All right. Good morning, everyone, and thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Mike Gold. One of the Biotech Analysts here. It's my pleasure to introduce Gaurav Shah, CEO of Rocket Pharmaceuticals. Just a quick reminder, the format for today is a fireside chat. If anyone has a question in the audience, please feel free to raise your hand and we'll address your questions during the discussion. Before we get started, I just need to read a quick disclaimer. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. With that, Gaurav, thanks again for joining us. Maybe I'll hand it over to you to make some intro comments before we get into the Q&A.
Thanks, Mike, for having us. Great to be here. Big picture, Rocket Pharma ceuticals is a gene therapy company. Our renewed and invigorated focus is on cardiovascular genetic medicines. We have three programs in the clinic. One hypertrophic, mostly cardiomyopathy called Danon disease, one arrhythmogenic cardiomyopathy called PKP2, and one dilated cardiomyopathy called BAG3. All are progressing rapidly. We also have a legacy pipeline of hematologic conditions. We just got an approval for severe LAD-I called KRESLADI earlier this year, for which we sold a PRV for $180 million. We're very proud of that. At this point, we are an integrated company from discovery to commercialization from the beginning to end. Today is a very important day. I'm very happy to announce here at Morgan Stanley that the FDA has now cleared our path to dosing the rest of the Danon trial.
We were previously on hold last year due to a safety issue. We were asked to treat three patients with a modified immunomodulation regimen and a recalibrated dose. We treated those three patients safely. The therapy was well-tolerated. The FDA has now given us a green light to move forward. Interestingly, the green light does not expand the trial at all. We'll continue with the 12-patient, single-arm trial. We already treated three, so nine more. Everyone needs to be treated at the recalibrated dose with the revised immunomodulation regimen, which is what we wanted, actually. We anticipate moving that trial forward as soon as possible. This was definitely the upside because there could have been the possibility that the FDA asked for a larger trial, given the safety issues earlier.
Because the safety was so pristine, I believe that they allowed us to continue the trial exactly as it is. We expect to start treatment for the rest of the patients soon and complete dosing by mid-2027. Importantly, we will provide a comprehensive Danon disease program and general portfolio update on October 6th this year at 4:30 P.M. The other important point, very important point that I want to make is about our current cash position and runway. We remain well-capitalized. Our current runway extends into the second quarter of 2028. I also want to remind investors that Danon disease has pediatric designation, so it carries the potential of an additional PRV at approval, which is important when considering the program's overall funding in the future.
We also have an active ATM with Cantor and honestly, several financing options available to us and a lot of flexibility given the cash runway to select the right capital at the right time. I wanted to make that point. Our focus, in the meanwhile, is really executing the Danon pivotal program and making future capital decisions at the time that they make the most sense.
Yep. Great. Thanks for that introduction, and congratulations as well on the feedback from the FDA. I know it's been a lot of work there, so it's great to see that. I guess maybe just give us a little bit of background on dosing for the Danon program. I know there's been some changes there and you're seeing good safety so far, but just kind of what gives you confidence that that's the right dose?
Yeah. So the original dose was 6.7 E13 vector genomes per kilogram. The recalibrated dose, and I don't say new dose, I say recalibrated dose, is 3.8 E13 vector genomes per kilogram. In Danon disease, because of impaired autophagy, we have very good evidence to believe that higher full empties actually lead to a more potent product for a variety of reasons. So having 40% or so more fulls, sorry, more fulls lead to a more potent product. Having 40% more fulls, higher full empty ratio, leads to the 6.7 E13 product in phase II having been stronger than we thought, more potent than we thought. So we had to recalibrate it down to 3.8 E13, so the new 3.8 E13 is the old 6.7 E13.
So we believe with FDA alignment and expert alignment that the new product in phase II is exactly the product that we treated patients in phase I. So that's the rationale for it. Also, two of the pediatric patients in the phase I trial had been treated at around 4 E13 with the old product. Even if this full empty calculation doesn't hold 100% true, those two patients did very well. In fact, they had the most profound reductions in LV mass index for at least three years. So we know that this range from about 4 E13 up to about 1 E14 is active, and we selected a dose that we believe is on the best side of the benefit risk profile.
Great. Can you talk a little bit about just safety and remind us changes to the immunosuppressive regimen, what you saw previously that triggered those changes, and then what you are seeing now?
Yeah. We first had a regimen in phase I that was a combination of pretreatment rituximab over two cycles, pretreatment sirolimus and ongoing sirolimus for about a couple of months, and steroids with as rapid taper as possible. With the more potent product, we found a higher incidence of TMA than we were comfortable with. What we did then is that we added a C3 inhibitor from Apellis. That C3 inhibitor was instituted about a year ago in two patients, and it worked for TMA. It did eradicate TMA, but unfortunately, it came with the paradoxical reaction of capillary leak syndrome for a variety of reasons we can talk about if you would like. When we saw the capillary leak syndrome, one of which case was fatal, we had to obviously remove the C3 inhibitor. It is not the C3 inhibitor itself, by the way.
It is the C3 plus the AAV, the torrential rain of AAV. The combination basically de-opsonizes the AAV that would have been opsonized with C3b, and the AAV then attacks endothelial cells. It is not something that we would have predicted, but it is what happened in the real world of the clinic. We pulled out the C3 inhibitor, number one. We have now extended the rituximab to be given over three cycles, same total dose, but we believe the extended rituximab further eradicates B cells and prevents classical complement activation. We added eculizumab only as PRN, in other words, as needed, which we have not needed to use. You only use it if there is evidence of TMA, and we have the steroids with the rapid taper. That is the new regimen, and so far it is working very well.
Yeah. Can you just talk about that immunosuppressive regimen you just described and differences across the field? Is this common now, the same-
Yeah.
Sort of regimens you're using? Are you using some different things than others or?
Depending on the capsid, companies are using anything from high-dose steroids alone to pretreatment, and ongoing eculizumab or C5 inhibitor. Some folks are doing exactly what we're doing. I think there's no right recipe. I think it depends on the disease, the specific capsid, the specific vector design. All of it matters. No two gene therapies are made exactly the same, and no diseases are exactly the same. I think for our programs, Danon, and we also use the same regimen for PKP2 and BAG3. For our vector designs, we feel that we've found the right mantra.
Yeah. Makes sense. I know you have to enroll now a total of 12 patients. You have three enrolled, so you need to find nine more patients. Maybe just talk about have you identified those patients, and then the process of getting them treated and how long that might take.
Yeah. We have identified well over nine patients. Our funnel has actually expanded quite a bit. Most of the patients who were previously qualified, a couple are no longer qualified, but most of them remain qualified. In addition, our funnel has drawn from our medical affairs group in genetic testing and a new ICD-10 code and other efforts at finding patients out in the real world. Our natural history study itself has enrolled more than 50 patients itself. So finding nine patients is going to be exceedingly easy, I should say. Of course, patients can't all be treated on the same day, even though the ongoing trial patients will be treated in parallel and not sequentially. There are logistics. We also want to mix it up with sites in Europe as well as the United States, three sites in each continent.
It is going to take a little bit of while. Our guidance right now is mid-2027, but obviously, we are moving as fast as possible.
Yeah.
Importantly, the October 6th webinar is going to give a lot of insight into both the top-down epidemiology and bottom-up. Top-down, I would say that we have looked at both phenotypic analyses, meaning finding hypertrophic cardiomyopathy patients and then finding which of those are Danon patients, as well as genotypic epidemiology, which is genetic testing at birth. Genotypic testing maximizes diagnosis at birth, whereas phenotypic, it goes up over time. Where that lands in the middle, we are going to do that analysis, and we are also going to talk about patients we have found in the real world in the United States over the last couple of years. That is a very important webinar for folks interested in Danon to tune into.
Yep, for sure. Can we just go back to the nine remaining patients? You mentioned there is a lot to choose from. Are there specific characteristics of patients that might respond better or not to your gene therapy, and can you do things to try and get those patients into the study?
In general, with this gene therapy at Rocket Pharmaceuticals, all gene therapies at Rocket Pharmaceuticals, and I would say all gene therapies in general, there is a point of no return.
Yeah.
Right? Any disease progresses so far that the fibrosis and other body reactions prevent gene therapy from entering and having an impact. We believe, and we have some empirical evidence to suggest that that point of no return is when patients have progressed beyond an ejection fraction lower than 50%. This is a hypertrophic cardiomyopathy, so the ejection fraction should remain normal. By the time it's diminished, it means that there's florid fibrosis, and when there's a lot of fibrosis, it's unlikely that the gene therapy will penetrate where we need. That's probably the point of no return. The only other patients excluded would be those who have neutralizing antibodies to AAV9. We do exclude those as well. I would say that for the male patients, that still provides 80% of patients as still eligible who have not progressed, who have not been transplanted yet, right?
The thing with male Danon patients is that although it is somewhat heterogeneous population, most male patients become symptomatic with heart disease in their double-digit years. They progress rapidly, and the median life expectancy for those males and/or transplant is 19 or 20 years old. So it's pretty homogeneous within a heterogeneous population.
Yeah. Makes sense. I also wanted to just ask you about durability of the treatment. You've treated patients, I think, a couple of years ago, so just maybe give us an update on what you're seeing there in terms of the durable effects.
Yeah. So for the patients who we followed on long-term follow-up, as far as we follow them, and we published this in The New England Journal of Medicine, and we've given informal updates more recently out to five years and more for some patients. The protein expression is florid as much as five years. In fact, the first patient treated, 101, was treated in 2019. He's seven years out. He's working, he's going to school. He was a patient who we weren't even sure got a full impact of gene therapy because he wasn't taking his steroids as expected for a variety of social reasons. But even that patient is seven years out, has strong protein expression, troponin, BNP, LV mass index are all looking very, very good, even seven years out.
That's been true of the other patients as well, at least as far as we follow them on long-term follow-up. Obviously, if they're lost, then we don't have that information.
Yeah. No, that's great. Maybe back to the registrational study, you mentioned primary endpoint is sort of consistent with your agreement with the FDA previously. Maybe just walk us through the co-primary endpoint and kind of what you've seen previously.
The co-primary endpoints are very much in guidance, following the guidance from the FDA for genetic rare diseases. Which is, if you can find a protein that truly defines the disease and show both preclinical models and clinical evidence that the protein expression correlates with some sort of clinical outcome, number one, so protein expression, LAMP2, and second is LV mass index, and that's something that we negotiated really face-to-face with Peter Marks when he was here and others at CBER. Because Danon is a disease of big hearts. So how do you show benefit to shrink the heart? It's very much common sense. We were looking for a year for other methods like should we look at LV strain? Should we look at cardiac output? At the end of the day, the simple solution was the right solution.
Combination of improvement in protein expression plus LV mass index reduction by 10% or more, and that's in fact been taken up by other companies as a standard of care or a standard endpoint now for these types of diseases. That has not been changed from our prior guidance. I should say that the trial is confirmed as 12 patients total. It is a responder analysis, and not necessarily all the patients need to meet those endpoints to be a positive trial. We'll have more updates on that as well later in October.
Okay. Understood. I wanted to get back to this idea of safety, and you have had three patients that have done very well. I think it is through about four weeks plus now. I guess remind us, previously when you saw these adverse events like TMA or capillary leak, did you see them very early in the treatment? Did they show up in that four-week window? Did some show up post four weeks or just?
Yeah. TMA, I myself looked at so many labs and sort of dreamt about these labs for many years. You know TMA by day four-
Okay.
Oor five. Capillary leak takes a little longer, maybe day five or six. I do not think in the real world we have seen capillary leak beyond Rocket, maybe one case at most. So it is not something that is commonly encountered. Hopefully it is not ever encountered again because people know that C3 should not be combined with gene therapy. But within a week, at most two, if there is no TMA or capillary leak, I think we are in good shape. What does creep up a little bit later across the board, we have seen this for most gene therapies, is immune transduction of liver cells, which sometimes turns into transaminitis, and that you want to see some transaminitis, otherwise it feels like you are giving water. That usually manifests between, say, week 2.5 a nd week six or so. But certainly for any of our programs, it has not been problematic at all.
Yep.
And been pretty well controlled.
Yep.
I should also add that how do I feel confident that this recalibrated dose is the right dose? We have done some non-clinical bridging studies that we revealed this morning. We will have more on that. We have done some analytical comparability between the phase I and phase II product. We will talk more about that, too. Importantly, in looking at transduction of heart and liver in the days and weeks following the gene therapy, our new product seems to follow very similarly to the pediatric patients in the phase I product. I feel pretty good that we are transducing these cells.
Yep. Great. I also wanted to just ask about your FDA interactions a little bit.
Yeah.
There has been a lot of leadership changes over the past year or so and more recently. Maybe just characterize your interactions there. Does the FDA have a favorable view towards gene therapies, and are you dealing sort of with the same group of people, or over time, has that kind of changed?
I would say the guidance for rare disease and gene therapy from the FDA has always been favorable. I think it is becoming more favorable even with the prior administration here, who has now changed. I think most of my colleagues at Rocket Pharmaceuticals and in the field would say that it is all about the reviewers themselves, the specific reviewers. There is less impact from higher up sort of making changes. Of course, I think we saw that a couple of times, but outside of that, those things that happened late last year and earlier this year, if we have a good relationship and a dialogue with the review team, with constant iterative mutual education discussion, even with patients and patient groups and those sorts of initiatives, that is the right way to go.
We've never really had an issue with any of our programs. Even when we had the prior administration, Danon and all the other programs were moving forward pretty rapidly without a lot of issues. I can comment on the CBER director. I think he's very open-minded, certainly to rare disease and gene therapy, so we're very excited about working with him and the programs moving forward.
Yeah, great. You've touched on this already, but October 6th you'll have a very comprehensive update on the Danon program. I think you mentioned maybe epidemiology. I guess, what else might we expect or should we be looking for?
We will have a broader portfolio update as well. I think we'll talk about, first of all, on the Danon, and we'll talk about the clinical profile so far. We won't have efficacy, just to be clear, just because it's so early.
Yep.
As you can just calculate, the first patient would not have been treated much more than three months ago, right? We don't have enough efficacy data. But we'll talk more about safety, the general experience across the phase I and phase II. We'll talk about the epi top-down, bottom-up, and we'll have some updates on the rest of the portfolio as well.
Okay, great. Maybe we can shift gears into some of the other programs.
Yeah.
You mentioned earlier, but I guess maybe just big picture question, what makes gene therapy such a good approach to treating these cardiovascular, cardiometabolic disease?
Well, I think for at least the programs that we're looking at, and I think most colleagues in the cardiac gene therapy field are looking at, you can't do anything other than DNA replacement. There's no small molecules. Many of these are transmembrane proteins or cardiac junction proteins. You can't just put a small molecule there and expect it to traffic to the right place. You have to hit them in the nucleosome at the DNA level, and there's no other way. So really, there's no alternatives other than transplant.
For most of these patients. I think that's what makes them compelling. I think Danon is a one-off. Danon is probably the most aggressive cardiomyopathy out there. The vacuoles build up pretty rapidly in the course of a couple of years. So reversing the cardiac modeling or cardiac remodeling, you can do within a year or two in Danon disease in a way that I don't think we're going to see across the other older patient cardiomyopathies.
Danon is a good test case. Building on that, BAG3 is a dilated cardiomyopathy. These patients usually don't manifest until a little bit later in their life, 20s or 30s. They have a slower onset of action. We do believe that BAG3 replacement with gene therapy is a viable approach. That trial is started, and we'll have more updates on that soon. PKP2, similarly, is an ongoing trial. We've treated three patients, and that's an arrhythmogenic cardiomyopathy. I think there it's a little bit more tangible to show a demonstrable benefit.
Without waiting for RV dysfunction, just with the arrhythmias themselves. We hope to have an update on that with the regulatory agencies soon as well.
Yeah. Just on those sort of Wave 2 programs you just mentioned, I guess, just given your experience with Danon, any key learnings that you can apply to these next wave to accelerate things, or what are some of the learnings?
I would say there's general lessons, right? There's lessons on safety. Treating patients with AAV-based gene therapy creates muscle memory in the organization. It's just like doing a commercial launch. There's a feel for it. There's a dialogue. There's experts around the table that you talk to. You just have an instinct when something happens, and you know it's going to go wrong or it's not going to go wrong. I think that learning applies across our portfolio. You mentioned Wave 2. I would call these three programs, Danon, PKP2, and BAG3, I would call them still Wave 1.
Wave 1.
There's a Wave 2 with at least three other programs, some of them as exciting or more exciting, in my opinion, but we'll be able to apply this across all five, six programs over time. The other learning, the general learning across the field is how to really interact with the FDA in a way that's collaborative, that's transparent, that's proactive, so that we're not surprised at the last minute. A vulnerable point I can make is that the lesson from LAD for KRESLADI, we did have a CRL there. We made assumptions based on what we were seeing other companies do, Orchard Therapeutics, bluebird bio, who had gone before us and gotten lenti-based therapies approved.
We had made assumptions on what the FDA would have wanted to see, and when we got there at the last minute, they wanted us to sort of copy exactly what bluebird bio and Orchard Therapeutics had done, and that cost us a year or more. In retrospect, I would've asked earlier, even if that delayed things by six months, I would ask early. That's what I'm doing with these programs now to make sure that everything is teed up well in advance.
Yeah.
Those are the general lessons across the programs.
Yeah. Makes sense. If we just focus more on PKP2 and maybe talk about the unmet need there, and the market opportunity.
PKP2, we think that there are at least 50,000 patients in the U.S. and Europe. One larger company who had pursued it in the past and dropped it, said it was 140,000, so it is somewhere in that range. I think that because of that large population, there is probably room for more than one biotech or pharma to treat these patients. There are a lot of patients out there. They are easily diagnosed because these are patients who exercise and have palpitations, unfortunately have sudden cardiac death. The current treatment of ICD is employed in about 80% of patients in the U.S., but it does not stop progression of RV dysfunction. It does not stop the anxiety that is debilitating for these patients, and there are also breakthrough arrhythmias that could be fatal. So there is a very high unmet need.
The patient community we have interacted with is really excited about the prospects of gene therapy, and at least the three patients that we have treated, we still have the phase I open, have done exceedingly well and the therapy has been life-changing for them.
Yeah. Can you maybe talk about some of the earlier data you shared and what impact you have had on sort of key endpoints and your thoughts around some of those endpoints?
Yeah. I would say that the endpoints fall into four categories, and these are the same four buckets that anyone discussing with FDA is going to have to talk through, right? One is protein expression, one is arrhythmias, one is RV function, and the fourth one is how a patient functions and feels. There's only four buckets. We're all going to arrange the chairs on a deck in our own way, but there's only so many chairs to arrange, right? Protein expression, we feel that we've looked at protein expression very thoroughly, using not just western blot and immunofluorescence, but also looking at trafficking of chaperone proteins that should be present in the cardiac junction if PKP2 is there. We've demonstrated improvement for all three patients. We've looked at arrhythmias. The common arrhythmias that people look at are PVCs, NSVTs, and T wave inversions.
Not all patients have abnormalities in these, but we've seen improvements where abnormalities existed in our patients. We've seen one patient who had a normalization of RV dysfunction, the only one who had RV dysfunction normalized that function. On the NYHA class and KCCQ scores, we've seen improvements across the patients we've treated. We started at a dose that we thought was the right dose to start with based on preclinical models. Therefore, we have less patients treated, but we do believe that we have the pivotal dose ready to go. The FDA has agreed with that, and now it's a question of which of those endpoints are primary or secondary, and how do you design the trial?
Yeah. I guess, you mentioned, I think you're going to have an update later this year on this program. Will it include sort of the path forward as well, and a phase II design-
Yes.
With, okay.
That's the plan. Those discussions are ongoing. I don't have exact guidance on when, but they're ongoing.
Okay. Got you. You hinted at this too, there's some competitors here. I know data's sort of early comparing across trials, but is there any way to think about any differentiation that's emerged early across the programs?
I think the programs are similar. Different patients are going to have antibodies to different capsids. I wouldn't declare a victory of any one over the other. I would say that the data that we've presented is directionally uniformly moving in the same direction for all three patients with no deviations, so that makes us feel comfortable that at least we have the right dose with the right patient profile to move forward to a pivotal trial.
Yeah. Understood. Maybe we can shift gears to just BAG3 and maybe give us a quick background on that condition, kind of next steps for that program.
BAG3 is super exciting. It is a program we inherited from the acquisition of Renovacor a few years ago. It does represent the largest bucket of cardiomyopathies, which is dilated. I think if we can crack the BAG3 code, there is a lot more to come. In fact, some of the technical Wave two programs are looking at other programs like that. BAG3 is a protein that has multiple functions. It is not so simple as Danon, which is just associated with autophagy. We think that a similar approach with mid-E13 dosing based on preclinical data that we have seen and demonstrated and publicized should afford some benefit. This is a dilated cardiomyopathy, so traditional LV endpoints are going to make more sense.
I do not know if it is ejection fraction or cardiac output or some sort of exercise test or LV strain or something else, but this is a playbook that has been played in the cardiac field in the past. While Danon we have to figure out, PKP2 we have to figure out from scratch, this is something that should have a well-trodden path.
Yeah. Maybe talk about timelines for that program.
BAG3 is in the clinic, and we hope to have more updates soon.
Okay. Got you. Maybe across the three programs we have been talking about, can you talk about just the capsid or key differences?
Yeah.
Are they anything different there?
AAV9, we felt that AAV9 is the right vector for Danon disease because Danon disease is not just disease of the heart, but also CNS and muscle. We know AAV9, AveXis, et cetera, penetrates CNS exceedingly well. Often, these are patients who present with learning disabilities first, even before they have any muscle pain or cardiac symptoms. AAV9, we believe was the right capsid for those male Danon patients. AAVrh74, of course, has tremendous experience in humans through Sarepta Therapeutics and others. At the dose that we are dosing all of our patients in PKP2, BAG3, and potentially future patients as well in the pipeline, which is mid to mid upper E13, the total capsid exposure is probably 1/3 that we have seen from Sarepta Therapeutics and others.
I know that there have been safety issues, especially liver issues with some of the other companies, but we are dosing about 1/3 the total capsid exposure because the dose is less and our full empties are a lot higher.
Yeah.
We do feel that at this range, AAVrh74 is an excellent capsid to penetrate the heart.
Okay, great. Maybe in the last few minutes, we just shift gears to your sort of LV-
Yeah.
Pipeline. You mentioned it earlier, KRESLADI. Maybe give us some background there and next steps to launch there.
Yeah. I am happy to say that yesterday we lifted the price, the WAC for LAD for KRESLADI, which is $3.9 million, a little behind KRYSTAL-1, and I think it is the third highest gene therapy at this point. That is based on health economics analyses, as well as the clinical benefit that we have seen in patients. The patients who do not get gene therapy can get transplanted, which is costly, has a lot of toxicities, and does not always work. KRESLADI, we are launching it in Q4. That remains on track. There are not a lot of patients out there, but we do have at least one, if not more centers that will be open to treat patients who have inbound interest. We are not putting any marketing or commercial muscle behind it other than making it available. It is a severe, devastating condition.
We're very close to the KOL and patient community here, and we're very proud of that launch.
Can you just talk about the estimate of patient numbers in the U.S. and how many of those roughly are identified?
There are 25. This is an ultra-rare disease. There are 25 total LAD-I patients born in the U.S., approximately 2/3 of those tend to be severe. Most of those severe patients pass away pretty fast. There are a lot more moderate patients out there because they add up over time. Within the severe population, which is where our label is and where we will treat patients, there are a small number of transplants each year. I would expect no more than single-digit numbers per year for severe LAD-I and KRESLADI.
Got you. I guess the latest thinking on your other LV assets or updates there?
Yeah. I started, or I was hired to start this company, at RTW based on Pyruvate Kinase Deficiency, PKD. When gene therapy works, it really works. We have treated four patients with PKD. Most of them have doubled their hemoglobin and kept it to normal over years. Fanconi anemia is an elegant gene therapy with no conditioning whatsoever. Most patients that we have treated have remained, in fact, all of them have remained bone marrow transplant-free over time, and most of them have corrected their bone marrow. We have those programs, we own those programs. In an ongoing way, we are looking for partnership opportunities. However, FA is also eligible for a PRV. For now, we have pre-prioritized to the cardiac portfolio, but those are always in our heart as well.
Yep. Okay, great. Looks like we are just about out of time, so why don't we wrap it up? Thanks so much, Gaurav, and congrats on all your progress.
Thank you, Mike.