All right. Welcome, everyone. Thanks for joining in. This is Gavin Clark-Gartner from the Evercore ISI Biotech Research Team. Really happy to be here down in sunny Miami for the first day of our healthcare conference. First up, we have the CEO of Rocket Pharmaceuticals, Gaurav Shah. Thanks for joining us, Gaurav. I'm going to turn it over to you just for an overview of the company, where things stand today. Then we'll get into it.
Thanks for having us, Gavin. Great to be down here in warmer weather in our midst. Rocket Pharmaceuticals, we're a gene therapy company. We have two platforms. One is cardiovascular AAV-based therapies. One is ex vivo Lenti-based therapy for hematology. We have three disclosed clinical programs in each with proof of concept in the clinic in most of these programs. The last one, BAG3, is just now entering the clinic now. The three hematology programs that we started with included LAD-I, Fanconi anemia, and pyruvate kinase deficiency. The three cardiovascular programs include Danon disease, PKP2, and BAG3. Our focus is increasingly going to be on the AAV portfolio given the high unmet need, the high patient numbers, the greatest opportunity for value creation there.
One thing we did this year was to pivot more and more toward the AAV programs as a way to be good stewards of capital, extend the cash runway, and focus the resources in the company on the most high-value programs. We are in the midst of getting the Danon program started back up again after a safety event last year. We are in the midst of getting PKP2 and BAG3 further in the clinic as well and very excited about the future.
Awesome. All right. Let's dive right into the AAV side. We'll start off on Danon since you just got the hold lifted, as you noted. Maybe just kind of walk through next steps, timing, cadence of dosing, all of that.
Yeah. The lifting of the hold from a timing viewpoint was really fast. It was really rapid, one of the most rapid that we've seen. Our focus really has been on structured benefit risk as we open the trial back up again. In terms of dosing, we had dosed in the Phase 2 six total patients. The goal was 12. Two of these patients had a capillary leak syndrome and associated edema that in one case did lead to patient death. We paused the trial. We were on hold for three months. In restarting the trial, we removed the complement inhibitor, which along with AAV9 was jointly responsible in our total analysis for the capillary leak syndrome. Without the C3 inhibitors, that's two patients that we cannot count.
We anticipate likely replacing those two patients and still having at least a total of 12 patients treated. We will begin that trial in the first half of 2026, treat three patients in a staggered fashion one month apart, go to the FDA, get alignment on a full and confirm a path forward. We've heard no indication otherwise that it's anything other than what they've said in the past in terms of a single RN12 patient trial, and then move forward pretty rapidly in a non-staggered fashion once we're past the staggered phase. All of that starts up in the first half of 26.
Yeah. Thinking about gene therapies, just given kind of the logistics involved in dosing, I mean, think about the timelines. First half is a fairly broad window to start. And then there's a minimum one month, but it's probably hard to sequence exactly for that one month given all the startup activities. Is this going to be rolling through to end of 26 into 27, or do you think it could be done kind of quicker for the first three staggered patients?
Our target is first half 26 as fast as possible. We've identified these patients. Patients have not dropped out of the trial. We have that group of patients that are still eligible. We do have to do a three-month troponin run-in, which adds some complexity to it. These patients, some of them also will need vaccines ahead of potential Eculizumab. There is some staggered time period that could extend beyond one month. Because the patients are already selected, we know who they are. We're going to try to make it as close to one month staggering as possible. Probably won't be perfect, but we'll try to be close.
Yeah. All right. That makes sense. Looking ahead then, as you're planning to give us the next updates for Danon, kind of as you progress, I'm assuming you're not planning to give us updates patient by patient and you kind of look at some of the patients together. Would you plan to give us data at the end or wait for a regulatory meeting also and give that in one update? What are you thinking?
I would say we do the staggered safety run-in, get alignment with FDA. As folks may recall, last year when we were going to finish the trial, we were going to do a comprehensive trial and epidemiology and patient finding update as well. We want to do all of that at once when we have real clarity in both the trial, where the patients are, and the full market opportunity to be able to give some wholesome information to the street at the same time at once.
Okay. That makes sense. That makes sense. Do you still have additional claims analyses that you have ongoing in the background or the commercial analyses?
We do. It's a lot of work ongoing both from the top-down perspective, really honing in on what the exact epidemiology is based on a variety of different sources, and then the bottoms up, which I think is going to be the real setup for the commercial launch.
Yeah. All right. Great. You mentioned this before. What gives you confidence that the FDA is still aligned on the 12 patient single-arm study and there's not going to be any changes to that?
You never know. As we know, the FDA's viewpoints are in flux. For rare pediatric fatal diseases, our opinion is that they're moving in a favorable direction. In general, all of our interactions with them so far have not been derailing. They haven't questioned things that are in writing already. The agreements that we already have in writing have not been questioned to date. We try to interact frequently and transparently with the FDA. When we do reference things like pivotal trial and study design, we haven't heard of any specific pushback. Every indication right now is that there's general ongoing support. We did design the Danon trial to be pretty robust in terms of stats and the assumptions because, as you know, patients who are not treated with gene therapy who have Danon disease progress pretty rapidly in two or three years.
They're on a heart transplant list or unfortunately passed away. Their heart grows pretty fast. As the NEJM article showed last year, treated patients have the exact opposite trajectory with shrinking of heart size. They're starting to feel better. Not just quality of life, but every single biomarker moves in the opposite direction in a positive way. There is a wide gap between treated and untreated. The design from an objective viewpoint makes a lot of sense. It continues to make sense. That is why I do not think there has been pushback. Obviously, we need to pivot. We need to be agile. We need to be humble. We need to learn and listen from the FDA right now.
Yeah. On that point of kind of trial design statistics, I think you were planning to give an update this year on some of those details. Is that planning to be with the next update on the clinical data, regulatory, commercial, all rolled together?
Yes. All one big update is the plan after the patients are hopefully treated safely and we have the FDA path forward.
All right. Great. Now that I guess the dust has settled a little bit after the safety events, what are you hearing from the community in terms of where they stand with adoption and if any of their perceptions have changed?
Yeah. First of all, our commitment to the patients, the families, the patient advocacy groups, the Danon Disease Foundation is unparalleled in the sense of how much we lean in and rely on them to help us understand the disease and to help them educate us and us educate them when we need to update on trial issues, which we have been doing pretty regularly. In the couple of weeks after this patient death happened, obviously, the community was shocked. We were shocked. We went through a mourning phase there for sure. About two weeks later, though, we had a webinar with the full patient advocacy group, which included some of the family of the patients who had been treated. There was almost unanimous understanding and ongoing enthusiasm for the trial, just understanding that this is a fatal disease. We are figuring things out.
The reality is that there are no preclinical models that predict safety in AAV for Danon, really in almost all AAV. There's no preclinical models that predict safety. We're going to have to learn from real live human beings with complex biology that just can't be replicated in preclinical models. I think these families are brave, courageous to understand that. They've stood by our side as we've stood by theirs. I think there's going to be enthusiasm as the trial opens up again. If we can replicate some of the data that we saw in the phase one, I think this community is really going to come behind the gene therapy. Also, there's no alternatives other than transplant. Transplant itself has a 50% 10-year survival rate with risk of retransplant.
Even transplanted patients who "do well" are feeble, frail, and have very difficult quality of life. I think that community is really waiting.
Yeah. Definitely. All right. Let's move on from Danon here. Let's go over to PKP2. I guess one place to start, what's the timing of FDA discussions? When do you think you'll have an update on kind of the registrational path to market?
We started that trial, added dose that we thought would be the final dose. It is. We do have FDA agreement that this can be the final dose. We're in discussions primarily about trial design. We're open-minded about what that trial design could be. At the end of the day, what we want to do is have a design that wins, not necessarily just the smallest design or the quickest path to market. You want the most robust trial that demonstrates unequivocal benefit risk to regulators and to payers. That's our focus right now. It's going to take some time just like it did for Danon. PKP2 is a disease that progresses more slowly than Danon. You don't see the rapid changes in months like you do in untreated Danon patients. It takes some time.
We're going to have to be thoughtful and disciplined about how we approach that trial design.
Do you have a preference for what endpoint you would want to pursue? Understanding it's a collaborative discussion. I know you've kind of spoken about composites before because there's heterogeneity and some patients have different manifestations. Like some patients have a more acute PVC involvement than there's QT inversions. What would you want to do if it were up to you?
I think we have to study, and we are studying the natural history data carefully. It may not end up being a single endpoint like we have in Danon disease, which is LV mass index. It may be a totality of evidence that includes a couple of arrhythmias, maybe some right ventricular parameters, and some clinical function as well along with protein expression. It could be a composite of things there, which is not unusual in the cardiac fields. We just do not know yet. We remain pretty open-minded and ask people to remain pretty open-minded about how this turns out.
Yeah. How important do you think kind of the symptomatic side, quality of life? I guess KCCQ is one of the measures. How important is that to adoption commercially?
We've seen the three patients that have been treated improve pretty substantively in how they feel and function day to day. These patients are a year out or more. At some point, we'll have updated data on that. It matters a lot because the right ventricular sometimes improves. You can't always tell because the EF itself isn't necessarily changed. You might see some improvement in function like we did in one patient on echo. In general, just having trafficking of these intracardiac membrane proteins or the junctional proteins in the right place when they were before maybe intracellular or they were in the wrong places before, seeing them go to the right place, there is a benefit that patients are feeling that isn't always necessarily translated to arrhythmia reductions and/or other clear biomarkers.
I think that needs to be part of the story, whether it's a primary or a key secondary. I think it's going to be an important part of the story just as it is for Danon.
All right. Great. Let's go over to BAG3, actually. There's been less focus there historically just as you're just getting into the clinic there. Maybe you could just kind of walk through not just cadence of site activation dosing, but then all the early measures you're looking at here. What's going to move first in this population?
BAG3 is a DCM. By the way, with BAG3, we now have entry into each of the big buckets of cardiomyopathy, hypertrophic with Danon, arrhythmogenic with PKP2, and dilated now with BAG3. Hopefully, that opens the door to many more like that to come at Rocket and beyond Rocket. The BAG3 program will start in the clinic next year. It's a DCM. DCMs are much better characterized. There's more DCM in general, so there's more research on it. Because it's a dilated cardiomyopathy, more traditional endpoints such as ejection fraction, LV strain, peak VO2, even six-minute walk test, et cetera, may predict good outcomes in patients. In some ways, it's a more predictable set of monogenic DCM disease states that I think we can go after starting with BAG3.
The BAG3 program is going to start with a phase I pretty traditional approach. We're starting again at a dose that I think could be beneficial. We do have a dose escalation built into the trial if we need to. Hopefully, we don't need to.
Do you have any expression targets here? Are you looking at co-expression of other proteins as well? What about that side?
We'll be looking at protein expression just like we do in all the other programs. Unlike PKP2, where there's desmocollin and other proteins that when they light up, you know that there's sort of joint signaling and joint trafficking to the junction. In BAG3, it's just BAG3 primarily. So there's no downstream proteins necessarily. I mean, we're still developing the validated potency assay, which will require some ancillary protein. So that's still in discussion, but not necessarily as part of the protein expression database.
Yeah. Okay. What about the cadence of dosing? How spread out is it also?
We've spread the Phase 1 out in a pretty traditional design, several weeks apart between patients, three patients. It's three to six per cohort. If there's no DLTs, we stick to three patients. We may or may not elect to enroll more depending on how those patients are doing. If they're doing well, we more and more want to leverage the phase 1 data given that we're trying to use a commercial-ready product. As much of the phase 1 data that we can leverage into pivotal trials as possible is good.
Yeah. All right. I did want to touch on the Lenti side. I haven't actually looked at this in detail. I just saw that the PRV got reauthorized in the House. I know you're going forward with LAD-I. Does that change anything on the Fanconi side too?
We've made a very conscious, intentional, deliberate effort to make sure that in this market landscape that we find ourselves in, that we're judicious with cash spend and putting resources, meaning people as well as money, in the highest value programs. Now, Fanconi is a program that we started with at Rocket. It's dear to me. It's dear to many of us in the patient community. At this point, we can either focus on building AAV or building everything. We think it's better internally to focus on AAV and to focus more and more on partnerships for the Lenti programs. The Kresladi PRV is important. Getting that done, getting that over the regulatory hurdle, we will commit to as Rocket. I think everything else, including FA and PKD, are partnering opportunities. Having a PRV opportunity for those, I think, is a great selling point for partners.
It is high return on little investment. Look forward to those dialogues with potential partners.
Is Fanconi PRV eligible?
Yes.
Okay.
LAD, Fanconi, PKD, and Danon are all PRV eligible. So potentially all non-diluted cash sources for the future.
Yeah. Maybe you could just, while we're talking about Kresladi, maybe you could just kind of update us on the CMC side or just kind of remind us what were the CMC discussions previously? What did you change? Why are you really confident in this go-around?
There were a host of basically virtually all CMC findings. There were a few, a handful, less than five that were focused on stability and sterility that were specifically gating for the approval. We have now addressed them, done some experiments mostly externally to validate and do exactly what the FDA asked for. We checked every single box exactly as asked for with no pushback. We have submitted the response to those gating questions and also a path to addressing the full gamut of PMC and PMRs. We feel pretty good about the package that was resubmitted. We are in discussions with FDA about questions, IRs, et cetera, and hope to get this approved by the PDUFA date March 28. We are very excited about that.
All right. Sounds great. We're just at time here. With another program going into the clinic, going to be an exciting year next year. Thanks for joining us, Gaurav.
Thank you, Gavin.