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

Thank you for standing by, and welcome to the Rocket Pharma Investor Conference Call. [Operator Instructions] I'd 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 us today. From Rocket, it's Chief Executive Officer, Dr. Gaurav Shah. On the line with me also for the Q&A session at the end of this webinar is Dr. Kinnari Patel, President and Head of R&D and COO of Rocket as well as Dr. Jonathan Schwartz, our Chief Medical and Gene Therapy Officer. As we begin, I'd like to briefly discuss the use of forward-looking statements on this conference call. Statements made during today's webinar and our responses during 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 factor of our annual report on Form 10-K filed with the U.S. Securities and Exchange Commission. As a reminder, the call is being recorded, and the press release and slide presentation regarding today's results is available on the Rocket website. On today's call, we'll be sharing an overview of Rocket's preliminary data from our Phase I trial of RP-A601 for adult patients with PKP2-arrhythmogenic cardiomyopathy presented earlier today at the American Society for Gene & Cell Therapy's 2025 Annual Meeting during the late-breaking scientific sessions. And with that, I'd like to now turn the call over to Gaurav.

Thank you, Meg, and thank you, everyone, for joining today's webinar on the heels of an exciting presentation earlier this afternoon at ASGCT by one of our principal investigators, Dr. Barry Greenberg for the RP-A601 Phase I trial. Bottom line upfront. We believe that we have reached both a safe and efficacious dose, and based on the overall risk benefit seen so far, we are no longer dose escalating in this trial and will move 8e13 vector genomes per kilogram into the next phase of development. And with that, I'm really excited to share preliminary data from the first cohort of patients, which was at 8e13 vector genomes per kilogram. That was Cohort 1, and there will be no more cohort in the Phase I study. The preliminary safety and efficacy results from the Phase I study show that RP-A601 was generally well tolerated and demonstrated initial efficacy. All three patients showed early signs of disease modification through improvements or stabilization across multiple biomarkers and clinical parameters. Now as we begin I'd like to briefly familiarize everyone with Plakophilin-2 arrhythmogenic cardiomyopathy otherwise known as PKP2-ACM. This is an inherited autosomal dominant progressive heart disease that's caused by mutations in the PKP2 gene and characterized by life-threatening ventricular arrhythmias, cardiac structural abnormalities and sudden cardiac death. PKP2 gene encodes for Plakophilin-2, which is a scaffolding protein critical for the assembly and stability of the cardiac desmosome. Loss of PKP2 at the cardiomyocyte junctions impairs the tissue structural and electrical integrity. This leads to progressive electrical instability and ultimately, arrhythmic disease and RV failure. The disease predominantly affects the right ventricle and leads to right-sided heart failure otherwise known as ARVC. However, since left dominant and biventricular forms have also been discovered. This has led more recently to the use of the term ACM. Now electrical manifestations can precede structural abnormalities, including fibro fatty infiltration of the heart muscle, mostly the right side and eventually ventricular dilatation, which then leads to ventricular arrhythmias and ultimately sudden cardiac death and sudden cardiac arrest at times. PKP2-ACM affects approximately 50,000 adults and children in the U.S. and Europe. Life-threatening arrhythmia and sudden cardiac death are hallmark features of PKP2-ACM. Most patients receive ICDs for primary prevention. However, this does not modify disease progression. While ICDs can be lifesaving, device shocks are traumatic and significantly impact the quality of life. They are often described as painful, unexpected and anxiety-inducing events. They're actually not near-death experiences, they're death experiences. These patients die and come back to life. Current medical management includes beta-blockers, antiarrhythmics and ablation. These address symptoms, but none of these are disease-modifying at the root cause. Heart transplant has historically been the only definitive intervention but has high rates of failure and/or second transplants. Exercise restriction is important to reduce arrhythmic risk for these patients. The restrictions don't just stop at strenuous endurance exercise or extreme sports but can affect other daily living functions even walking up the stairs or taking a hot shower. These are all known to increase the risk of arrhythmic events and the chances of sudden cardiac death. RP-A601 consists of an AAVrh74 capsid encoding the full length wild-type PKP2 protein using a cardiac-specific promoter. The use of the AAVrh74 capsid has been associated with a relatively favorable safety profile in the e14 range, along with strong cardiotropism. We know that systemic AAV gene therapy has been associated with immunologic toxicities, including TMA and hepatotoxicities and while there are noted safety risks, these are far less frequent for rh74 at the e14 dose range, which we thought we may have had to go up to in a heterozygous disease such as PKP2. Fortunately, we do not. In preclinical studies, RP-A601 demonstrated strong cardiac tropism, improved survival and reduced PVCs and arrhythmias in a conditional PKP2 knockout model. As you can see here, the RP-A601 Phase I clinical trial was designed to assess safety and preliminary efficacy in adult patients with PKP2-ACM. The eligibility criteria, you can see here on the left included male or female age 18 years or greater with genetic and clinical PKP2-ACM diagnosis and an ICD implanted at least more than 6 months prior to enrollment. Patients with severe RV dysfunction, LV ejection fraction of less than 50% and/or NYHA Class IV heart failure were excluded. The first three patients were enrolled into the first cohort of the single IV infusion of RP-A601 at 8e13 vector genomes per kilogram, and all three of these patients received an immunomodulatory regimen that included steroids, sirolimus and rituximab that was used to mitigate the potential immune-related toxicities. And we're also conducting a parallel natural history studies to support the overall development of this program. Now looking at baseline characteristics for the first three patients in the trial, all patients were NYHA Class II, meaning they had mild symptoms of heart failure and had an extensive history of prior and current beta-blockers and/or antiarrhythmic agents in addition to having an ICD. One patient had mild-to-moderate RV dysfunction on echo while the other two showed normal RV function at baseline. Now let's take a minute to talk about safety. The data cutoff for safety was May 6, 2025, and generally, RP-A601 was well tolerated. Most adverse events were mild or moderate and self-limited, consistent with other AAV therapies, and there were no dose-limiting toxicities. Now one patient, 1003, the first patient treated, experienced a treatment emergent SAE of bacteremia with sepsis, Grade 3 ALT elevation and limited episode of pancreatitis during the period when he was receiving immunomodulatory therapy, and it's most probable that this patient's SAEs were related to immunosuppression and not to the AAV therapy itself. All reported SAEs for patient 1003 resolved rapidly within two months and without any further clinical manifestation or sequelae. Notably, we did not see any arrhythmia-related SAEs, TMAs or myocarditis. On this slide, we see that all three patients showed evidence of demonstrable cardiac transduction of RP-A601 as seen by #1 Vector Copy Numbers, which range from 3 to 8 per diploid nucleus at the most recent visit and also by mRNA expression, which was observable at 3 months and sustained at the most recent visits. These were not shown during the ASGCT presentation. The next slide shows Western blot analysis for PKP2 at 6 to 12 months. Expression was maintained or increased. Here, PKP2 expression is quantified as the ratio of nanogram PKP2 to microgram total protein. And you can see here that the first patient, 1003, already had relatively high expression at baseline. There is variability at baseline in this disease. Our current belief is that both PKP2 expression and background total protein expression increased in concert meaning that as PKP2 protein expression increased, so did the background total protein expression. This resulted in what looks like maintenance of the same ratio even though the PKP2 protein increased as you'll see in a couple of slides. It's important to note that this ratio can change from disease cells to healthy cells. So the ratio may stay the same while still reflecting higher PKP2 here -- I am sorry, it's important to note that the total protein can change from disease cell to healthy cell. So the ratio may stay the same. Also, the 0.5 nanograms per microgram of PKP2 expression may represent fully normal expression. That's our current theory, given that all patients seem to regress to that level of protein expression over time. And with this Vector Copy Numbers, it's unlikely to go much higher. This theory, of course, remains to be validated. Now the other two patients, 1011 and 1010 had lower expression at baseline and saw an increase by 110% by 6 months for 1011 and by nearly 400% at 6 months for 1010. Patient 1010 did demonstrate a strong increase at 3 months that appeared to normalize by 6 months, again, possibly reflecting improved overall protein content. So despite little changes in overall PKP2 expression, a more sensitive cell-by-cell immunofluorescence analysis of PKP2 shows increasing desmosomal PKP2 over time as a percentage of the total cardiac muscle area. We used to call this slide the Christmas tree slide. The Christmas tree has now become a forest at 12 months. In correlation both the Desmocollin-2 and Cadherin-2 immunofluorescence graphs show an increase in respective protein staining areas. Please note that Desmocollin-2 is a direct binding partner of PKP2 while Cadherin-2 is not. The observation that the expression of both is increasing, is consistent with the possibility that increased PKP2 is functional and able to recruit these proteins to the intercalated disc. And now for the forest slide, we can see the same trends visually with discernible Cadherin and PKP2 co-staining at the intercalated disc at 6 and 12 months post infusion. This slide shows clear localization of PKP2 to the intercalated disc, which can appear as short worms or discs depending on the orientation of the cell. On a cellular level, we see strong visual evidence that protein is not just present, but is reaching its target. And this leads us to believe that increased PKP2 expression is having a functional impact in remodeling the desmosomal cell-to-cell junctions and this may be stabilizing or increasing plaque density at the intercalated disc with more functional cell-cell connections. This may be increasing expression or trafficking of other key components connecting the cytoskeleton to those regions where these network of proteins needs to work together for cardiomyocyte function. Our approach focuses on restoring that integrity not just patching the glue, but reinforcing the nails and reconnecting the transport network. So these junctions can mature, stabilize and function reliably under stress. Collectively, the data suggests that RP-A601 drives an increase in the number of desmosomes at 6 months post dosing and a further increasing -- increase in desmosomes at 12 months. Remember, this is the same patient with no change in total PKP2 by Western blot, yet the increase in desmosomal PKP2 signal suggests exogenous PKP2 is able to target heart tissue correctly and mechanically transform the intracellular site. And before we move to the next slide. Remember, green and red, when you add them up, make yellow. So on the bottom right, you see the yellow forest, which shows the localization of protein to the desmosome specifically. Patient 1011 also experienced an increase in total PKP2 that plateaued at 0.5 nanograms per microgram and similar to patient 1003, Desmocollin and Cadherin also increased expression over time, most notably at 6 months. Patient 1010 showed an increase in total PKP2 protein that plateaued at 0.5 nanogram per microgram. The quantitative immunofluorescence data show a small increase in PKP2 here, but a more comparable increase in Cadherin and Desmocollin at 6 months post dosing as seen with the other patients. And once again, the increases in Cadherin and Desmocollin are highly suggestive of improved protein trafficking, increased desmosomes and generally stronger cell-cell connections at their intercalated disc. And now for clinical results. In terms of functional assessments, both patients who had more than 6 months of follow-up remarkably moved from NYHA Class II to NYHA Class I. NYHA class is a commonly used method to classify the severity of heart failure. NYHA class I actually corresponds to an absence of symptoms or limitations of heart failure. As noted previously, with the baseline characteristics, only patient 1011 had diminished RV function by echo at baseline, and this patient saw an improvement to normal. The other two patients were normal at the beginning and after treatment as well. They remain normal. The two patients with the longest follow-up had major improvements in KCCQ scores as well with a 34-point improvement for the first patient, 1003 and a 41-point improvement for 1011. Please note that even 5-point improvements in KCCQ score are considered clinically meaningful. As in Danon disease, clinical and global functional improvements usually take more than 6 months, and we think something similar is occurring here as molecular changes translate into clinical improvements over time. And now let's talk about the arrhythmias. We're pleased to share preliminary indications of improvements or stabilization across multiple clinical markers of arrhythmia burden, which was assessed by ambulatory rhythm monitoring and EKG. And importantly, as you see by the variable arrhythmia burden at baseline, we do not think that any single marker can be sufficient enough to form a conclusion. And we'd rather see the importance of having a comprehensive data set, just like we've done for Danon to show the true clinical benefit across many different factors. For example, we don't think PVCs alone tell the full story. They can be variable due to exercise, caffeine intake, even hot showers. 1003, the first patient had a modest PVC burden at baseline, but nevertheless, still saw a 63% reduction. The second patient 1010 with a higher PVC burden saw a 60% reduction in PVCs and demonstrated elimination of NSVT episodes and reduction in EKG leads with T-wave inversions reduced from 6 leads to only 2 leads. Patient 1011, who had the highest PVC burden and T-wave inversion in 4 leads saw a more modest reduction in PVCs and no change so far in T-wave inversions at 9 months. We believe that longer follow-up, of course, is necessary to fully understand RP-A601's ability to modulate electrical abnormalities, but these early results are certainly encouraging. In summary, RP-A601 was generally well tolerated. There were no dose-limiting toxicities. RP-A601 promoted desmosomal localization of PKP2 and associated transmembrane intercalated disc proteins between 3 and 12 months after treatment. We observed preliminary indications of improvement or stabilization in arrhythmia burden, heart function and quality of life. Now before we open the call up for Q&A, I want to really reiterate what I 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. In summary for today, RP-A601 administered as a single 8e13 vector genome per kilogram infusion with a transient immunomodulatory regimen, was associated with acceptable and reversible adverse events that were largely mild-to-moderate in severity with the most serious event occurring in a single patient and was -- that was predominantly related to immunomodulatory therapy and was reversible and reversed. So three points. First, a single 8e13 vector genome per kilogram RP-A601 infusion conferred evidence of increased overall and myocardial distributed PKP2 with increased expression and co-localization of other desmosomal and adherens junction proteins. This is highly consistent with a much more normalized cardiomyocyte cell-to-cell interface. Secondly, these cardiomyocyte histological modifications were accompanied by evidence of PVC reductions in the three patients, elimination of NSVT presence on 24-hour monitoring in the only patient who had NSVTs at baseline and a reduction in the number of EKG leads with T-wave inversions in one patient. RV function assessed by echo remained normal for two patients and actually improved from mild-to-moderate to normal in the one patient for whom it was deranged at baseline. Thirdly, patients reported quality of life as measured by KCCQ-12, has improved by more than 75% from baseline for two patients who had more than 6 months of follow up. These two patients also reported fewer functional symptoms by investigator assessment with improvements in NYHA Class from II at baseline to Class I or asymptomatic at most recent visit. The initial results suggest that RP-A601 has the potential to confirm normalized myocardial intracellular structure in PKP2-ACM patients with concomitant potential for stabilization or improvements in RV function, improvements in cardiac preexcitation and arrhythmogenic substrate and improved overall symptoms and functional capacity. With that, as I said, at the bottom line upfront. We have determined based on the overall benefit risk of the first cohort of patients treated that 8e13 vector genomes per kilogram will serve as our final dose and no further dose escalation is necessary. We plan to move forward with designing the next phase of development, including a potential pivotal trial for patients with PKP2-ACM. Thank you. And with that, operator, let's please open the call to Q&A.

[Operator Instructions] Your first question is coming from Andrew Tsai from Jefferies.

Congrats on the very nice data update. So my question is around the dose. What makes you confident this is the right dose for the pivotal trial? What variables led you to land on this one -- this dose, especially because if the SAEs were due to steroid, why not dose higher and get more efficacy? And then secondly, what would be the anticipated patient size and timing of the pivotal trial start? Or is that a subject of FDA discussions?

Great questions. So number one, I'll start with the preclinical mouse to human one. The way we picked our dose is that we used our learnings from the Danon program and the preclinical mouse data seem to suggest that we should start somewhere in the mid-e13 range. We started a little bit higher than the mouse efficacy just like we did for Danon. That was a formula that seemed to work there. And that's why we started with that dose. In terms of why we think this is the dose. Well, the VCNs are already 3 to 8, several months after treatment, you can't really go higher than 3 to 8 safely. We think that we're hitting a plateau of protein expression for the reasons I mentioned earlier. And we're seeing what we think are early and encouraging signs of efficacy. Obviously, we need to follow these patients for longer to be sure. And I think longer follow-up, 1 year, even 18 months for some of these patients might help a lot in understanding what the endpoint should be. In terms of the timing and size and next steps, we're not going to be able to comment on that now, but we are going to start exploring what the next phase of development would look like.

Your next question is coming from Greg Harrison from Scotiabank.

Congrats on the data. Given the protein expression that you've seen here in these early stages, what are your expectations for the impact on arrhythmia burden at 12 months and beyond?

Greg, thanks for the question. It's hard to know. I think we are seeing an impact already even before 12 months, certainly at 12 months. We'll see how the patients with the higher arrhythmia burden at baseline perform further out at 12 months and beyond. I would emphasize again that it's a fingerprint here that we need to look at, not any single either PVC or other arrhythmia. There's a signature here, there is an ARVC risk score, for example, that combines a lot of these as predictive factors for fatal arrhythmias, and we'll be looking at all of that in concert as we develop the next phase of development. But based on what we see right now, we're hopeful that these trends continue and -- into what's a good pivotal trial design.

Great. And then based on the trends you've seen so far and maybe any read-through from the Danon program, can you just comment on your expectations for durability?

From Danon, as we presented at AHA, we had durability up to 5 years with 3-plus protein expression at 5 years. So cardiomyocytes don't turnover. We have basically the same cardiomyocytes that we were born with. So unlike other organs, we don't anticipate a lot of turnover there. So durability, we think, will be maintained and that's the learning from the Danon program so far.

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

This is Paxton on for Rich. Congrats on the data. Just had a couple of questions with regards to the safety profile. So specifically, based on the SAEs observed with the immunosuppressive regimen, do you anticipate making any further changes to that? And what kind of gives you confidence that these AEs won't occur in more patients in the future? And then I have a quick follow-up.

Yes. I think that -- we don't anticipate any changes to this regimen. It's not really a burdensome regimen and what gives us confidence on SAEs. I mean, rh74 has a good profile and certainly in the e13 range, I think where rh74 programs did run into some hiccups were more in the e14 range, so given that we didn't even have to go to the e14 range, we do feel good about it. Obviously, time will tell. In terms of these particular patients, most SAEs or AEs with AAV tend to occur in the first 2 to 4 months. So now being beyond that, obviously, one never knows, and sometimes things can come back. But based on what we see so far, the current regimen feels pretty good for this dose 8e13.

Got it. That's helpful. And then just another quick one on safety. Given ICDs are really highly prevalent in this population, what are some of the late onset safety concerns that you're monitoring in these patients and just how does some of those safety considerations differ from your other programs like Danon?

Yes. I'll hand this one over to Jonathan for late onset safety concerns after the first few months.

Yes. I mean that's not been really a part of our experience to date, really with any of our AAV programs or our lentiviral programs. There obviously are always hypothetical risks of hepatocarcinogenesis due to the heavy AAV transduction in the liver. But most of those concerns are really isolated to very specific murine experiments where there's been integration at a Rian locus in the mouse that doesn't exist in human beings or primates for that matter. And largely, that's not been borne out in the clinical experience, including some of the AAV programs now that have really generated upwards of 5 years of data. So obviously, all of the patients will be monitored long term for any number of things. And we don't envision that there would be any ICD-specific gene therapy-related delayed safety concerns.

Your next question is coming from Josh Schimmer from Cantor.

First, for an autosomal dominant condition, it seems like the baseline protein expression levels maybe even well below 50% or even closer to 10% to 20%. How do you explain that?

Josh, thanks for the question. So I wouldn't interpret the one there, as 100%, right? They are low. I would say that 100% is probably somewhere near the middle of that graph. That's number one. Number two, we should never hang our hat on a single assay for protein expression. There's a lot of variability in how we measure total protein. One of the issues with this condition, Josh, is that, cadaver hearts, when you take PKP2 out, the PKP2 protein degrades really quickly. So there's no real understanding of what normal looks like. We're sort of surmising based on the evidence here with putting together the Vector Copy Numbers, the RNA and where the protein seems to localize around 0.5 in those graphs. So there is going to be variability. Now as far as the autosomal dominant condition issue, there's going to be variability in these patients. And I think, all we can do here is just confer the maximum dose possible that's safe.

I would just further that in. That's a very Josh Schimmer question, by the way. So thank you for that. I think the issue is that you're going to have -- most of our patients are -- patients all have different truncating mutations, but even though they are all truncating, there's still going to be differences in those mutations. And in some of those situations, you will potentially have elements of protein that are nonfunctional. I think it's highly likely that patient 1003 who had somewhat higher baseline expression of PKP2 on Western blot, had some presence of dysfunctional protein, which is why on Western that patient didn't increase, but nonetheless, on immunofluorescence in which we're able to measure not just total number, but the percentage of protein or protein as a percentage of overall myocardial protein, things increased and why we saw the increases in those additional proteins that make up the desmosome in the intercalated disc.

Okay. Got it. Second question is two patients with very good reduction in PVCs, the middle patient there, not quite as good. Why do you think given such robust protein replacement, there are still meaningful rates of arrhythmia, does it reflect perhaps scarring damage, fatty infiltration into the heart that happens as the disease progresses. And then if so, would starting earlier likely have a more dramatic effect? And how might you plan on exploring that?

So I'm going to go out here. I'm going to answer the question, but I'll say upfront, it's speculative. If you look at that patient who has been followed for 9 months and the PVCs went down a little bit, 9%, you can also see, first of all, that the RV systolic function, it actually decreased from mild-to-moderate to normal, right? It started mild-to-moderate, it ended up normal. Remember, RV dilatation and failure is what is fatal for these patients, not the arrhythmias because the ICDs ultimately will catch the arrhythmias in most cases, right? So this patient had improvements in RV function, which to us is even more meaningful than a single parameter such as PVCs. Secondly, note that they had a 76% increase in KCCQ score from 54 to 95. NYHA Class decreased from II to I. They are moving a lot more. They're -- maybe, they're exercising. Exercise increases PVCs, so this patient may have a decrease in PVC, but it's not captured here because they're clearly moving around a lot more.

Okay. Got it. And then the question about perhaps moving into younger patients to try to catch the disease sooner.

Yes. sorry. So we will ultimately try to move this earlier, in drug development in general, we want to start with the highest unmet need. That's where the biggest -- we're going to get the greatest access and buy in as well as maybe the best pricing. So we want to start there. But eventually, all gene therapies should be seen like vaccines. I don't want to say vaccines in the current administration lingo, but preventative of future true disease that these patients develop. So it's early in life as possible, genetic testing is a big part of our program, and we're very active in those efforts as well.

And then last question for the patient who developed bacteremia sepsis, pancreatitis, et cetera. Were there any obvious risk factors that you could identify that may help mitigate that kind of side effect in the future? And how are you thinking about that immune prophylaxis regimen going forward at this dose?

Great question. With every patient that we treat at Rocket and also learning from other patients who have had adverse events on other programs, we constantly try to monitor anything that would be predictive of SAEs. There was nothing particular in this patient that would have worried us. But the good news is that with Dr. Barry Greenberg, he intervened very quickly with a combination of antibiotics and steroids to minimize this AE, and it went away pretty rapidly.

Your next question is coming from Mani Foroohar from Leerink Partners.

I also have a 37-part question with four follow-ups. Just teasing, no, I have a broader question, which might take just as long to answer. I know there's been some discussion of do you move younger? Do you move dose up, et cetera? Kind of looking out to pivotal design and end points a little bit early. But as you think about that design, what subset of patients should/will you be focused on enrolling?

This one I'll give to Kinnari.

Thank you for your question. So for us, we are really focused on similar patient population to the Phase I. So I believe the inclusion-exclusion criteria will virtually remain the same for the initial pivotal study. At this point, we are following these patients, these three patients a little bit further along just to make sure that we're able to tie up everything from not just the biopsy data, but all the way to some of the PVCs and arrhythmias as well as NYHA classification. And based on that information, we'll approach the FDA to design a pivotal study but that is the starting point. For life cycle management in the future, we do want it both move to younger patient population and ideally patients without an ICD, but that's really going to be a 2-step process -- 2 to 3-step process.

Your next question is coming from Cory Jubinville from LifeSci Capital.

Congrats on the data. Kind of a follow-up to the previous two questions that have been asked. As it relates to unmet need, you put out these estimates of -- conservatively, there may be about 50,000 PKP2-ACM patients in the U.S. and Europe. Obviously, the end goal is to treat all patients, but this can be a relatively heterogeneous disease. And so how are you thinking about the immediate prevalence of those that would be addressable as you approach commercialization or a pivotal study? What's kind of the prevalence out of that 50,000. How should we be thinking about that?

Yes. In every gene therapy application, you want to find patients who have enough evidence, signs or symptoms of disease to benefit from treatment, but also patients who are not so far progressed that it's too late, right? So that's true for Danon, that's even true for Fanconi Anemia, that's true for all the gene therapies that we've certainly worked on and probably out there. I think here, 80% of these patients have ICDs, which means that most of them who are diagnosed already have signs and symptoms of disease and possible fatal arrhythmia. So I believe that if we exclude those who have antibodies to rh74 and exclude those patients who are very early and don't have an ICD placed yet, possibly the majority of the rest of the patients could benefit from treatment. So I think the addressable market like Danon, is going to be a large part of the total population here.

Got it. That's really helpful. And as a second question, from the data we're seeing today, right? We've seen a large improvement in PVC burden in 2 out of 3 patients in addition to some improvement in other ECG metrics where relevant non-sustained ventricular tachycardia, some T-wave inversions. Can you just provide some additional context around PVC burden, NSVTs, T-wave inversions, et cetera? Of course, it's intuitive that lower is better. But what does it mean from the patient perspective to experience a lower PVC burden, experience less NSVTs in the context of their disease. And as it relates to a potential pivotal study, what metrics in your view kind of carry the most weight and how are you thinking about the plethora of clinical endpoints that could be used as registrational endpoints going forward?

Great question. And first of all, PVCs and especially NSVTs, while to us, they're just numbers, and they're tracings that we can read on an objective culture monitor. For patients, they're actually highly problematic and palpitations and especially NSVTs do not feel good for these patients. So improving this burden itself is helpful even beyond reducing the risk of ICD firings, right? That's one point. On the end points, I think the bottom line right now is we just don't know. Like Danon, we're casting wide net, and there is a fingerprint here that will emerge that will help us define what the primary endpoint is of pivotal study. We're not there yet, we should follow these patients a little bit longer to know for sure. I do think -- Yes. And we will, of course, try to take advantage of regulatory pathways such as accelerated approval if we can.

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

This is Ikenna Okafor on for Tyler Van Buren. Congrats on the data again. I was wondering, as we approach commercialization, what is your level of confidence in your manufacturing? And I had a second question, could you provide any update on the natural history study you have ongoing?

Both of these for Kinnari.

Thank you for the question. In terms of manufacturing, as you know, we have built out our Cranbury Facility in New Jersey. And this manufacturing facility was really built out not just to support Danon, but also our PKP2 program. So we have enough capacity and capabilities to do both of these programs in-house for at least the next several years, 5 years or so. So that is our plan number one. Regarding natural history, understanding the patient disease is really critical. So we did start a prospective natural history study in conjunction with this Phase I study. That study is enrolling patients, and we're collecting the data, while there are other avenues also available for this natural history, we're partnering with different groups across U.S. and Europe that have other pockets of natural history studies going and looking to get access to their data. So our totality of evidence that we will have will keep adding to it comprehensively, both from retrospective chart reviews to prospective studies and information. And the third component is we want to get all of this information together by the time we head to a pivotal study and beyond hopefully to a BLA pathway.

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

Maybe a bit of a naive question. So it looks like there's a pretty significant variability in the expression of PKP2 at baseline. Is there any relationship between the expression and disease severity or is that way too simplistic to look at? And I have a follow-on.

Yes, good to hear from you. Yes, it's possible that first patient 1003, who seems to have higher expression at baseline was the patient with lower PVCs. And he's certainly improved in how he feels over time. but didn't have much in the way of NSVTs and PVCs to improve. So it could be true. And the other patients have higher PVC burden at baseline, and they have lower expression. So that's -- 3 of 3 is certainly a trend, but we'll see and learn more from more patients.

Okay. And my other question is, are you guys monitoring ICD firing in these patients? And is this something that's going to be reported at some point?

Yes. So great question as well. None of these patients had ICD firings after therapy. One of the patients did have ICD firings in the months prior to therapy, but I would just caution us to understand that there's often change in dose or adjunctive medications like amiodarone and beta-blockers that could affect that. So it's hard to interpret. We'll capture these certainly long term, especially for full approval to see less ICD firings over time will probably be important.

Your next question is coming from Gavin Clark-Gartner from Evercore ISI.

Congrats on the data. I just had one 37-part question. So coming back to potential for accelerated approval and considering endpoints there and understanding it's still a little bit early, how exactly do you kind of capture the heterogeneity of the benefit? Like to put a finer point on it, patient 1011 they had a really great symptom improvement, but limited arrhythmia, whereas patient 1010 they had a large arrhythmia benefit, more limited on the symptoms. You kind of alluded to looking at like ARVC risk score. I was wondering, do you think that appropriately captures the different suite of benefits, would you have to adapt this scale in some way? Any kind of color on how you're thinking about the accelerated endpoint would be really helpful.

I mean -- thanks, Gavin, thanks for the question. So the playbook here has been a combination of protein expression, certainly with mechanistic proof like we're seeing here would be part of an endpoint for an accelerated approval pathway. What the other arm is like for Danon, we had LV mass index, maybe a combination of these arrhythmias that may be RV function, it could be another bucket. I'll tell you just the story of Danon is that about a month into the trial, we were all brainstorming what the endpoint should be. And actually, Barry Greenberg said, it should be LV mass, it's obvious to him. And we didn't think about that for a long time. Later, we went through every other endpoint and ultimately came back to LV mass. So it's a little bit early in the journey to know where we land for that other arm of the co-primary or composite endpoint. But there's a lot to choose from here. We're casting a wide net and again, we're so early that it's hard to sort of conjecture any more than that.

That's helpful. Maybe just a quick follow-up. What's your level of conviction that just following the patients for longer will be enough to discern as opposed to treating additional patients?

Yes. I mean we like to be efficient and as well as thoughtful in our development programs. I think that we would rather move pretty quickly in developing a CMC package that could be ready for commercialization, so move the Phase I forward to the next phase with the final CMC product that we can leverage data from for either an accelerated or full approval pathway. So that's why we'd rather just move forward than staying in this Phase I with a nonfinal product.

Your next question is coming from Kostas Biliouris from BMO Capital Markets.

Congrats on the data. Maybe a couple of questions, clarifications for us. How are you thinking about the safety of the vector moving forward as you expand the trial, given the recent unfortunate death of ELEVIDYS patient and the fact that Sarepta did not see a relationship between dose amount and safety? My second question is on the two patients that you showed improvement in the clinical endpoints. When -- do you know when this improvement occurred? Was it at 6 months, before that or after 6 months? And the third question is, now that we have data from other investigational therapies, in that indication as well, any thoughts about the competition there and what could differentiate you from other therapies?

Can you hear me? I think I was on mute, I am sorry. So I'll have to ask you your first couple of questions again, but just to remind you -- but on competition, what I can say is that we started at a dose that we thought would be potentially the final dose, and I think it is, right? So I think that's one advantage. I can't really comment on other programs, otherwise it's a large market, there could be room for more than one, but being first is hopefully an important advantage. So we're happy about that at the moment, given that we're hoping to move this particular dose forward. Then you also asked about when we thought we saw actual improvements. I think it's 6 months and beyond. Even if you look at some of the localization of proteins. You don't see that much change at 3 months, you really start seeing repopulation and expansion of health of desmosomes at 6 months and beyond. And I think that's when we're starting to see some of the benefits that we see. So just like Danon, I would say, 6 months and beyond, is the earliest. And sorry, your first question, I just -- I forgot.

So the first question is on the vector. As we know, the vector is the same as ELEVIDYS. Recently, we saw an unfortunate event with ELEVIDYS. I know that you are using a lower dose Sarepta, saw data where there is no dose dependence on safety. So I'm wondering how you think about the safety risk moving forward given that event?

Yes. So without too much conjecture again on another program. What we've learned from that and other events in the industry, especially when we see CMV infection beforehand and/or any liver issues, we are very careful and aggressive about getting hepatology consult, ultrasound, really looking across the spectrum of liver abnormalities just to be very sure that we're minimizing any safety issues. So there are learnings from that ELEVIDYS death. Our dose is lower, though. I know maybe it's not dose dependent, but I do believe that total vector exposure does matter. We have really strong full-empty ratios as well. So in addition to a lower dose, I believe we're also minimizing the total capsid exposure for patients and being thoughtful about how we screen these patients upfront.

Your next question is coming from Mike Ulz from Morgan Stanley.

Congratulations on the initial data as well. Maybe just a few quick questions regarding the FDA. Obviously, there's been a lot of changes recently. I guess, number one, do you anticipate any issues in being able to interact with the FDA? And then two, do you anticipate any changes in sort of the FDA's supportive view towards gene therapies and accelerated approvals, et cetera.

Beautiful question. Probably no one knows, but I will hand this to Kinnari for an opinion.

Thank you for the question. So regarding the FDA changes at this point, given that we have multiple programs in development at different stages, what we've seen is the continuation of granting of meetings in person, and video conferences and ongoing dialogues back and forth informally as well. So at this point, I do not see anything changing for Rocket's program specifically or in gene therapy. And I think one of the reasons that we believe that to be true and will hold true for the programs we work on is these are not nice to have programs. These are programs that have devastating disease, a significant unmet medical need and no other treatment option. So given the orphan drug designation, many of our products have an RMAT designation, and others we have in fast-track designations, which are all the regulatory bells and whistles to have more frequent dialogues with FDA. We believe that will continue for our current programs that we have. And as we learn more and as we progress these programs forward, certainly key milestone FDA meetings will be made public.

Your next question is coming from Sami Corwin from William Blair.

Congrats on the data. Given some of the parallels between this program and Danon disease, I guess I was curious what kind of learnings you could apply from Danon to this program to accelerate its development? And then I know this clinical data is early, but if these initial improvements were maintained in these patients, do you think it's possible that they could avoid heart transplant in the future? Or does that kind of go back to the question of needing to treat patients earlier in the disease.

Yes. I think there are many learnings from Danon, and we're trying to apply all of them. Obviously, it's a different disease. We are casting a wide net, which is key, right? Looking at a bunch of different biomarkers, just like we did for Danon to ultimately hopefully come up with the ones that matter the most and are most meaningful for patients and for regulators. Also many learnings on the CMC side from how to develop good full empties on -- how to develop good potency assays, how to validate these as early as possible in the process of development. So a lot of learnings there. In terms of the prevention of heart failure and affecting mortality, I think that, as you saw, one of the patients here did normalize their heart function. We will ultimately be looking at parameters of RV function with MRI and other modalities as well to understand this better. But I think even stopping right ventricular progression in its tracts, even stabilizing it versus the inevitable progression that these patients experience would be a pretty big win and could ultimately affect patients' mortality in a way that's probably more meaningful than just reducing PVCs. And I think we're starting to see that just with that improvement on RV function that we demonstrated today.

Your next question is coming from Yun Zhong from Wedbush.

Congratulations on the data. The first question is on your interaction with the FDA. And given that you only have data from three patients and also heterogeneity variability that has been talked about on the call. So do you expect any information to be available from your natural history study to help your discussion with the FDA or maybe potentially anything available from such natural history studies being conducted by other companies, publicly available information to help could be helpful?

Yes. I can't comment too much on the natural history just because it's something that's actively being developed in conjunction with a couple of different institutions. We do have a strong retrospective database to draw from that we could use to support any discussions. And we're, of course, starting this prospective study as well. I think the natural history studies like for Danon will help inform what our assumptions should be for the endpoints that we end up selecting and could really help us define the size and type of trial that we develop.

Then a little technical question. So on protein expression measurement, the 398% seems to be quite accurate versus what you reported from Danon program is only based on immunohistochemistry staining. So when you report data from Danon disease, we'll be able to provide this kind of Western blot information, quantification data from Danon program as well?

Yes. I'm happy to see this is the first Danon question today. I think we'll be able to quantify that over time. However, Danon disease expression is very different. It's a metabolic disease, the metabolic condition of the cell and the patient itself affects protein expression in an epigenetic way. So quantifying protein expression at a single time point doesn't actually correlate with anything meaningful. In fact, some of the patients who benefited the most at Danon had low-grade protein expression likely because -- and it probably varied over time. So this is a little bit different. In terms of quantifying here, we are still working up the techniques that's part of development, refining the techniques to really figure out what the numbers look like in Western blot as well as immunofluorescence. There are suggestions to look at additional ways to look at tissue as well and today's ASGCT team will be taking all of those in consideration as we develop our pivotal.

Your next question is coming from Eric Joseph from JPMorgan.

And let me add my congrats on these data. Gaurav, you noted some factors that might impact some of the cardiac parameters here, right, might be there some variability. Can you just talk a little bit about sort of how -- in the baseline protocol, how long and how frequently patients were assessed for PVC and NSVT and the extent to which you might be looking to sort of normalize, standardized assessment as part of the potential pivotal study going forward?

Thanks, Great question. I'll hand it to Jonathan.

With respect to arrhythmia monitoring, I think our goal has evolved to -- when we do ambulatory rhythm monitoring, looking over a longer period of time as opposed to a shorter period of time. And although it's called 24-hour ambulatory rhythm monitoring. In fact, we are of the belief guided by a number of expert advisers that going beyond 24 hours is a much better way of capturing what's really happening in a patient. So to the extent that patients are wearing the Holter or similar monitor not just for 24 hours but for longer, we are doing that such that if they can have it on for a week or something close to that, then we feel like that's the optimal assessment. If anything, on the Phase I study, when we started, we were doing 24 to 48 hours. And then by the end, we were -- by all of the recent visits, we're doing something more like a week. So if anything, we're underselling the benefit that we've seen because when we measure it at the latest time point, we're measuring for longer periods of time and giving patients more time to show things like NSVTs, which is why we're very pleased to see that in the one patient that did have a significant baseline burden, it appeared to be reduced or eliminated at most recent visit.

Can I just clarify? So it's just one assessment for arrhythmias but -- over either a day or a little bit longer than a day period, at least prior to treatment. And then perhaps longer intervals with post-treatment assessment. Is that correct Jonathan or did I misunderstand?

Yes. No. I think we are evolving exactly how we capture these arrhythmias. And I think what Jonathan is saying is that as we develop the protocols further, we want to capture arrhythmias for longer, just so that we really know what's going on. So yes, beyond that, I don't think we can comment much more.

Okay. And one more if I can just squeak, one last thing. Can you just talk a little bit about sort of green failure rate as -- in accruing this study just to get a sense of either patients that might be eligible for the natural history study or really just to get a sense of what accrual success might look like in a forward trial?

Yes. This is a disease that is pretty well recognized out there. There's a smaller gap between diagnosed patients and true prevalence than there is for Danon. So it's certainly -- there's a lot of patients out there. In terms of screening failures, we can't comment on that at the moment. We need more information. And I just want to make one point, again, on the arrhythmias. We're also looking at ICD interrogations. And so far, those data seem to support what we've shown here on the Holter monitors.

Very importantly, when we do the baseline assessment, we're capturing that at a couple of different time points during the screening process that are separated by multiple weeks. So that we're really trying to make sure we're getting an optimal baseline. And as I mentioned before, we're trying to do this for more than 24 hours. We're doing this for several days on end or a week so that, again, we're doing things that will limit the noise and the variability. That said, any of these parameters that are measured at a single time point will require subsequent verification confirmation. Like so many other things in these difficult-to-treat diseases, you really want to see trends over time as opposed to just saying, okay, yes, it looks great at 6 months, we've won.

Yes. And also to reiterate what we said in the prepared remarks, reliance on any one endpoint like PVC is probably not smart, right? We got to look at the whole fingerprint here.

Your next question is coming from Whitney Ijem from Canaccord Genuity.

Congrats on the data. This is Joohwan Kim on for Whitney. Maybe two really quick ones from us, and I may have missed this. But I'm just thinking about next steps from here, what is currently included from a cash guidance perspective? And then based on the data with this vector and with respect to your thoughts on AAV9 for cardio, can you share any color there in terms of your earlier-stage pipeline BAG3, for example, in terms of learnings that we'll be able to translate?

Our cash guidance just based on the recent earnings is we have cash into Q4 of 2026, and that does not count any PRVs. So any PRVs would be additional on top of that. And it accounts for ongoing development of all of these programs that you're aware of. And -- yes -- and sorry, the second question again?

In terms of the second question. So in terms of -- given the positive data with this particular vector and as you're thinking about your earlier stage pipeline, any learnings there? Or any potential changes there for the BAG3 program in terms -- given kind of what you have seen?

Yes. So we still like AAV9 for Danon. It's a disease that involves not just the heart, but also the CNS and muscle and certainly with CNS, AAV9 has proven efficacy. So for Danon, AAV9 was the right vector. I think if we're focused on cardiac, based on what we're learning here, we like rh74. It is the vector, the capsid that we're using for BAG3 and also for potential future Wave 2 programs that are going to be up and coming in the coming years.

Thank you. That completes our Q&A session. Everyone, this concludes today's event. You may disconnect at this time, and have a wonderful day. Thank you for your participation.