Thank you for having us. Welcome to 2026. Thanks, Tessa, for hosting us, and J.P. Morgan as well. Standard disclaimer, forward-looking statement disclaimer here, so Rocket is a late-stage biotech company. We have a pipeline of gene therapies that are designed to correct the root cause of complex and rare genetic diseases. We have two platforms, AAV and lentiviral, and we do everything from discovery to manufacturing, including in-house manufacturing for AAV and we think that the secret sauce to success in gene therapy is in asset selection and we're focused on assets that target medical conditions that are not only rare but are devastating or fatal, often in childhood, and that have a direct mechanism of action that can be targeted and focused on the protein that is responsible for the disease and have a reasonable market size to create a business opportunity that can expand over time.
As of September 30, 2025, Rocket reported $222.8 million in cash, cash equivalents, and restricted cash. We expect that these resources, excluding any sale of a PRV that could be granted on the Kresladi approval that's slated for March 28, 2026, the cash that we have now will be sufficient to fund operations into the second quarter of 2027. And while we don't expect major revenue from Kresladi, given that it's ultra-rare, a BLA approval could yield this PRV, which there are some analogs that are out there currently, but we view that opportunity as strategic non-dilutive capital that could extend our runway much further and support investment in our growing cardiovascular pipeline. 2026 is the year of execution for us. We are going to advance three cardiovascular programs where we believe we can generate durable clinical data and therefore create long-term value for patients and shareholders.
In 2026, Rocket enters a more focused company, focused on cardiovascular, each with a clear biological rationale, a defined regulatory path, meaningful long-term value potential, as well as a pipeline of other cardiac programs right behind. We have been, as I said, increasingly focused on putting our resources towards AAV platform, including our lead late-stage program for Danon disease, which is a devastating heart failure syndrome associated with autophagy and leading to heart failure early in life. Now, in the context of Rocket's refocus on programs with the clearest regulatory and commercial paths, we made the extremely difficult decision to deprioritize internal investments in Fanconi anemia, including withdrawal of both the U.S. BLA and European MAA applications. This prioritization does allow us to concentrate resources in areas where we can have the most immediate and sustainable impact for patients and shareholders.
We are seeking alternative options, potential partner options for both Fanconi and PKD so that they may see the light of day and that patients may benefit from access to these therapies. We have recently shared that we've limited our current LV investments to a Kresladi approval for the treatment of severe LAD-1, which, like I said, has an upcoming PDUFA on March 28, 2026. Now, in 2025, looking at last year, we fully immersed ourselves in becoming the leader in cardiovascular gene therapies. We now have over five years of efficacy and safety data with our cardiac gene therapies, have treated numerous patients across these programs. We support these programs through our proprietary AAV manufacturing that's in-house at our more than 100,000 sq ft facility in Cranbury, New Jersey, which is close to Princeton for those who wonder.
Each cardiac program was hand-selected to be the first, best, and/or only in class, has an on-target mechanism of action with clear endpoints, and contains a sizable market to maximize patient impact. Cumulatively, our clinical programs focus on all three of the major phenotypes of genetic cardiomyopathies. There's hypertrophic, there's dilated, and there's arrhythmogenic, and we're going to talk about each one of these. Altogether, these programs represent more than 100,000 patients in the U.S. and E.U. with a multibillion-dollar commercial potential. Looking forward this year, that was 2025, this year, we expect to continue to advance and provide updates in the final clinical stage for our lead program in Danon disease. We also expect to initiate our clinical trial in BAG3, and we will get further clarity from FDA on a trial design for pivotal Phase II study for PKP2. We'll talk about each of these shortly.
But first, let's talk about Danon, which is sort of the first cardiac gene therapy of its kind to demonstrate benefit through gene therapy. And this is a severe X-linked cardiomyopathy that's caused by deficiency of LAMP2. This leads to progressive cardiomyopathy, arrhythmias, and early mortality. The mutation in LAMP2, or the series of mutations, results in the accumulation of autophagic vacuoles. They're like these cells do not have a vacuum cleaner or a recycling center anymore, especially in cardiac and skeletal muscles. And with impaired autophagy, male patients often require heart transplantation, in fact, invariably require heart transplantation, and typically pass away during adolescence from progressive heart failure. When transplant works, patients often need a second transplant, and mortality at 10 years is greater than 50%. So that's the male experience.
Females with Danon disease can also be affected, but they often have a delayed presentation because they retain some LAMP2 from their other X chromosome. So back for a second. The prevalence of Danon is estimated to be between 15,000 and 30,000 in the U.S. and Europe. Last fall, we shared a top-down approach and the results of that approach and how we have supported this range in more detail. We'll have further updates toward the second half of this year on both the top-down approach and bottom-up approach, including patients that we've actually found with Danon disease, both male and female. So in the next few slides, you're going to see slides that have already been presented. We have some verbal updates to share, though.
These are data on biopsies and protein expression of LAMP2 that we have already published at AHA at the end of 2024 and also in the New England Journal of Medicine. Nothing is new here. However, I am happy to share verbally that we continue to see strong durability in RP-A501 for Danon disease. For the patients in the Phase I trial who were treated, 100% of them continued to express LAMP2 either grade one or greater, with the shortest follow-up at 36 months, and two patients who have actually passed the five-year mark. This is the first time that we've shown long-term expression that's durable and invariable in cardiac gene therapy, greater than five years. This is the green slide, the magic key slide from the NEJM and AHA data from the end of 2024.
This is really, really transformative in a way that only gene therapy where you're replacing faulty DNA with correct DNA can be. We show key efficacy assessments across every parameter representing change from baseline to most recent follow-up, in this case, out to 54 months in one patient, and we are in the process of processing updates from additional patient visits, and we'll share those at some point. Again, two patients have passed the 60-month mark and continue to show similar benefit, so all our patients in the Phase I trial, adults as well as pediatrics, continue to flourish beyond the age where they would typically demonstrate heart failure, be on a transplant list, or unfortunately even pass away, and we know that these patients are not only alive and surviving, but they're thriving.
LV mass index, which, by the way, is also a component of the co-primary endpoint for the pivotal Phase II trial that's ongoing, is a measure of left ventricular mass as measured by echo or MRI. And here you see an ongoing and durable robust reduction in LV mass index over time out to four years, with a median reduction of around 24% at the most recent visit. Now, LAMP2 protein expression and LV mass improvements, again, are the co-primary endpoints for this ongoing pivotal trial we'll talk about in just a second. And this design itself is one that was set with the FDA before a clinical hold occurred last year. This clinical hold occurred because of an unfortunate safety event due to a patient death associated with a capillary leak syndrome. It's the first time we've seen this in the field.
It was thought to be, through extensive data analyses, to be the result of a combination of high dose of AAV therapy with a C3 complement inhibitor. At that time, Rocket paused dosing. We conducted a comprehensive root cause analysis, and we modified the protocol and resubmitted to the FDA. We got the hold removed in under three months, which is really record time. We recalibrated the dose to 3.8e13 vector genomes per kilogram, which is down from 6.7e13, which was the original dose in the Phase I. We also accounted for this higher full-empty ratio, which we haven't disclosed publicly, but it was a substantially higher full-empty in the Phase II compared to the Phase I, which supported the reduction or the recalibration in dose to around 4e13.
We will now implement a safety staggered run-in, a staggered safety run-in that will treat three patients in the first half of this year, and after that, we will revert with the FDA and establish what the rest of the trial looks like. We don't anticipate there should be much change, but we have no indication that there will be any change, but there may be additional patients that are added. Now, I want to note that this recalibrated dose, which should account for the improved full empty, is not new to these studies, to the pivotal Phase II study. Based on weight and age-adjusted dosing in the Phase I, two pediatric patients, the last two that were dosed, received lower doses around 4E13, which is this recalibrated dose.
Those patients had either similar or superior efficacy with actual cleaner safety profiles compared to the initially intended higher dose of 6.7e13. Both of these patients just had their three-year visit last year and continued to demonstrate robust durability and efficacy. We will, like I said, mention we will resume dosing in the first half of 2026 by treating these three next patients one month apart each. This, if they pass the safety profile, will give us confidence that the program is advancing with the appropriate balance of safety and efficacy. The revised protocol also reflects lessons from others in the field more broadly and is designed to preserve the biological activity we observed in Phase I while reducing risk in subsequent patients. We will report in the second year with agreement with FDA on a go-forward path to complete the study.
Our next most advanced AAV cardiac program is the AAVrh74 gene therapy for the treatment of PKP2 ACM, arrhythmogenic cardiomyopathy. This is an inherited autosomal dominant progressive heart disease caused by mutations in the PKP2 gene. It is characterized by life-threatening ventricular arrhythmias, structural abnormalities of the heart, and sudden cardiac death. Loss of PKP2 at the cardiomyocyte junctions compromises both structural integrity and electrical signaling, leading to progressive electrical instability, arrhythmias, and ultimately heart failure. These days, most patients are managed by ICDs for primary prevention, but there are no disease-modifying therapies available at all. Gene therapy has the potential to directly address the underlying cause of disease by restoring the PKP2 protein and cardiomyocytes, stabilizing cell junctions, improving electrical conduction, and potentially halting or even reversing disease like we saw in Danon, rather than just preventing further complications.
PKP2-ACM is about twice the size of Danon in terms of prevalence, affects an estimated 50,000 adults and children across the U.S. and Europe, although the true prevalence is likely higher given the challenges of diagnosis. Many individuals remain undiagnosed or misdiagnosed, as in Danon, because early symptoms such as palpitations, fainting, or arrhythmias that can overlap with other cardiac conditions. As awareness, genetic testing, which is common across all these programs, and family screening improve, the number of identified patients is expected to increase, underscoring the unmet medical need and the opportunity for a targeted gene therapy approach. With this program, RPA-601 for PKP2-ACM, we are currently in a Phase I study, and we are assessing its safety and preliminary efficacy at 12 months post-infusion.
A natural history study is also being initiated to provide context for the Phase I trial, along with capturing further retrospective natural history data. So the preliminary data from this Phase I trial for adult patients with PKP2 ACM was shared mid-year last year at ASGCT. And overall, the preliminary safety and efficacy results show that the gene therapy was generally well tolerated and demonstrated initial efficacy. There were no dose-limiting toxicities. In all three of the patients who were treated, the gene therapy promoted desmosome localization of PKP2 and also promoted associated transmembrane intercalated disc proteins between three and 12 months after treatment. We saw preliminary indications of improvement or stabilization in arrhythmias, heart functions, and quality of life. We've already presented this data previously. PKP2 ACM is an active area of interest in gene therapy, and there are multiple groups exploring this approach.
We actually view that as a validation of the biology and the unmet medical need. We believe that there are sufficient numbers of patients to support more than one successful therapy in several types of patients and disease characteristics as well. What differentiates Rocket's approach is not just choice of vector, which is different across the programs, but it's a combination of evaluation of cardiac tissue targeting, efficient myocardial transduction, and the actual effects on efficacy that we're seeing in these patients. We're using the RH74 vector that's selected for cardiac tropism, and again, we've observed clear localization of this protein to the intercalated disc, so it's not just that we're seeing improvements in Western blot and immunofluorescence, but the proteins are going to the right places. Now, we believe that we have reached the right dose to demonstrate both safety and efficacy for RP-A601 and PKP2 ACM.
So we're no longer dose escalating. The 8E13 vector genomes per kilogram dose will be the dose to move forward into the next part of development. We're in discussions with FDA, and we're focused on defining the right registrational pathway for PKP2 ACM this year. A number of the common clinical features of this disease are correlated with the risk of ventricular arrhythmias. Therefore, we don't think that a single marker is going to be the marker like we have LV mass index in Danon. Therefore, we see the importance and the criticality of a comprehensive data set similar to Danon to show the clinical benefit across many factors. We also think that longer follow-up is likely, at least one year to 18 months, needed to further elucidate our endpoint selection for the pivotal study.
We expect FDA alignment on this design and a path forward for the pivotal Phase II study in the near term. It's important to emphasize that dose alone is not a proxy for success in gene therapy. We have to look at differences in capsid biology, tissue distribution, and intracellular trafficking. They all matter. Our focus has been on achieving meaningful myocardial transduction and protein localization that translates into clinical benefit rather than just optimizing to the lowest dose that's possible. Based on the totality of data so far with this program, we believe RP-A601 has the potential to be a differentiated disease-modifying therapy for patients with PKP2 ACM. The third program, which is what I believe is a hidden gem for near-term growth of the cardiac portfolio, is BAG3 dilated cardiomyopathy.
We had IND clearance last year, and we are working toward initiation of the Phase I study. DCM is the most common form of cardiomyopathy versus HCM and ACM, which were represented by Danon and PKP2. It's the most common form of heart failure due to genetic cardiomyopathy and is characterized by progressive thinning of the walls of the heart, resulting in enlarged heart chambers that are unable to pump blood. Mutations in the BAG3 gene are among the most common mutations observed in DCM. The BAG3 protein is an interesting protein. It's expressed primarily in the heart, but also other tissues. In the heart, it plays a role in multiple key cellular functions. Loss of BAG3 leads to accumulation of misfolded and damaged proteins, which can impair the heart's ability to contract, thus leading to impaired cardiac function and premature death.
We view BAG3 DCM as our potential largest market opportunity to date, with around 30,000 individuals affected just in the U.S., and this is our next durable value-driving engine that is distinct from both Danon and PKP2. Patients with BAG3 DCM have an urgent medical need, and the current medical and interventional therapies, including implantable ICDs, pacemakers, and/or heart transplant, do not consistently prevent disease progression and are associated with major morbidities and mortalities, including inappropriate ICD shocks and transplant-related complications. Ultimately, they do not address the underlying pathophysiology or genetic mutations. Because BAG3 plays a role in multiple critical myocardial cell functions, we believe that the AAVrh74 gene therapy has the potential to restore or stabilize cardiac function in these patients. We are going to use the same approach of rh74 that we are going to use across cardiovascular programs and have used in PKP2.
We believe this vector offers efficient myocardial transduction even much more than for muscle. And also, this approach allows us to apply lessons that we're learning from other indications. Finally, from a competitive viewpoint, while BAG3 is gaining increased recognition as a genetic driver of dilated cardiomyopathy, we believe it remains less crowded in the landscape overall relative to other cardiomyopathy indications, allowing for thoughtful, data-driven, unfettered clinical development. Where are we in BAG3? We are currently in the process of initiating the first-in-human Phase I trial. This study will be a multi-centered dose escalation study that's designed to evaluate the safety, biological activity, and preliminary efficacy of RP-A701 in adults with BAG3 DCM. We'll also be looking at BAG3 protein expression and functional cardiac endpoints such as ejection fraction and exercise capacity.
So looking forward into March of 2026, we anticipate the potential approval and commercialization of Kresladi. This is summarizing what we look forward to in 2026 for severe LAD-1, which represents Rocket's first opportunity to bring a commercial gene therapy to patients. So we hope to move from a late-stage clinical stage company to a commercial stage gene therapy company. Again, severe LAD1, which we have not mentioned much here today, is an ultra-rare condition affecting a low single-digit number of patients annually, making Kresladi a highly targeted launch for these patients. And while we do not expect substantial revenue, approval could bring a PRV. There are analogs in the field as to the value of the PRVs, as additional non-dilutive capital and thus further extend our cash runway.
We also see the potential commercial launch of Kresladi serving as a way to build infrastructure and capabilities for our future larger AAV program launches. So that's the first catalyst. For the AAV programs, there should be three potential catalysts. First, the initiation of clinical activities for BAG3 DCM, and these are not in any particular order, with the dosing of our first patients in 2026. Second, we will announce our alignment on the initiation and continuation of the pivotal Phase II study for PKP2 once we get the alignment with FDA. And third, we will resume dosing with Danon and hopefully establish a safety profile and come back with a clear path forward to approval. So it is a year of execution, a year of excitement, and we look forward to sharing more as things evolve. Thank you very, very much.
Okay, great.
Thank you so much for this presentation. So I'd love to start with a little bit of a bigger picture question for you. The presentation really outlined the strategic priorities for the company. How do you think about relative risk across your portfolio, and which of these assets do you think could deliver the highest reward?
Well, you asked different folks in the company. I think everyone's going to have what they think is the highest value driver. I believe Danon is something in the cardiac gene therapy field that is unique because it's possible to demonstrate a clear differentiation between untreated patients and treated patients in a meaningful way that regulators will understand, patients and caregivers will understand, and payers will understand. It's also a large enough market to be the single highest near-to-medium-term value driver. So I would say Danon.
I think BAG3, like I said, is also a hidden gem with endpoints that are relatively easy to define, and there are precedents for those endpoints. So that's how I would sequence them in terms of value driving. Okay. So let's just jump right into the Danon program. Can you specifically talk to precisely what the gating factors are to resuming patient dosing here? It's mostly logistics at this point. Just getting IRB approvals and other technicalities to resume dosing, we do anticipate moving forward in the first half of this year. So we're close. Just one point to note also is that there's a three-month troponin run-in before patients are treated, and we can't use last year's troponin values. We have to rerun them as well before the treatment. So we're getting through those.
Okay.
Something we've been trying to think a little bit about is, and would love to get your thoughts and perspectives. What is a reasonable rate of complement-mediated thrombotic microangiopathy in the context of this disease state where there's meaningful unmet need?
I would say that I'll make a couple of points. It's a great question. I don't think TMA risk is going to be zero for high-dose AAV therapies. I think there will always be some risk. The overall benefit risk has to work out. The TMA cases that we've seen, as far as we know and others have seen in the field, have resolved. So those patients long-term, we believe, will demonstrate clinical benefit despite having had TMA because they're reversible events. We're not talking about capillary leak, just TMA, right?
And so there is a ratio or there's a percent of TMAs that I think is acceptable for regulators, patients, and all stakeholders. I don't know what that percent is, but it's probably not zero. Danon is a disease, just to reemphasize, that leads to mortality around the age of 19 or 20 in boys and in the 30s for females. And once patients know they have Danon, they often go on a transplant list within two or three years anyway. So a low modest risk of TMA for this community has been deemed acceptable. They've communicated that with us as well. As long as it's reversible, the benefit of the gene therapy far outweighs that risk.
Okay. Okay. And thinking ahead here to your anticipated treatment of three more patients at your recalibrated dose level, how do you think about what defines a positive data set?
Our hope is to replicate what we saw in Phase I, the green slide, the transformative slide. That's the hope. There's no reason to think otherwise, and the safety as well was tolerable in that Phase I trial for the patients that were followed for at least a year at the right dose. So that's what we hope to replicate. Obviously, we can't guide to that, but that's the hope. Okay. And what makes you confident that this dose will drive sufficient efficacy and a safe profile? So we mentioned briefly earlier that two of the patients, the pediatric patient in the Phase I, were treated at around the same dose, and actually, they had the earliest and most robust efficacy that's now durable out to three years.
So it could be that there's a range of dose here between four and six, seven e13, and actually the lower end could be the best dose just based on that pediatric data. So that reassures us quite a bit.
Yeah. And I'd also love to talk a little bit about the feedback that you've gotten from the kind of physicians and institutions that you interact with in the Danon community. What is the feedback that you've gotten on the overall emerging profile of the asset so far, and what are they looking to better understand?
I think I can speak to that. They're all different, right? So Danon, PKP2, and BAG3 patient communities are all very different. I can speak for what I know about the Danon community.
These boys and females have one of the most aggressive cardiomyopathies, if not the most aggressive cardiomyopathy known to humans, especially the boys, so they're used to illness. They're used to coming in and out of hospitals. They're used to uncertainty, unfortunately, so a ray of hope has transformed this community in a very, very big way. Even when we had this very, very unfortunate patient death last year, I will say that after processing it, we were able to get on a call with the Danon Foundation, the Danon community, and there is still very strong interest in the trial, even amongst the families whose boys are affected, right, and I think this is a unique type of situation. PKP2, these patients have ICD firings that are highly anxiety-provoking. They live in constant fear. There is the early mortality from the heart failure as well.
So it's also a community that's really looking for something different because there's no disease-modifying therapy. So I think that's what we're seeing with these aggressive genetic cardiomyopathies. They're not like the slower-moving cardiovascular ischemic-related cardiomyopathies and others that evolve over time. These are very dedicated, focused, and cohesive communities that are really looking for hope.
And how is—I believe you have a concurrent natural history study. How is that progressing, and what have you learned so far in the study? For the natural history study? For which program? For—oh, sorry. Danon.
For Danon, yeah. Yeah. So there is a concurrent concomitant natural history study. Just to be clear, it is not the comparator arm. The comparator is the pretreatment of the same patients before they were treated as the comparator.
This complementary natural history study to the main trial of 36 patients, both males and females, it is progressing. It's enrolling. It will be enrolled by the time of the BLA. We are learning a lot about how these patients would do without treatment. Right now, it's still validating the same points that we saw in the retrospective data set where LV mass increases year by year and that these patients decline. They decline pretty rapidly. This doesn't take five years. You can see the change year to year. Again, this is why we were able to negotiate a small pivotal design with the FDA because of the big differentiation there.
Okay. Sorry, I'm just doing a time check here to keep us on track. I think you've outlined 12,000 U.S. Danon disease patients after age adjustment and accounting for non-HCM presentations.
Are there any ways we should be further breaking down the population to think about who would be most likely to come on RP-A501?
Yeah. The numbers that we have shared and will share on overall prevalence, of course, include males, females, transplanted patients, pretransplanted patients. We have not talked about the addressable market in a lot of depth and detail. I will say that just focusing on males for now, males invariably progress to heart failure by the late teens or early 20s. So we anticipate that most males should be eligible for this therapy who are not transplanted. For females, we'll define that further as we go.
Okay. Okay. And just switching gears here and maybe briefly touching on a couple of other topics. So maybe on PKP2-ACM, are you planning to present for their follow-up from those three patients this year?
We have not decided yet, but I think if there's meaningful change from previous, we may. But for the most part, we've gotten what we want out of these data sets to inform a pivotal trial.
Okay. You beat me to the punch. Do you think you have enough information to know the best design and de-risk the study to the best of your abilities?
It's a great question. The Phase I does remain open. So it's possible we collect more data. But between protein expression, arrhythmia changes, and structure and function, and how patients function and feel, we have what we need. What we don't have is the natural history build-out as a comparator. At the end of the day, we'll have to start a pivotal Phase II trial. For anyone who does that, that's where the risk is going to lie.
Our challenge is to design the trial that captures the highest probability of being positive if the drug actually works, right? So I think in a short time period, we're not going to learn that much more about how these patients fare in the first year to 18 months. So I think we have what we need. However, the Phase I trial does remain open for data collection if patients would like to enroll.
Okay. Okay. Great. And how is the regulatory review proceeding around your BLA for Kresladi?
We're about mid-cycle. And so far, there don't seem to be any showstoppers. That's what I know right now. But we remain cautiously optimistic given how the landscape is evolving and how others have experienced this. We're cautious, but so far, things are moving forward as expected.
Okay. Okay. Great. And I'd be remiss if I didn't ask about manufacturing.
Can you talk a little bit about your capabilities at Rocket? And what are your near and long-term plans?
Our internal capabilities are all focused on AAV. We have enough capacity, enough space, first of all, and the infrastructure and capacity overall to support all of these programs that we've disclosed, right? Danon, PKP2, and BAG3 at commercialization. If we grow beyond those programs, we may have to build more. We believe that having in-house manufacturing controls cost of goods in a very, very meaningful way, thus driving the highest margins. That's number one. Number two, it also controls timelines and puts the control in our hands so we're not dependent on outside vendors and CDMOs. Third, it allows us to improve the process as needed over time and just manage the life cycle in a much better way.
This was an investment at a time when biotech was in a much higher high. XBI was 160 or so when we built out this manufacturing facility. And it was a good investment because it's going to pay for years to come, pay back for years to come.
Okay. Should we maybe in the last couple of minutes, if you could just remind us of your cash position?
Yeah. So.
What that cash gets you through? And yeah, any other considerations there?
So not accounting for PRV, which could form additional non-dilutive capital after the PDUFA date if we get the approval. So not counting that, the cash of $222.8 million as of Q3 last year, we'll obviously have an update soon, gets us into quarter two 2027. So it's a nice runway even without the PRV.
But with the PRV, the potential PRV, I should say, it extends this much further.
Okay. Okay. Great. And are we going to hear about wave two programs at Rocket this year, or is that farther out for the company?
No, the wave two is still very active. We just slowed things down to focus on the highest value drivers right now on Danon, PKP2, and BAG3. But we have other programs that are right behind, ready to apply the learnings and ready to go. And I don't want to commit to one program a year or anything like that, but there's enough to keep the pipeline steady and stable for many, many years to come.
Okay. I think that might be a good place to leave this co nversation. Thank you so much.
Thank you, Tessa. Thank you, everyone.