We're going to get started with our next session. I'm Andrew Tsai, Senior Biotech Analyst at Jefferies. Thanks for listening in. It's my pleasure to have the Rocket team with me. To my direct left is Gaurav Shah, CEO, and to his left, Meg Dodge, SVP of External Affairs. Welcome, both of you.
Andrew, thanks for having us.
As always.
Great to be here.
Yes. There may be some people in the audience who are less familiar with the Rocket story. Can you help us level set where you are, what programs you're working on, your strategy, and then catalyst milestones over the next six to 12 months would be very helpful.
Great. We are Rocket Pharmaceuticals. We are a cardiac-focused genetic medicines company, primarily focused on genetic cardiomyopathies that while each one is a rare disease, together they're not rare. Each disease is rare, but rare disease is not rare. It ends up becoming very common when you add them all together. Our focus is on three genetic cardiomyopathies. One is a hypertrophic one called Danon disease, a disease of autophagy that primarily affects both boys and girls, but boys in their early years and females later in life. We are in a pivotal trial aimed at an accelerated approval path in agreement with FDA for that program, and are actively enrolling patients right now for the safety run-in portion of that. The next program is an arrhythmogenic cardiomyopathy called PKP2, which is the most common type of ACM, which is the second big bucket for cardiomyopathies.
In that program, we're in a phase I trial. We've found the pivotal dose, and we're in discussions with FDA regarding the next steps for an accelerated or full approval pathway. The third cardiac program is BAG3 dilated cardiomyopathy, a devastating disorder, multifactorial in nature with regard to the protein. In that program, we are entering phase I. We're about to start treating patients. Three big programs in cardio genetic medicines. Historically, Rocket has been a two-platform company, cardiac being one with an in vivo AAV approach. The original programs in the company were bone marrow programs, where we use an ex vivo lentivirus technology, LAD-I, Fanconi anemia, and pyruvate kinase deficiency.
We're very happy to get the first FDA approval from CBER this year for LAD-I with a product called Kresladi, which we got done through the accelerated approval pathway and we're in the process of getting that out to patients as soon as possible. That also came with a large PRV sale, which allows us to have cash runway for another two years into second quarter of 2028. We are a genetic medicines company focused in cardio, but also have a legacy programs in ex vivo lenti bone marrow-derived disorders. Moving forward, we're going to continue to focus on cardiac, build that out. We have other programs that are behind the scenes and that are also rare, but you add them all together and we're talking about hundreds of thousands of patients and really opening the door to cardiovascular genetic medicines here.
Right. Hundreds of thousand patients on a gene therapy price. It's a huge opportunity. Okay. Starting with some bigger picture questions. When we think about gene therapy, it's gone through this important maturation period over the past few years, safety, manufacturing, clinical execution. How are you guys thinking about these aspects, and what differentiates you from other gene therapy players out there?
I would say primarily we are very proud of the fact that we invested early on in an in-house AAV manufacturing facility. What this allows us to do, in addition to having a long-term path to reduce cost of goods and good margins, is that it allows us to develop the process and the release criteria and potency assays and all those aspects of things in our hands, and control is the most important thing with regard to CMC discussions with FDA, because often there's back and forth with FDA. It's iterative dialogue, and having it in-house really accelerates those pathways, and also ensures that we control the product and not somebody else. We're very proud that the Danon program is being produced in-house and the other programs will be as well. I would say that's one big differentiating factor.
The other is just that we have the experience, and we've gone through these programs with multiple patients. We've developed a muscle memory for how to treat these patients, how to read labs, how to pivot around safety issues, how to maximize efficacy, and for example, how to read protein expression. I think out of the companies in this field, we have the most in-depth experience with regard to those key aspects of drug development.
Very good. Makes sense.
I can add a few words, Andrew. I think the sector as a whole for gene therapy is also in a period of execution.
I mean, we got earlier guidance this week from FDA, and so if you compound what it's going to take with respect to execution, that means that we as an industry have developed our science tremendously, but it's going to be a matter of manufacturing, as Gaurav said, clinical engagement, and also regulatory engagement.
Right.
FDA has really tried to step up, and so I think we're in a period here next of working with the agency to really bring genetic medicines to the forefront on both the development side, the manufacturing side, as well as the regulatory front.
Right. You guys are very thoughtful and careful about all these, thinking things through. To your point, the FDA, I think they released a new guidance document or something early this week.
On Tuesday, yes.
FDA really wants to collaborate with you guys.
Yeah, I would also say that guidance documents are important, and they're a good template for us, for the whole field. At the end of the day, with the FDA, it's about individual dialogues and collaboration with the review team. We've had a track record of being engaged respectfully both ways and getting to a good landing spot for all of our programs, and I anticipate that'll continue.
Great. Maybe before we touch on the Danon program, which to me is the core thesis of your story, but congratulations on Kresladi's approval though where you earned a PRV voucher. How are you thinking about the sequencing treatment center onboarding and the overall TAM of this product? When can we learn about when you might launch the pricing strategy, the reimbursement strategy, and so forth?
I can take this one. What we tried to do and what we aimed to disclose to The Street and to the community in 2025 was a reprioritization of the pipeline. That's when we defined ourselves as being a cardiovascular-focused company. With that, we had Kresladi at the finish line with a potential FDA approval on the cusp. What we really wanted to do was get that across the finish line and then be able to talk to partners about getting those lentiviral programs into the hands of someone that's better able to commercialize them. We've gone through the steps to prepare to make Kresladi available to patients. We're talking to potential partners about assuming that program.
However, in the event that you can't find the right buyer for what I call a custom-built house, we're prepared and able to make Kresladi available to patients. If you're asking about our preparation to be able to make Kresladi available to patients, that'll be later in 2026, towards the tail end of the year.
Got it. When I think about how this reads across to your other programs on should you launch, gain payer access, reimbursement access, gain experience launching, feels like there could be potential scale as your other follow-on programs become approved. Is that kind of fair? Anything else you'd add?
Yeah, consider it muscle memory. Once you go through the process of developing your in-house commercialization team and going through the steps to have a company be able to provide access for a therapy, you can apply that to other programs. Yes, it's building the infrastructure, but it's also developing the team, the knowhow, and the skill set to be able to do that directly so you can apply it to other programs.
Right. Okay. Very good. Shifting gears to your Danon program, it's great to see that it's been resumed, bigger picture, help us frame the U.S. market opportunity of Danon. How many U.S. patients you think there are, how many diagnosed, identified, for instance? Just so we can have a sense of the peak sales opportunity here.
I would say that we will be able to answer that question in much more depth during a full program update that we anticipate second half of this year. We will have a top-down breakdown of the Danon opportunity that's based on epidemiology as well as genotyping. We'll also have a bottom-up approach going out there and seeing where these patients are and who they are. We'll have that update. I would say that historically, we've stuck by the number of at least 15,000 patients in the U.S. and Europe. Danon is a frequency of hypertrophic cardiomyopathy, and you can extrapolate from the HCM population to figure out how much is true Danon disease out there. There's a big gap between true prevalence of Danon and actually diagnosed Danon because Danon disease was identified as a genetic cardiomyopathy, as recently as the early 2000s.
There just hasn't been that much time for people to understand what Danon is, how it manifests, and also even doing genetic testing for cardiomyopathies is a relatively novel thing. There's going to be a gap between true prevalence and diagnosed. Even beyond this update, our next step ahead of the commercial launch is to find these patients through genetic testing and other means. We'll answer the question, but that's sort of the big-picture answer.
Okay, very good. Can you remind us in the phase I program, which led you to have this accelerated approval pathway in this phase II pivotal that you're doing? What did you see in phase I for these Danon patients? On the phase II co-primary endpoints, what did you see in phase I that gives you the confidence you'll make it through the goal line in phase II?
In phase I, we treated six patients who were followed for more than one year. Out of those six patients, we had results that were published in The New England Journal of Medicine about a year and a half ago, and those results showed that all six patients had florid protein expression. In fact, a couple of them out to five years or more. We showed that all of them had a reduction in left ventricular mass index, LVMI, which is now agreed upon as one of our co-primary pivotal endpoints. In fact, protein and LVMI are the co-primary endpoints for the ongoing pivotal trial. In phase I, we showed that all six patients would have met that endpoint at the one-year point if this were a phase II trial. That gave us a lot of confidence to move forward into phase II.
Those patients showed massive reductions in troponin and BNP for as long as we followed them until the NEJM paper.
Great. 100% success rate, basically in phase I. You started the phase II, although you faced a little slight hiccup last year with the partial clinical hold, but then you got it resolved very quickly within three months, and then now you're resuming it with the initial safety cohort now. Can you kind of describe what happened?
Yeah.
What learnings have you had with that experience?
Early in the phase II trial, we saw a higher incidence of thrombotic microangiopathy, TMA, than we would have anticipated or that we saw in phase I. In an effort to further mitigate the risk of TMA, and by the way, the patients who had TMA early in the phase II trial, they've resolved the TMA, and those patients are fully resolved with regard to the safety issues and hopefully moving on to look at efficacy. To address the TMA, what we did is we added a C3 inhibitor. The issue that we faced as soon as we treated patients with the C3 inhibitor is that there was a paradoxical unlocking of direct endothelial damage with the combination of a torrential rain of AAV9 plus a C3 inhibitor.
It's not what we expected, but there's no good preclinical models for cardiomyopathies, and some of these things play out in the real world and the clinic. We had an unfortunate case of a patient death due to the combination of C3 plus AAV9. In the resumed trial, which we negotiated with the FDA very rapidly, lifted the hold in about three months, we agreed to remove the C3 inhibitor. That addresses the capillary leak syndrome, the endothelial damage risk that we saw with the C3. It keeps the TMA risk on. In order to mitigate the TMA risk further, we did an analysis of the patients and the product, and we determined together with FDA that the phase II product that we were using was likely higher in potency than the phase I product because it was an enriched product with higher full-to-empty ratios.
Because of the higher full-to-empty ratios, the potency applied to both efficacy and safety. We recalibrated the dose to a lower dose to match the phase I potency. While the new dose appears lower in number, it's around 4E13, it is intended to match the dose of the phase I product, which is closer to 6.77E13. We're moving forward with a recalibrated dose, absence of C3, and a couple of other tweaks in patient selection as well as drawing out the doses of rituximab over time to further eradicate B cells ahead of treatment, and that trial has resumed.
Okay, it makes a lot of sense. We should not expect capillary leak syndrome because there's no C3. TMA risk is heavily reduced because now we are back to the phase I equivalent dose kind of thing.
Correct.
Okay, great. Now you're trying that out in the initial batch of three safety patients. Have you dosed the first patient by chance? When does the third patient get dosed exactly?
Yeah. We have initiated dosing. We haven't guided on exactly when we'll finish, but we'll have a comprehensive update as mentioned in the second half.
Second half. Okay. Is it fair to say that TMA generally pops up pretty immediately after dosing? If you see something, I don't know how to ask it, but is it true?
Yeah
Is no news good news kind of thing?
I would say no news is good news. TMA usually manifests, in our experience, in the first two weeks or so. Yeah.
Great.
We'll have a comprehensive update as soon as we can.
It makes sense why you'll share a comprehensive update in the second half. My understanding is the initial three-patient cohort are staggered dosing a month apart. There's a strategy to talk to the FDA. You come back to The Street in that update.
That's correct.
Those FDA discussions kind of thing.
That's correct. To be clear, the FDA has asked us for a three-patient safety run, and they have not commented on what the rest of the trial would look like or that it should change. We don't anticipate it would change, but we do want the optionality of discussing with, again, what the best trial design is moving forward. The original agreement was a 12-patient single-arm trial with a co-primary of protein plus LV mass index. We have no indication that that's going to change, but we were asked to go back after the safety dialogue, so we want to make sure that we do our due diligence there before coming back.
Right. Understood. As you dose establish what's needed, and then you dose more patients, which I understand it can be done not sequentially, but just all at once.
Correct.
As I think about the likelihood of success, sure, optically, the phase II dose now seems like a lower dose. At the same time, it is the phase I equivalent dose where you saw 100% success rate. Confidence should remain unchanged. Is that the line of thinking from you guys?
We are hopeful both on safety and efficacy, just seeing what we've seen through our experience that this phase II is intended to match the phase I. If all goes well, I think the safety overhang is the main thing to get through in the near term.
Right. Once you talk to the FDA, can you just remind us then the original plan for an accelerated approval, how many patients out to one year was the original agreement? Best case in your minds, how many patients left after the three patients are dosed would you need to fill that original agreement?
I would anticipate that they probably want to see all the patients in the trial treated with the same product in the same way. While we have started treating patients at a different dose and slightly different immunomodulation profile, I would anticipate that we might have to treat a total of 12, three plus nine, but we'll see what happens. It's a discussion.
Okay. There could be an upside surprise given your base case. Okay. Second half 2026, you'll come back with a seemingly major update because it's not only next steps, but also top-down or epidemiology. I'd assume you'll share the bar for success, too, from that FDA meeting, to be clear.
Yes, absolutely. This is an update that's been long in the making. Because of the event last year, it got delayed. The update would include certainly status of the trial, next steps to finish the pivotal trial, epidemiology bottom up, top down, and also an understanding of what it's going to look like to have a win on the trial. All of that, we'll have a comprehensive update. That's correct.
Thanks. Okay. Then shifting gears to then PKP2, we'll just wait for Danon, and fingers crossed everything turns out right. PKP2, maybe talk to us about the disease indication. How big is this indication relative to Danon? We can go from there. Yeah.
Yeah. PKP2 now borders on what is in the common knowledge base or common sort of spirit of how we understand cardiomyopathies. These are patients who often have sudden cardiac death or palpitations at a young age, especially when exercising. This becomes a cardiomyopathy that we are familiar with in day-to-day life, right? Athletes and runners and others. This PKP2 is a disease of the junction between cardiomyocytes, which are not in ideal condition because of the lack of PKP2 protein. Because of this, these patients have recurrent arrhythmias manifesting as PVCs, NSVT, T wave inversions, and often fatal arrhythmias for which they need ICDs placed. 80% of these patients do have ICDs placed. The population here is at least 50,000 in the U.S. and Europe. It's, again, rare but not so rare. It's one of the more common types of cardiomyopathies out there.
The phase I is ongoing, but we've treated all the patients we need in order to go to the FDA with the phase II trial design and approach. All three of our phase I patients had manifestations of protein expression, improvements in arrhythmias, and general improvements in clinical status out to at least one year. With that information, we've gone to the FDA. We're in discussions with them as to what a pivotal trial would look like, and more on that in the second half as well.
Second half. Okay. With the phase I data set, how would you say you compare to competitors, actually, on those efficacy measures?
I've seen the data from others in the field. I should first of all say that because it's a more common rare disease, there is room for more than one treatment. There's a lot of patients out there with a high unmet need. Having said that, we're reassured by the fact that all of our patients that we treat, although they were only three patients, they saw the improvements that I described pretty uniformly. There was no patient who got worse suddenly or certainly. I think we're positioned well to be in the lead for this program, and it's not always about the number of patients treated, but having the right types of patients and the right endpoints to-
Right
Lead to a win in a trial if the drug works, right?
Right.
I think we're in pole position for that.
I'd also add that in the phase I, we align with what we feel is the proper dose to proceed with respect to the pivotal phase II study. We feel that we're moving forward with the phase II, with the dosage that we used that was efficacious in the phase I.
Got you. The phase I cohort was three patients. Are you dosing more in the meantime as you talk to the FDA, to be clear, in phase I?
Yeah, we will dose more patients, not because we need to do that for the phase II discussion, because it just gives us more information. There are patients who are waiting for the treatment, we're opening the trial up again. It's not necessary for the FDA dialogues themselves.
Right. I guess for the initial batch of three patients, would you consider sharing data, is my question, the additional phase I data, not only on new patients but also longer follow-up? Is that a second-half event?
Potentially, yeah. We would like to share the long-term follow-up results from those three initial patients. As Gaurav was alluding to, having additional patients enrolled and treated in the phase I at the same dose that we plan to proceed with, will be further support of a BLA submission later on down the road.
Right. With your Kresladi experience, your Danon experience so far, just with your FDA discuss, it seems like you have a knowhow or advantage or a good relationship with the FDA on study design, big picture. PKP2, is that the strategy? I think Danon, the original agreement was 12 patients, and that's it. Is that the strategy here for PKP2 for you?
I would say Danon is a one-off very aggressive cardiomyopathy with an easy-to-understand pathology. This is a disease of big hearts. It makes sense that the endpoint here should be shrinking of the heart. That made a lot of sense. It's also a disease that rapidly progresses in natural history unequivocally. That leads to an easier dialogue when it comes to justifying a single-arm small trial. I don't think that's going to apply to any of the rest of the genetic cardiomyopathies, including PKP2 or BAG3 others. It's a different dialogue from Danon and I would not expect the same outcome.
I see. Any color how FDA discussions are going by chance?
I would just use the word collaborative.
Sure.
I think in all of our programs with the review team that we've been assigned, especially for these programs, it's always been sitting at the table figuring out how to design a trial where we can win if the drug works. Not designing the smallest trial or trying to have the biggest short-term win. It's about getting the drug approved in a way that the FDA agrees with, and it's also we try to go for written communications there as well. While it takes time, I believe that we're going to get to a good outcome here.
Great. Lastly, the BAG3 program. Sounds like you're starting phase I. Backtrack one more time. BAG3, how many patients you think there are? In this phase I, what is a good no-go scenario for you?
BAG3 as a patient population is probably somewhere between Danon and PKP2 in terms of the prevalence in the U.S. and Europe. Our phase I program, the IND is cleared. We're going to start treating patients soon. The cohorts are designed as three plus three, so three patients, unless there's a DLT. We may elect to treat more than three patients if the first dose looks like it's working, so that we can expand the trial and get more information in anticipation of a pivotal phase II discussion, like for PKP2.
I see. What would be a reasonable efficacy endpoint?
Dilated cardiomyopathies are part of a better trodden path with drug development. Because the left ventricle is dysfunctional, it's easier to come up with endpoints where the left ventricle improves, such as EF, peak VO2, and even exercise testing. There are ways to measure the left ventricular function in a predictable way, where there's drug development expertise and regulatory precedent already in place. Whereas for Danon, we had to have these discussions from scratch with the FDA and come up with a new endpoint. We feel good about once we get to that point to have an easier dialogue with the agency.
I see. Okay. With the PRV sale of Kresladi, the big picture, you have cash, I think you said until second quarter of 2028?
Correct.
You can execute on a lot of these milestones starting in second half 2026, it sounds like, across these programs.
Yeah. Lay low and get things done. That's the motto this year.
Okay. Was there anything else you wanted to add, but otherwise?
I don't think so. I think we're at the beginning of a journey for cardiac genetic medicines, and we're very excited about the future.
Yes. Much respect to you for pioneering these spaces and best of luck into second half.
Thank you.
Thank you, Andrew