had a lot of discussions with people around what is the value of a PRV and how and 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, etc.? What are the timelines for those programs, and how should we think about PRV award and your views on that end market for those assets?
Yeah. 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 do anticipate approval starting in 2025 with LAD-I.
And the PRV could apply to LAD-I, Fanconi, and Danon, right? So that's a future source of non-dilutive capital that keeps us sleeping well at night.
Great. That's helpful. Thanks and congrats again.
Thank you. And we're now at the 30-minute mark. We do have a few more questions, and we'll continue to take more questions. Your next question is coming from Mike Ulz from Morgan Stanley. Your line is live.
Hey, guys. Thanks for taking the question, and 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 at, I think it was 12 months and continued to improve over a longer period, but then sort of reversed a little bit. Anything unique with that patient that you can call out or explain that? Thanks.
Yeah. The only thing I would call out there is this was a 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. In fact, for 1006, you can see he's the one patient who was higher on LV mass index at month six, and that's likely because of the higher dose. He required more steroids, so I'm not surprised that his 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 an adult. He's living independently, working a 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 of 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.
Very helpful. Thank you.
Thanks, Mike.
Thank you. Your next question is coming from Eric Joseph from J.P. Morgan. Your line is live.
Hi. Thanks for taking the question, and also thanks for updating us for this long-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, trying to 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 study plan treats that? Just wondering how it sort of accommodates for any kind of outsized or outsized-performing patients on LV mass decline and whether a responder analysis is also part of that assessment. Thank you.
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 null hypothesis is so stark that these patients don't remodel their hearts to develop the 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 of patients who have that degree of reduction would fulfill the primary endpoint.
Okay. Great. Thanks for taking the question.
Thanks, Eric.
Thank you. Your next question is coming from Dae Gon Ha from Stifel. Your line is live.
Hey. Good afternoon, guys. Thanks for taking the questions, and 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 two assessments, understanding that ICD is what's going to move the decision point between using either of these metrics. And then a clarification is, with the phase two fully enrolled, just wanted to get your latest thoughts on when the completion of dosing could happen. Thanks so much, guys.
Yeah. Hi, Dae Gon. 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 two. 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 three-month troponin run-in that some patients have to get through, but we'll get further updates as they come.
Sounds good. Congrats, guys. Thanks.
Thank you. Your next question is coming from Richard Law from Goldman Sachs. Your line is live.
Hey, guys. Good afternoon, and congrats on the data. Gaurav, you guys presented the data in a few places today, including AHA, this webinar, and also publication at New England Journal of Medicine. Can you highlight in contrast any differences or additional insights across the presentation? And then I have a couple of follow-ups.
Yeah. The one big difference in the NEJM versus what we showed today was the five-year biopsy for patient 1001. That was great news. It's just new. It just came out recently, so that's why it wasn't in there. The other difference, so 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 NEJM 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 on our presentation, we showed MRI changes over here. That's the only difference.
And again, to reiterate, that's slide number 12 that shows that all six of six patients reduced their LVEF by more than 10% at 12 months using best available either echo or MRI. So those are the two differences.
I see. Got it. And then for the LAMP2 expression, since the band within each grade are pretty wide, can you discuss how the LAMP2 expression trended over time within each of the grades? Or I don't know if you can provide numerical values, I think, especially for, say, patient two and three that drop from nine months to the later months. And also, what is the standard deviation or variability in LV mass reduction or LAMP2 expression in these measurements?
Yeah. 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, the 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, etc. So there's day-to-day variations that's going to drive up some protein expression some days and down some days. So I wouldn't read much into that. I think the bottom line is that as long as patients have a grade one improvement or more, all patients have been associated with long-term benefit. As you can see here, even patients like 1006 who had grade one for quite a while and patient 1001 who had low protein expression for a while, when you move to slide 11, both of these patients have remarkable benefits over time.
While we haven't quantified more specifically what level of grade one or grade two or grade three, 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 one 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? Thank you.
Yeah. I'll hand this to Kinnari.
Yes. A couple of things that we've put in effort for is, 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 is working with NDT and other organizations to have a grounds of genetic testing availability for patients with cardiac gene therapy, including LAMP2 initiation.
Great. Thanks, guys.
Thank you. Your next question is coming from Jason Zemansky from Bank of America. Your line is live.
Thank you. Good afternoon. Congratulations on the data. I appreciate you taking our questions. Wanted to circle back on one of your comments earlier regarding LAMP2 expression. Appreciate there's a level of variability here given a lot of different parameters. But after five 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? Thank you.
Thanks, Jason. That's a great question, and it's 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 new cells that come from stem 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 five 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 canine and clinical settings, of durability of episomal AAV transduction out to 7-10 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 heart extrapolation, it would be logical that the durability of benefit that we'll see could last for many years and potentially multiple decades. Thanks for the color.
I guess to kind of layer on another question here, is it not necessarily the extent of production per cell, but overall the number of myocytes that have been transduced? I think the more myocytes that are 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.
Perfect. Thanks for the color, guys. Appreciate it.
Thanks, Jason.
Thank you. Your next question is coming from Gil Blum from Needham & Company. Your line is live.
Hey. Good afternoon. And allow me to add my congratulations. 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 his overall response is a little lower? Does this have to do with the patient's baseline? And I have a follow-up.
Yeah. 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 had 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 he has greater benefit long-term than he 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. Yeah. And very importantly also, I think, I mean, the extent of response in patient 1006 has really been pretty substantial across 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 extent of fibrosis that's there.
We'll learn more about that as we have a larger data set from the phase two, and we'll take a deeper dive into things like the extent of fibrosis on MR in each and every patient that we're able to study, especially as we get a larger phase two data set.
Thank you for that, and maybe a closely related question then, so in your view, is there a patient baseline dependent ceiling effect for left ventricular mass reduction? Thank you.
I think the only really critical parameter at baseline that we identified in this phase one study was the patients who have a diminished ejection fraction, LVEF that'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 one and has continued into the phase two.
Thanks for taking our questions.
Thanks, Gil. Thank you.
Thank you. Your next question is coming from Whitney Ijem from Canaccord. Your line is live.
Thanks for taking our question and congrats on the positive data. This is Joanne on for Whitney Ijem. And maybe two slightly different 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? Thank you.
Kinnari, we'll 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 studies, we will be starting the female studies, especially in the severe female 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 one for PKP2 that we'll apply into a pivotal trial design.
Great. Thank you.
Thank you.
Thank you. And our last question is coming from Sami Corwin from William Blair. Your line is live.
Hey there. Congrats on the long-term data, and thanks for taking my question. I know it's a bit early to start 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 Danon disease 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? Thank you.
Yeah. No problem. So hi, Sami. Thanks for the question.
So I think the EF question and the label, we can't anticipate. I can say, though, that we always try to go for as broad a 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, these patients need to come in, get three 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. Great. Thank you.
Thank you. Ladies and gentlemen, this concludes today's conference. Thank you all for participating. You may now disconnect. Have a great day.