Yeah, we can get started. Good. Okay, great. Thanks everyone for being here for TD Cowen's 46th Annual Healthcare Conference. Our next session we have here is with Rocket Pharma, and from Rocket we have Gaurav Shah, the CEO. Thanks so much for being here. It's really a privilege to have you. I guess let's go ahead and get started on your overview, the history of some high of before we get into QA. Go ahead.
Great. Thank you, Tara. Yes. Cowen as well. It's always back here, Boston. Rocket Pharma, we are a large gene therapy company. We are linearly into everything from discovery to development, internal for AAV commercialization. Our focus is rare cardiac diseases using the AAV platform. We also have a hematology and immunology platform using LV ex vivo. More on that in a, in a bit. At the end of last year, we had $189 million, and that will be sufficient to cover cash into Q2 2027. I thought I'd use this time to go through what I think are the most important milestones for the year, and that'll be a way to talk about each program one by one.
First and foremost, we're very excited that we have a potential approval with the PDUFA date of March 28, 2026 for KRESLADI, which is our LAD-I ex vivo Lenti program, something that we've been working on. You asked about history since near day one of Rocket more than nine years ago. LAD-I is a primary immunodeficiency, affects children whose neutrophils cannot extravasate to fight sites of infection, most boys and girls pass away in their single-digit years. We are excited to be partnering closely with the FDA to try to get this over the finish line this month. That is, of course, an opportunity to get an infrastructure built around commercialization, it's also an opportunity for non-dilutive financing through PRV.
The recent numbers have been trending up, we're very excited about the potential of non-dilutive, dilutive capital that could then potentially push us past Q2 of 2027. That's KRESLADI. That's milestone one this month. two, Danon Disease is our signature lead program in the AAV, rare cardiac space. It's a disorder of autophagy. Patients in their heart cells cannot extract debris that builds up because their system of autophagy, the garbage recycling center, is disrupted because these patients lack LAMP2, which is a gene and protein required for autophagy. Without autophagy, this debris builds up, and the heart muscles cannot contract in sync, leading to heart failure. It's X-linked, it affects boys more than girls and before girls.
Most boys only make it to 19 or 20 years of age without a transplant. Even transplant is hard to come across and is associated with more than a 50% 10-year failure rate and or the need for a second transplant. Really a fatal, rare, devastating disease in boys, but also in girls and women. Danon disease, we've had a program for a while. We published our phase I data in The New England Journal of Medicine which showed that in six of six patients, we have prolonged protein expression, improvement in labs like troponin and BNP, and improvement in heart function three to five years after treatment. In fact, two of the first patients who were treated are past five years, continue to have those results as well as protein expression.
Danon entered a phase II pivotal trial. Last year in attempts to improve the immunomodulation regimen to reduce the risk of TMA, we introduced a C3 complement inhibitor. The combination with AAV9 of which, we believe led to massive capillary leak syndrome in two patients, one of whom passed away last May. We were put on hold. We were able to negotiate a lift of the hold in less than three months with the FDA through collaboration and transparency. The trial is now up and running. We have agreed with the FDA that we would enroll three more patients without the C3 inhibitor and with some other tweaks to the regimen, one month apart, at least one month apart, and come back to them to finish discussions about the final trial design.
The current trial design that we've agreed upon is a 12-patient single-arm trial of treated patients versus their pre-treatment baseline with primary endpoint of LV mass index plus protein expression. Once we treat these three patients safely in the near term, we hope to go back to the FDA and get clarity or ratification of a similar design as we've already discussed. The Danon program is the pivotal program. It is something we're very excited about here at Rocket, but also with the patients and the patient community and the physicians who are dealing with these very sick boys and girls. That's the second milestone, second half of this year. One is KRESLADI Danon program update, which will include discussions about safety on this trial, but also a overall program update, including where patients are, both top-down and bottom-up efforts to find these patients.
Number three is PKP2. PKP2 is an arrhythmogenic cardiomyopathy. I should take a step back and say that in our cardiac portfolio, we've now addressed a large component of HCM, hypertrophic cardiomyopathy, which is Danon ACM, which is arrhythmogenic cardiomyopathy, which is PKP2 and DCM dilated cardiomyopathy in BAG3. We've now addressed three of the biggest buckets of genetic cardiomyopathies that are out there. It's a real entry into the rare cardiac space for Rocket. Coming back to the third milestone, PKP2, we treated three patients in a phase I at the right dose, meaning the final dose without any dose escalation of 8E13 vector genomes per kilogram. We saw in all three patients moderate improvements in arrhythmias, right ventricular function, protein expression and trafficking to the intercalated disc, as well as improvements in how patients function and feel.
We saw consistent improvements across three of three patients. Went to the FDA, agreed that we can start talking about a pivotal phase II design. The big milestone this year could be a discussion and finalization of that trial design with the agency. Again, this is something that's not going to happen in the first half, but potentially in the second half. That's PKP2. Number 4, the fourth catalyst is BAG3, the dilated cardiomyopathy. We have an IND that's open. We anticipate starting the phase I trial this year. That's on track, and that's the fourth major catalyst I would say. Each of these diseases is relatively rare. If you add them all together, though, the Danon, PKP2, and BAG3 patient populations, we're looking at more than 100,000 patient prevalence between U.S. and Europe.
While each rare disease is rare disease is not rare. Those are the four currently existing pipeline catalysts. The fifth catalyst I would say is we are very proud that we started the company with an LV ex vivo portfolio, including LAD-I, which has the PDUFA date coming up, Fanconi anemia and PKD. We are looking to potentially externalize or partner these assets as yet a fifth catalyst at some point. KRESLADI, Danon, PKP2, BAG3 and the LV portfolio all could be potential milestones and catalysts by which we can continue to build Rocket and thank you for your attention.
All right, we can move to Q&A. Maybe I'm going to invite you to sit next to me so we can be closer. Got caught. All right. As you're resetting up your microphone, I'll get started. I like the way you outline that by milestones in order of programs. I feel like we can go through the questions in a similar manner. Starting with KRESLADI, you know, with the PDUFA date that you have coming up. You mentioned at the end that you'd be interested in essentially partnering that. I'm curious, what's the rationale for partnering a program like that and what would a attractive partnership look like to you?
Well, I think we've gone through a journey at Rocket with many years of clinical successes, a couple of setbacks with the LAD-I CRL and the patient safety issues on Danon. We've had to really learn how to focus and prioritize. We would love to do everything. We just can't. If we try to do everything, we'll do nothing, right? We've taken a deliberate approach to focus on rare cardiac starting this year. Actually, starting in the middle of last year, which required us to size down our LV capabilities, both in-house, and just general capabilities, and to refocus our resources and money on AAV.
Therefore, given that these programs do work, obviously KRESLADI, the Kaplan-Meier curve on there is something that is one can only dream of with a 100% survival over five plus years in some cases. The Fanconi program works. There's minimal safety issues on it. PKD in our phase I is also a very exciting program where the hemoglobin is normalized or near normalized in all patients treated. These are gene therapies. When gene therapy works, it works. I think that there is an opportunity to partner with a group who can take these to the finish line and maximize access for patients and physicians and families. That's the approach.
Which program gets partnered or not, it's too early to tell, but the whole LV portfolio is something that we want to partner in order to maximize both patient access and shareholder value for ourselves.
Mm-hmm. If a partnership takes more time than, you know, the next few weeks for LAD-I, you would begin launching that on your own...
Correct.
Regardless. Okay. All right. I think we should move on to Danon. I will say, you know, when I was a brand new associate and writing my very first initiation, it was on Rocket my first week as an associate, and I just remember sitting and writing for hours and hours on end about Danon and thinking like, "Man, I can't imagine a better indication for gene therapy than something like this." Here we are today, we're in the pivotal trial, and you know, you have some ongoing FDA discussions and a lot going on this year for that. I'm curious, you know, during this interruption period, what are the major learnings from that you're really taking forward? Especially as you're, as you begin to redose patients, how are you looking at what success looks like for each of those redosed patients?
I think that the biggest learning in gene therapy, I believe is to go fast, you have to go slow.
Mm-hmm.
You cannot rush things. You have to take time to do the proper analyses work with the agency and other experts around the world to really figure out how to optimize safety gene therapy works, but it's hard and to think otherwise is foolish. For these patients coming up, we've optimized the program as best we can. We have recalibrated the dose to account for a higher full/empty ratio, which in Danon and with AAV9 might portend more potency. The same dose with more full empties might be a more potent product, likely is a more potent product, and therefore we have to adjust down the actual dose delivered to match the phase II with the phase I product, right? That's a big change.
We've removed the C3 inhibitor, which we have very good reason to believe was responsible for the capillary leak syndrome in combination with the AAV9, with the high massive dose of AAV9. We have tweaked the criteria by which we administer the C5 inhibitor eculizumab we would administer earlier than usual just with these changes. We've changed some things about how long and frequently we minister rituximab in order to abrogate B-cells ahead of treatment. Those are the four big changes. This is the best foot forward. We feel good about it. I feel good about it. There's no way to know, of course, until we see the results. The unfortunate thing with AAV on safety is that there are no preclinical models that predict what happens in the clinic. We didn't see TMA in preclinical models.
Certainly, there's no capillary leak issues in the, in preclinical models. We have to learn these safety improvements real time with people. I must say that the Danon community, because of the devastating fatal nature of the disease, and their openness, they've been very supportive in figuring this out together for the long-term health of Danon.
Yeah. That's great to hear. I'm not surprised to hear that either. How about then, with the FDA, so with those interactions that you have with the redosed patients. You expect to give us a regulatory update later in the year. What could that potentially look like besides a protocol modification? Is there any chance that they may ask to change the pivotal trial design, more patients than this? You know, what are the potential scenarios that could come out of this?
We've heard no indication from them that there's an intent to change the design itself.
Mm.
Of course, we don't know. We have to be humble and take our time to do this the right way, right. I think the FDA's philosophy, I think is very pro-rare disease. It's very pro-gene therapy. We don't know what's gonna happen until it's done, just to put that caveat out there. We've got no indication that the FDA intends to change the actual trial design. What I don't know is how many patients we will need to continue to treat at this recalibrated dose. Is it enough to finish a total of 12? Is it a new 12? Is it something else? That I don't know, and I think that's the discussion. Some of it's gonna depend on what the safety looks like, and other factors.
I will say that our experience with the Danon reviewers at the FDA so far, has been pretty consistent, rapid, and collaborative.
Okay. With that review group and all of the recent changes in the FDA, can you maybe take a few minutes to discuss at a high level what your thoughts are for FDA receptiveness to, you know, biomarkers, and previous alignment that you have on endpoints and how confident you are that, you know, the previous interactions with the review group and anyone at the FDA, could remain predictable and you know, in line with your expectations?
I think that where we've been deliberately thoughtful since the beginning of Rocket, since day one, nothing has changed here, is that the diseases that we pick are either fatal or highly devastating, and most of them manifest at an early age. I think all of those factors are part of this focus from the current agency on rare pediatric-focused disorders using bespoke gene therapy. I think all of those factors fit. On top of that, in Danon, we've been able to demonstrate, if you look at the green slide and from the NEJM presentation or on the website, 100% consistent improvement across every parameter we looked at, whether it's troponin or BNP, protein expression, reduction in vacuoles that you see on TEM, NYHA Class improvements, KCCQ improvements, LV mass index, which is the most important one.
Every single cell there is green. Compared with patients who are not treated, whose LV mass we've demonstrated increases by about 8% a year, their troponins increase. They're moving toward heart failure. They're not going from NYHA Class II to Class I , they're going from Class II to Class IV , right? In contrast with what's obvious in a rapidly progressive disease in the mid-teens, I think the results here are exactly what I think, what the agency is talking about when we're talking about demonstrating results in a small trial. That's my view. I don't think that's true of all programs out there. We feel good. That's not to say that the dialogue is done, but I think we're standing on strong ground with Duchenne. The same is true for LAD-I with the potential upcoming approval and we hope the same is true across the portfolio.
Yeah. Definitely. Okay, you also said, later in the year that you'll be updating a little bit on epidemiology.
Yep.
You know, without front-running that maybe a little sneak peek, maybe just tell us how has your market research changed and evolved over the years? Is the market opportunity larger than you originally anticipated? Smaller? Maybe similar but shifted male and female? I'm just curious how that's evolved over time.
It's still a work in progress. I think as rare disease epidemiology research develops, numbers change over time. Right now, we're still thinking around the same ballpark in general. Certainly, the addressable market and the market opportunity and revenue opportunity is similar, as it's always been. I think that we will be able to do two downloads the second half of this year. One is exactly what you asked, a top-down analysis of, the true patients out there using both phenotypic and genotypic methodologies, and then patients that we've actually found in the real world. I think at some point those two will match. One thing in Duchenne that unlike Duchenne, unlike cystic fibrosis, even unlike Fanconi anemia, this is not a disease that's been well characterized because it masks as other things.
It masks as Fabry or Pompe or learning disabilities in many cases, or muscle pain. The link between Duchenne as a clinical disease and the gene was only made in the 2000s, so there just hasn't been that much time for awareness. Over time, I think the true epi will come out, but we are part of creating that awareness.
Okay, great. All right, down the line, the next one you mentioned PKP2. Can you start by comparing and contrasting the data that you have so far versus at least the other two-.
Yeah.
... that we know of that have clinical data?
I mean, having looked at these data sets myself, they are complicated. Little things go a long way, right? Do you use a two day Holter versus a seven day Holter to monitor rhythms? How much are we interrogating devices versus looking at Holters? How much are we thinking about PVCs versus T wave inversions versus NSVT? How closely are we looking at heart structure and size and function? How well are we capturing how patients are functioning and feeling? I think those nuances are not comparable across programs. In some ways, I would plead the 5th in commenting on the other data. What I can say is that for even though we've only treated three patients, all of them have demonstrated improvements and no worsening, and improvements certainly.
The arrhythmias we've measured in the right ventricle size where we've been able to measure it in all three have demonstrated an improvement in how they function and feel. I think that's differentiating without necessarily commenting on the other data.
Okay. Fair enough. All right, for the next trial, I know you're working on a potential design and endpoints, so maybe you could update us on your current thoughts there of what you would most like to assess and how you would like to assess it.
Duchenne, I will say we got, we found probably the most aggressive cardiomyopathy, genetic cardiomyopathy that's out there, where patients get worse in a couple of years and move to transplant within three or four years. That's not gonna be the case for any of the other genetic cardiomyopathies, I think we have to be more thoughtful, deliberate, and take our time to figure out the right trial design to actually win and have a positive result. We haven't certainly finalized any sort of trial design, but under consideration, of course, are single-arm trials versus pre-treatment, single-arm versus natural history. Randomized crossover design, I think is just as viable, if not more likely to produce a positive result if the drug works. We will be careful to have 100% agreement with FDA before stating what the actual result is.
I would say those are the trial design options. There may be more. In terms of length, I think this is gonna take longer than Duchenne to demonstrate a difference between treated and untreated. Instead of a year, it could be a little bit longer. I don't wanna capture an exact guess there either. All in all, we still anticipate a gene therapy appropriately, gene therapy size trial, right? Not something that's gonna blow the bank here for PKP2. We're excited. We're in those dialogues. We have been, and we hope to get some clarity on that later this year.
Okay, great. I think, among investors, just the street in general, one of the biggest questions here is the market opportunity of this versus implantable devices.
Yeah.
Maybe you could position that for us.
Well, ICDs are the standard of care in PKP2 ACM, and they work. About 20- years ago, there were breakthrough fatal arrhythmias, in some papers you can say 50%. That doesn't happen as much anymore. There are still fatal breakthrough arrhythmias, but they're more rare. ICDs are a good treatment. More than three-quarters of patients who have the disease will get an ICD. ICDs are associated, number one, with intense anxiety, and it's horrific anxiety because when patients get these shocks, it's not a near-death experience or a death-like experience, it's a death experience, right? Their heart stops, and they're shocked. When that happens repeatedly, these patients live with fear, anxiety, social issues, and they just can't function normally anymore.
That's 1 thing that we need to correct for by reducing ICDs and getting ahead of the problem, even at some point preventing ICD placements or the need for them. The long-term issue for these patients, though, is that this is a disease now of the right and left ventricle, but primarily the right ventricle. The right ventricle fails over time. ICDs don't prevent that. They don't treat that at all. I think getting a gene therapy approach both to reduce arrhythmias and long-term to improve and stabilize right ventricular function will translate into long-term mortality. That's the clinical unmet need here.
Yeah, I would say that's pretty compelling. Well said. Okay. All right, again, down the line. Let's do BAG3 next. Maybe you could just tell us what is it that excites you the most about this program?
Yeah, DCMs are more prevalent and diagnosed than HCM. It is one of the most, if not the most diagnosed kind of cardiomyopathy. BAG3 is a large chunk of DCM. What excites me is that figuring out, first of all, safety, but efficacy in BAG3 could open the door to many other DCMs that could really capture a big chunk of cardiomyopathy. The other thing is that BAG3, because it's a DCM patients have reduced ejection fraction, so this is a better trodden path. When in programs and companies who have looked at cardiomyopathies with DCM, EF has been an endpoint. You can look at LV strain, you can look at peak VO2. There's other ways to capture endpoints that has already been done, so we're not gonna be trying to figure this out and create something from scratch.
I think there's already a body of work that could support a variety of endpoints. In BAG3, we hope to capture one or two of those as we have our trial started. For now, what I'm excited about is the phase I, just getting patients treated, getting through safety, and then having this dialogue with experts and FDA. I will call BAG3 a, sort of a hidden gem. We're, I'm proud of the partnership and eventual acquisition of Renovacor that led to the BAG3 program a few years ago. It was a bet we made then. We think that BAG3 will eventually could become maybe the biggest genetic cardiomyopathy program that we have, even more than PKP2 and Danon.
We're investing in that as sort of a hidden gem, but until we see the data, we'll just sort of be quiet about it.
Okay. Well, before we see the data, what would you, what would you call success? I know you mentioned safety there.
Yeah.
That you'll get the safety data from this, take it to the FDA. Is that something that, I mean, where, really where our focus should be on in that initial data is just looking at safety, or are you gonna have preliminary efficacy measures as well?
Safety overhang in AAV is major. Even getting through safety in any of these programs, I think is a big leap forward. We are gonna be starting in BAG3 at a dose that could be a functional dose. We are dose escalating, but we're trying to start at a dose that, like Danon, worked the first time around. If we see safety, then I think we're gonna give these patients a real shot at efficacy as well. Yeah, safety's a big hurdle.
Yeah. Okay.
I won't say hurdle, a big river to cross and looking forward to the other side of the river.
Definitely. Okay, great. I mean, I guess in the remaining minute that we have, maybe you could tell us what is the most underappreciated aspect of Rocket right now?
I think we've evolved as a company and as a team and with our advisors in how we think about gene therapy, and I think we've arrived at a place where we can truly be leaders in this field, through transparency, deliberate thinking, taking appropriate measured risks, and being mindful about resources and resource allocation. I think we're uniquely positioned because we've gone through everything we've gone through, both clinical successes and challenges, and we've come through all of it, feeling confident in our inner stride.
Great. Okay. With that, we are out of time. I thank you so much, Gaurav, for being here.
Thank you.
Thanks everyone for listening.
Thank you.