All right, good afternoon. I'm Eric Joseph, Senior Biotech Analyst with J.P. Morgan. Our next presenting company this afternoon is Rocket Pharma. And to bring us to the story, it's my pleasure to welcome CEO Gaurav Shah. After the presentation, there's a Q&A session. Just wait for the microphone. If you have questions, we'll get it over to you. Folks joining on the webcast, also feel free to submit questions via the portal. So with that, Gaurav.
Thank you, Eric. Thank you, J.P. Morgan, for having us. It's always great to be here, and San Francisco is ever-changing and never-changing at the same time. Good to experience together. So the key message today is that a one-time therapy that potentially cures a fatal and devastating disease of childhood because it addresses the disease at the most fundamental level possible, the DNA. This is such a profound change in the way we've thought about medicine in the history of our species, and it could change the future of our species as well. I'm gonna show you this in several different disease types that Rocket has been working on, and it applies to many, many future disease states as well. Our mission at Rocket Pharma, we're a gene therapy company, is to develop first-in-class and best-in-class curative gene therapies for patients with devastating diseases.
We start with rare, but we can expand beyond rare at the right time. I'm pleased to announce this year for the first time, that we are now a fully integrated commercial-stage gene therapy company. Our therapeutic areas include bone marrow and heart. Rocket is the only company with safety and efficacy, efficacy data for gene therapy targeting the heart. At the end of the last quarter readout, we had $437 million in cash. This is sufficient to fund operations into 2026. So here's the pipeline, and, many of us come from or have worked in larger pharmaceutical companies. This is starting to look like the pipeline of a major business unit in a pharmaceutical company. In this case, rare disease, obviously. We have 6 programs now. 5 are in the clinic, the sixth one to enter later this year.
And also, that's not to mention wave two, which is always mysteriously lurking under the surface. I'm gonna go through some of these programs. Rocket has an in vivo platform of AAV-based therapies that target the heart and potentially other therapeutic areas in the future. We have an ex vivo cell therapy platform, genetically modified cell therapy platform, that addresses bone marrow-derived disorders. Each rare disease may be rare, but rare disease is not rare. There are 400 million people in the world with a rare disease. Half of them are children, and 80% of these diseases are monogenic in origin, means one gene is faulty and is responsible for the entire spectrum of disease. The costs are high. In fact, the cost of a cardiac transplant in the U.S. can be way north of $1 million.
So there is a market, there's an unmet need, and each of these therapies can address the diseases at a root cau- or root level that is potentially completely cured. Danon disease is the first disease I'll talk about. It's a multiorgan disease that primarily affects the heart, but can also affect the skeletal muscle of the CNS. It's X-linked. There's something that all of us have as a process for normal homeostasis called autophagy. It's not a diet. It can also be a diet, but autophagy is the way that our cells clean out debris. It's the recycling center, the garbage takeout of our cells. And the on switch for that recycling center or vacuum cleaner is the LAMP2 gene and protein. Without LAMP2, debris builds up in the heart, it builds up in the muscle, it builds up in the CNS.
Because it's X-linked, it affects boys more frequently and earlier than females. Boys, unfortunately, only live until the age of 19 or 20 without a transplant, and even with a transplant, there's about a 50% 10-year mortality with transplants. It's a great target for gene therapy, for sure. There are 15,000-30,000 patients in the US and Europe combined who have Danon disease. Again, it is rare, but also not so rare. These are the data from our phase 1, and as I'll explain, these are completely transformative for Danon disease. We treated 6 patients who we followed long-term and are now evaluable. The ages were from around 11-21.
Some of these patients have now been followed for four years, and this is a disease state in which you can map the journey of the gene through multiple tissue, biomarker, lab, imaging, and clinical endpoints, as we've done here. First of all, we showed in all these patients adequate protein expression, meaning grade one or higher in all six patients. This was associated with a profound drop in troponin, which is the marker of cardiac injury. Equally, a drop in BNP, which is a marker of cardiac failure, heart failure. This was accompanied by decreases in LV mass. So Danon is a disease of large hearts. Shrinking the heart in as little as three months in some cases, but certainly around a year, is really unheard of in the field of cardiology.
What's happening is that the gene therapy is pulling out these vacuoles, these debris, from the cardiomyocytes and really shrinking the heart. And that translates also to improvements in clinical outcomes, including NYHA Class. Most of these patients drop from 2 to 1, from symptomatic to asymptomatic, and increases in KCCQ scores, which are quality-of-life scores, in some cases 25 or 30 points. Again, pretty rare in the world of heart disease. Now, this is a very precious slide to us. The top left here shows increasing protein expression out to month 6. Brown, the brown dots are actually LAMP2 protein that's been restored. And in the second panel from the top, these are H&E stains, and you can see the large vacuoles on the left disappearing over time.
So you can actually see, and you can count the number of vacuoles that decrease, in some cases, 75% or so, in the patients who have been treated, again, associated with improvements in clinical outcomes. So very rare in the history of medical development or medicine development, can you trace everything from protein expression through clinical outcomes and map the journey in such a predictable way across many patients? So this led to our choice of a primary endpoint, together with the FDA, which includes protein expression and also LV Mass Index. You can see a drop in LV Mass Index in all four of the low-dose patients, which is our chosen dose in phase two, from one year and beyond.
Other disease-modifying therapies that have recently been approved in Fabry, amyloid, and hypertrophic cardiomyopathy are also associated with decreases in LV mass index, as you can see here, and we even see a deeper decrease or improvement in Danon disease patients treated with gene therapy. In fact, in some cases, down to 50% reductions in heart size over time. Of course, the patient stories tell everything, and as I mentioned earlier, the patients that were treated in phase 1 were treated between age 11 and 21. Means that the 21-year-old is now 25, and instead of being in a hospital or at home waiting for a transplant, or what's worse, passed away, this patient is actually going to college. Another patient who is also older has a full-time job. These are the stories that we hear.
One of these patients walked a 10K. I can barely walk 1K. So, so really, this is a transformative therapy that's really never been seen. We were so happy in September to reach a conclusion after a long journey with the FDA regarding our pivotal trial design. So our pivotal trial will have 12 patients followed for 1 year, like I said, with a co-primary protein expression, plus LV mass index reduction. There are several secondary and exploratory endpoints that will support the full approval. So this first, 12-patient, 12-month study will support accelerated approval. The same study will be followed longer in agreement with FDA to potentially convert into full approval. This trial is enrolling, and we've chosen the low dose to move forward. Like I said, 6.7 E13 vector genomes per kilogram.
We're proud to say that all the manufacturing for this clinical trial and also the commercial product will be done out of Cranbury in our own facility, which was a labor of love, but the OpEx is behind. Sorry, the CapEx is behind. Only OpEx ahead there. So this product actually compared with our phase 1 product that was outsourced, we worked with a great CDMO on, has improved productivity. Quality is highly comparable and is more potent in terms of full/ empty ratio as well versus the phase 1 product. So, we look forward to share these results when they come. That's Danon Disease. That's a glimpse of our cardiac gene therapy portfolio. Fanconi anemia is our lead program on the bone marrow side, using ex vivo lenti.
Fanconi anemia was one of the first programs that we started with our colleagues in Madrid at CIEMAT. In Fanconi anemia, we actually were lucky to push the field forward in a very big way. For the first time in the history of ex vivo lenti, we were able to get positive results with 0 conditioning. There's no conditioning, no cytotoxic conditioning. Fanconi anemia is a disease of bone marrow, where the DNA repair pathway is damaged, so it affects all the cells in the body, but especially the bone marrow, because the stem cells fizzle out over time. So you actually don't need chemotherapy to wipe out the existing stem cells because they die out on their own over the course of the first decade of life.
And if we infuse these patients with enough gene-corrected cells, they will have a selective proliferative advantage over the weak cells that are fizzling out anyway. So some of our colleagues at CIEMAT and some of our folks at Rocket, the smarter ones than me, realized that you could get this therapy done without conditioning, and we tried it, and it worked. 8 out of 12 patients who had this therapy and followed for at least one year had positive vector copy numbers, meaningfully positive vector copy numbers. These patients also had improvements in MMC resistance, which is the way that we know that their stem cells are now working. They're not Fanconi cells. In fact, if you put some of these patients' bone marrow side by side with a person without Fanconi anemia-...
And you compared the marrows in terms of their response to mitomycin, which should kill the stem cells. Both these treated patients and non-Fanconi patients would have the same 50, 60, 70, 80% resistance to MMC resistance, to MMC that you see here. So you can't even diagnose patients as Fanconi anemia anymore. You wouldn't even know that this is a Fanconi anemia patient after this therapy was given one year and beyond. Very excited to state that we're filing our BLA and MAA first half of 2024. Fanconi anemia is eligible for a PRV, as is LAD-I. LAD-I is the heart and soul of a lot of folks at Rocket and some of our partners.
When I first started this, this talk, and I said a one-time therapy that potentially cures a fatal disease of childhood, there's no better example than LAD-I. These are patients who lack a protein called CD18 on the surface of neutrophils, and unfortunately, they have recurrent, devastating fungal pneumonias, other infections. They're frequently in the hospital in early childhood, and two-thirds of these patients pass away by the age of two. This ex vivo lentiviral gene therapy option restores CD18, and you can see here that over time, in 9 out of 9 patients that were treated on our pivotal phase 2 trial, there's restoration of CD18, anywhere from 20% to... What is that? 90% or so, with an average around 50%. So these are patients who have less than 2% CD18 at baseline.
As one of our principal investigators say here, "These are no longer LAD patients. These are, these are not patients anymore. They're normal people who are walking around just like many of us are." This Kaplan-Meier curve on the left is the dream of any research physician who's engaged in drug development, 100% survival, no deaths, out to more than three years. Also, this survival was accompanied by significant reduction in incidents of hospitalizations. So when gene therapy works, it works. We're thrilled that this is the first year that we have a PDUFA date, March 31, 2024. So we, we are engaging in commercial setup, and never saw this several years ago, and we're humbled by it and honored by the opportunity to bring this therapy to many patients beyond the clinical trial itself.
The largest lenti indication is called PKD, pyruvate kinase deficiency. This is a hemolytic anemia caused by mutations in PKLR. The frequency of PKD is 32,000 in the U.S. and Europe. The penetrance is about 25%, so up to 8,000 patients have PKD. Our gene therapy addresses the more severe or moderate-to-severe half of this population. These were results that were discussed at ESGCT, so nothing new here, but the first time as a company that we're presenting the full phase 1 results in four patients, two adults, two pediatric. As you can see on the left, these patients had baseline hemoglobins around seven, and they had six- to seven-point increase in the two adults here. That was accompanied by improvement in hemolysis markers, including LDH and bilirubin as well.
On the right side, the pediatric patients also had very meaningful improvements in hemoglobin 3-6 points. All 4 of these patients are no longer transfusion-dependent. So our plan here, we are starting a phase 2 trial. We had a very productive dialogue with the FDA at the end of last year, in which we agreed to a single-arm 10-patient study, and the primary endpoint would be a 1.5-point improvement in hemoglobin at 12 months. This will support accelerated approval. Second cardiac indication is called PKP2. Last year, at this conference, we announced this was our 5th program, and that we were in IND filing stage back then. This is an arrhythmogenic cardiomyopathy.
It used to be called ARVC, when the field thought it was more right ventricular base, but now we know it affects both the right and left ventricles, so it's called ACM, arrhythmogenic cardiomyopathy. PKP2 is the most frequent cause of ACM. This is now certainly not. It's certainly bordering on more common diseases. I think we've all heard of athletes and, you know, sports women and sports men who are running or playing basketball and have some cardiac death. ACM accounts for a large chunk of those patients, and PKP is a large chunk of each ACM. So while it's a rare disease, it's starting to come into collective consciousness. PKP2 is a protein that's on desmosomes. It's the junctions that link cardiomyocyte to cardiomyocyte, and this is the most prevalent disease that we're targeting.
It's at least 50,000 patients in the U.S. and Europe. Some groups have estimated larger numbers than 50,000 even. So I'll just show the mouse model here. There's a cardiac. Sorry, a conditional knockout model, a PKP2 knockout model, that we worked up together with NYU, and we treated these mice with an AAVrh74 version of PKP2. We pivoted to AAV 74, rh74 instead of AAV9, because rh74 has greater amount of data in higher doses, even E14 to E14 range. rh74 has not been associated with some of the side effects that AAV9s in that dose range have been.
Because we believe that in this population, you may actually need to push the dose to get adequate protein expression, we thought rh74 is superior to AAV9, and it was also shown to be superior in our mouse models that we worked, that I just showed you earlier, versus AAV9. On this model, you can see 100% survival in mice that were treated versus untreated mice, and improvements in right ventricular area on the top right, and improvements in arrhythmia on the bottom right, reduction in PVCs, premature ventricular complexes. The PVC point is key because in our phase 1, that's one of the endpoints we're looking at very carefully and may potentially be a primary or part of the primary endpoint cohort for our pivotal phase 2 study. But for now, we're starting the phase 1. This trial is enrolling.
Our starting dose is 8E13 vector genomes per kilogram. This is a very important dose to mention because it's above the dose that worked in mice and similar to the dose that worked in Danon. So it's possible that we may be able to start seeing something even at the lower doses here. But it is a dose escalation program, so we have the possibility of going to the E14 range because it is an rh74 specifically. The sixth program, last but certainly not least, is BAG3. This came through in the acquisition of Renovacor. BAG3 regulates multiple functions in cardiomyocytes, and a mouse model, I've shown this slide before, was positive. That led to this collaboration and then acquisition of Renovacor. This will also use rh74, and we plan an IND toward the end of 2024.
This has a similar prevalence of 30,000 or so as Danon disease. Together, these three cardiac gene therapy assets, if you pool all the patients together, it's more than 100,000. So this is what I was saying earlier. Each rare disease is rare, but you add them up, you get to 100,000, you can get to 1 million, you can get to 10 million. And we're very proud of the fact that we're just cracking the door open to the possibilities of gene therapy. We have a fully integrated facility in Cranbury, New Jersey, where we can do everything from discovery, to manufacturing, to commercialization. Even some of the commercial folks live down there now. Wave two is coming, and like I said, underneath the surface, the iceberg is bigger than above the surface.
Wave two, like wave one, will draw from first, best, and/or only-in-class programs with on-target mechanism of action and clear endpoints and sizable market to maximize the impact of the number of patients that we can. At least two therapeutics with areas, which are cardiovascular and hematology, but potentially more to come. Very proud to work with some of the smartest people in the world in terms of gene therapy, drug development, and commercialization. And I'm gonna invite two such folks, Kinnari Patel, our President and Chief Operating Officer, and Jonathan Schwartz, our Founding Chief Medical Officer, and the one and only first-in-class Chief Gene Therapy Officer in the world. So please come up for a Q&A as well. Thank you so much for coming and listening. Back to you, Eric.
Yeah, of course. Thanks, Gaurav. Wait, just as a reminder, folks have questions, we'll bring a mic over. But just by way of getting started, I'm sure a lot of folks in the room are interested in sort of the operational progress in the pivotal Danon disease program, and noting that the trial is now open to enrollment. Can you just talk a little bit about sort of how the patient screening process has been and maybe, you know, when you might anticipate kind of treating the first patient, like the type of disclosure that might surround such an event?
No, it's a great question. So, there is a large list of patients. In fact, we didn't think that we were gonna end up with a 12-patient trial. We thought it would be much larger, so we prepared with a much larger list of patients that we reached out to. So, there, there's more than enough patients for the trial. We have not disclosed specifics on enrollment yet, except that we are enrolling. And I think in this case, because it's a pivotal trial and we're working so closely with the FDA, we'll probably wanna treat a group of patients and follow them for some time before we actually disclose anything about where we are on the trial or data. And then that's probably the best way for the drug itself in the long term.
Forgive me for getting into this, you know, stated clearly in the protocol design, but is there sort of a baseline assessment period for patients participating in the study prior to treating them, or do they kind of have those criteria, those data readily at hand to be eligible to participate in the study?
Yeah. So there, there's a couple of screening visits. One is certainly we've got to make sure they don't have neutralizing antibodies to AAV9. And then we wanna make sure their ejection fraction is adequate, and then, they get pre-treatment biopsies to ensure that there's no LAMP2, but that process usually takes a month or so, and, yeah, there's not much more to disclose there.
Okay.
Jonathan? He's looking at me.
Well, there will be a running period for biomarker assessment that each patient will undergo after the baseline...
... assessments that Gaurav just described. So we'll be able to observe patients for a period of three months, in some cases, possibly even a little longer, just to get a gauge as to some of the circulating heart failure and heart injury biomarkers that are often very abnormal in Danon disease. And changes in any number of additional clinical parameters that will really help determine patient's baseline and potentially also give ourselves and health authorities greater confidence with respect to the meaning of any stability or decreases post-treatment in any number of the abnormal cardiac blood markers, radiographic markers, or other parameters that we'll be following.
Maybe I'll just add to that a little bit. One of the reasons we're doing that is because this is a single-arm study. While we have natural history activities underway, FDA has really agreed, saying: "Hey, how are the patients baseline? And post-gene therapy at one year, how are they doing?" So to really ensure that we have a great control of the baseline versus where they met at a year after therapy, we thought having this information being collected allows us more than one baseline endpoint. To have multiple endpoints to at minus three, minus two, minus one month, in order to really compare and contrast how well the patients are doing. So this is really to strengthen our ability to differentiate clear benefit risk.
Yeah. Each patient serves as their own control, right? So this helps fortify that data set.
One of the common question we get is around just the variation in expression that can occur when assessing changes in histology, really LAMP2 expression, right? How are you accounting, I guess, for or seeking to minimize variation in LAMP2 expression that could occur, right, upon across biopsying patients?
Yeah. So we're not quantifying it precisely anymore. We're just grading it, grade 1, 2, 3, or 4. Even the patients who had grade 1 protein expression, they all had grade 0 at baseline, but even those patients who just got grade 1, had essentially the same improvements across every biomarker that we talked about earlier. No better or worse than the patients with grade 2 or grade 3. So you don't need a, you don't need a lot of protein. A little protein here really goes a long way. And if you think about it, once you turn the on switch for that vacuum, vacuum cleaner on, over time, the vacuum cleaner will work, right? So you give it 3, 6 months, you give it 1 year, and all these patients have cleared out their vacuoles.
Even the one patient 1001, who had the lowest amount of expression, it was grade 1, but if you tried to quantify it, it was more like 5%-10% at most. Even that patient had a profound drop in troponin, BNP, and LV mass. So you really don't need a lot of protein. So the variation may be there, may not be there. We assume that the biopsy we do that at the 1-year mark will capture that protein if it's there.
Can you talk a little bit about the pivotal program for patients outside the U.S.? If I remember correctly, I think a CTA is still pending there, so I'm wondering whether you similarly expect biomarkers to be used as a primary or an approvable endpoint in Europe.
Yeah.
Yeah. So we have the same study that is gonna be serving both US and EU, and we have agreement with EMA to do that. So at this point, we're just operationally getting the EU site up and ready with the CT application and the IRB clearances. So we expect that to be up and running shortly in the next few months to come. But it's between US, UK, Europe, EMA region; it's gonna be total of 12 patients with the same endpoints and the same study design.
Okay. Excellent. And I guess, I guess beyond the agreed upon, sorry, biomarker-based endpoint, I guess, what, I guess, what do you think would be required to, you know, facilitate full approval of, of A501, yeah?
Maybe I'll start here, but the discussion that we did have with the FDA was highly collaborative, and it felt like we were problem-solving together. That's a question they asked, and that's why they wanted us to define both the co-primaries and all the key secondaries up front, so that we don't have to go back and say: "Okay, well, now let's talk about a full approval." The good news was that we got a path to accelerated approval in September. The great news is that it's also tied to the full approval. We didn't expect that. Sustained trial followed for longer, up to five years, with a little bit more focus on clinical outcomes, which are all captured in the key secondaries and exploratory endpoints, including quality of life measures.
No additional patients needed to, you know, backfill or anything?
Yeah.
Okay. All right. Maybe just on the bone marrow disorder portfolio, I guess, you know, are approved currently in LAD-I . Maybe just kind of talk a little bit about sort of the objectives commercially speaking with that asset and the extent it might sort of-
Yeah.
prime the field a bit for the follow-on candidates, particularly 102 in Fanconi Anemia.
Yeah. So LAD-I, if you include severe and moderate, there are several hundred patients in the world. Severe patients are much more limited, not so many, and I think our plan with LAD-I is not to send a lot of mind power and also money on marketing, et cetera, you know, to find all the patients out there, but rather serve and set up some of the best qualified treatment centers anywhere in the U.S. and at some point in Europe, so that the patients who are interested in the therapy can come here. So this is primarily a PRV opportunity from a business side. We're gonna make the therapy available to patients, but we're not doing a large campaign commercial.
We are gonna set up the infrastructure to get ready for Fanconi anemia and Danon disease and other programs to come in the future.
Any other questions? Yeah.
Thank you. How are you going to select the Danon patients? It sounds like you have two or three times more patients than you need right now. And what were the initial criteria, and how are you gonna change them, given you have to cut down?
Yeah.
That's a really tough question, right? 'Cause it's a question that a lot of families are reaching out to, saying, "Hey, would my kid get one of the 12 slots?" So we're just making it based on first to center and then passing the inclusion/exclusion criteria. The remaining patients, I think what's remarkable working in the rare disease field, is they not only care about getting access to their kid, but they wanna make sure that therapy becomes available and commercially viable for future kids, right? So a lot of the kids that do not qualify for the study or may have already reached the end of 12 patients that we need, we're gonna enroll them into the natural history so we can understand and give them a better comprehensive review of how their disease is progressing.
Hopefully, before it's too late, we can actually make this commercially available and get patients access or have it available, compassionate use or something later along with the lines when we have a pivotal data available.
I wonder also whether you're hoping to achieve a certain diversity in study site participation here, just given that-
Yeah
... you know, you kinda do have some concentration of where these patients ultimately are treated.
Yeah, that's a great point. Because this study also serves Europe, we wanna make sure, for example, payer reasons, right? We at least have one patient treated in Germany, at least one or two in the UK. So the N of 12 is really gonna divide it up so that majority of patients will be in the US, but we will have some slots or treatment opportunities available in the European patients as well.
Okay.
Yeah. I just wanted to clarify for the BAG3, were you migrating that to rh 74? And then, second part is your criteria for your sites. What are some of the criteria for your sites or that, these therapies are being dosed safely?
Yeah. So we are migrating to rh74. We think that for the same reasons as for PKP2, we think that we can push the dose higher. In adults with PKP2 and BAG3, we may need to do that. And there's just more data with rh74 in the E14 range to make us comfortable and to make the regulators comfortable. So yeah, we are pivoting to rh74, and that's an IND for later this year. In terms of what makes a site sort of the right site to treat these complicated therapies, you want sites with the expertise in that field, for example, in this case, transplant cardiology.
Any sites with intense and immense immunology experience, because, you know, there's near-term acute events like TMA, there are longer-term events like T-cell mediated immune responses, and having a group of physicians who work and think together and also collaborate with us, right, who have stored up a lot of knowledge in this field as well, it's very important, and so we have to handpick these centers. Fortunately, these centers can, at the next stage, become our centers of excellence and the first treatments commercially.
Gaurav, how large is your natural history study population right now? And I guess, should investors anticipate some disclosure review of, you know, the findings from that population, some longitudinal assessment as you're conducting the pivotal studies?
Yeah. So I'll directly answer the question and then also just talk philosophically about the relevance of natural history in Danon and maybe the other programs. So if you put together the retrospective and prospective database, at the end of the day, we're gonna have more than 200 patients to draw from. That doesn't mean every patient will have been followed for the primary or secondary endpoints that we want, but that's the total database to draw from by the end. And we will share data from the natural history as it evolves, just like data from the trial itself. Probably wait until we have a large enough group of patients and outcomes to be meaningful. I will say, though, that the natural history is important, not as a direct comparator, but as a way to fortify our assumptions that we have already for Danon.
Our assumption is that untreated, these patients will have zero protein expression, and they're gonna have increasing size of the heart, approximately 8% per year, versus treated patients who have protein expression and seem to have 20%-30% decrease in heart size after 1 year. So that's like an alligator mouth. It's a wide alligator mouth, which is why we have a relatively small trial. But the comparison is not with our actual natural history, it's with these assumptions and also with the patients as their baseline with this short run-in phase, like Jonathan mentioned. So the natural history is important, but we've already proven that point.
Okay, thanks.
Okay. All right. Any last questions from the floor? If not, I think we'll leave it there for time. Thanks so much, Gaurav.
Thank you.
Thank you.
Great.