Welcome, everyone. We're going to go ahead and get started. I'm Gavin Clark-Gartner, one of the senior biotech analysts here at Evercore ISI, and really happy to be joined with Gaurav Shah, who is the CEO of Rocket Pharmaceuticals. Thanks for joining us, Gaurav.
Thanks for having me and having us, Gavin.
Absolutely. All right, why don't you just give us a quick overview of where things stand at Rocket today?
Yeah, sure. So we have a pipeline of six programs, five of which are in the clinic. The mix is a lenti ex vivo portfolio as well as an in vivo cardiac gene therapy portfolio. And for, I would say, the lenti portfolios, two of them are already submitted for BLA MAAs. LAD, we anticipate approval next year, continue to look forward to that. LAD and Fanconi are associated with PRVs because they have rare pediatric designation. And I do want to note one thing, which is that once you get the rare pediatric designation, you have the PRV opportunity at the approval, whether or not this legislation is renewed, right? So for Fanconi, LAD, and for Danon, we do anticipate PRVs. And the Danon program is fully enrolled as of September. We're continuing to dose patients.
We'll have a broader program update in the first half of 2025 that we look forward to. The PKP2 program, we've fully enrolled the low-dose cohort, and we anticipate some preliminary data in the first half of 2025 as well. And PKD, we are ready to go, but we've decided to prioritize the other programs first, but do anticipate PKD being up and alive in 2025. And then finally, BAG3 is sort of our third cardiac program we're very excited about, and that we anticipate an IND filed in the first half of 2025. So first and second half of 2025, there's a lot that we look forward to.
All right, great. So let's dive into the Danon program. And I'll start with a few more operational questions, and we'll go a little bigger picture. Just operationally, you guys announced that enrollment is completed. We've gotten some questions on when dosing itself will be completed. And typically, companies don't quite announce that granular level of detail. But just given where you're at, would it make sense to consider providing that update?
Potentially, we could provide that update. I do want to just answer the why is there a difference question. After enrollment, patients still have to undergo screening of other labs like troponin mandated by the FDA because it is a key secondary endpoint. And also, this is, in some ways, a heavy protocol. We're looking at a lot of different measures, so it just takes time to get all of those up and running. So that's why the enrollment is different from the actual dosing. And I think that's something that we could consider point taken.
Yeah, makes sense and for the enrollment, I think there's a three-month observational period associated. Can you do any of that observation before a patient is formally enrolled in the trial?
If the patient's been on a natural history already with us, then yes. But typically, doctors aren't really measuring troponins in most patients, right? And certainly not on a monthly basis. So those that we take from natural history, yes, but there's a lot that we don't.
Yeah. All right, that makes sense. And you alluded to this in the last call, but there's a certain number of responders in the Danon study for it to be a positive study. So hypothetically, and I'm making up the number, maybe it's five, six, seven, but let's just say it's six because that's a nice easy round number, half of the study. First six patients hit 12 months. They're all responders. Would you guys announce that, or would you keep the trial running? How exactly does that work?
I think it depends on how close spaced those patients are. If they're all within a few weeks or a month or two, then we might as well wait, right? And if there's a big lag between that number of patients and the final one, then we might want to announce it earlier. But regardless of when we announce it, there is definitely a list of patients and families who are waiting for this trial or for the therapy to come to market. Especially with the New England Journal of Medicine article last week, there's been a big buzz in the patient and patient community. So it's in their best interest and our best interest that once we have data, we start talking to regulators as soon as possible to try to get this on the market.
So all of that could happen before all 12 patients have reached 12 months, but I think we'll be able to provide more details on that in the first half of 2025 as well.
Yeah, that makes sense. And just following up on the last point that you mentioned, since you did present the updated data and also publish it in NEJM, have you seen an influx of new patient demand or whether that's physician demand? What exactly have you seen over the last couple of weeks?
I would say that we already had tapped into demand without a lot of effort, just populating the clinical trial itself. We had originally thought the trial was going to be much bigger than it is, so it wasn't difficult to find the patients to begin with. So I would say in the last two weeks, it's probably too early to tell. We are going to be hosting a patient-focused webinar for patients and families, updating them on the New England Journal results, and we'll be able to answer their questions in the coming days. So hopefully, we'll have a better answer to that soon.
All right, great. You also have a natural history study that's ongoing for Danon.
Yeah.
What's the status of that? How important to the regulatory process is this?
It's very important. It's not a matched prospective match type design where we're matching each patient with a natural history patient. In fact, instead, each patient is compared with their pretreatment baseline, right? So they're their own comparison. But the natural history study helps fortify the assumptions that we made for this trial. So it is important. It is enrolling. Both the retrospective and prospective cohorts are enrolling quite nicely. And that's an important part of the puzzle when we go to the regulators with the data set here.
All right, great and thinking beyond accelerated approval, thinking out to full approval, what's your latest thoughts on what that path to conversion is? And I guess to ask it a slightly different way, if you just replicate long-term what you've already shown with the phase one data, why would that not be deserving of a full approval?
Well, that could take five years, right? That's the bottom line. But the same trial followed out for up to five years is the path for full approval. We've incorporated into the secondary endpoint several clinical outcomes endpoints, such as hospitalizations and obviously time to transplant, as well as quality of life measures, how a patient functions and feels. And those would then become the primaries for the full approval. And this has been already pre-negotiated with the FDA.
That's within the same study?
Within the same study, right?
That makes sense, and just thinking about timelines too, does it have to be out to that five years? Or if you're really seeing a lot of these measures move in, I don't know, two or three years, could you have a discussion at that point?
We could. I think we could reserve the right, but I would estimate it's in the three to five-year range, but the study is out to five years.
Yeah, that makes sense. What are your latest plans in the female population for Danon, and how much of the prevalence do they represent?
Yeah, the female study, there's a lot of interest in it within the Danon community. Even the FDA would like to see it started as soon as possible. We're going to finish this trial, and we're already making plans for the female trial right on the heels of the current male trial. In terms of how many females, well, obviously it's an X-linked disease, so at birth, it's one to one. Over time, because females live longer, it's two to one favoring female. So this is a very important part of the life cycle for sure.
Yeah, that makes sense. Shifting and thinking commercially for the Danon program, when are you planning to present the next kind of commercial update and patient-finding update from your perspective? I know you're leveraging the ICD-10 code that was recently established. Maybe any update on that front?
Yeah, this is an important piece of the puzzle as well. And I recognize the high level of interest in looking at some more epi data, both bottom up, top down as well as bottom up. From the top down, we continue to fortify our literature reviews. We continue to look at claims database information, genomics database information. And we're also looking at a bottom-up approach where we're identifying patients. We're not putting a lot of effort into the bottom-up yet, just because it's something you do when we're closer to commercial, and we want to be able to identify patients that are closer to actual treatment. But we are starting to look at top down and bottom up. This is information that will be presented, I would say, as part of this broader update that I was referencing in the first half of 2025.
I'm very excited about that.
Yeah, that makes sense. What else should we expect from this first half 2025 update?
We haven't decided, but probably the epi will be the cornerstone of it and then wherever else we are with the overall program, we'll be able to update.
Okay. But I guess just to be clear too, you're not planning to present any interim clinical data with that?
No, no, no, no, no. Correct, correct. Nothing safety or efficacy-wise because it is a pivotal trial, and we need to see it through the end.
Yeah. All right, great. How have genetic testing changes for cardiologists over the last couple of years? Where do you see that going in the future? And how do you really drive that across the board, not just for Danon, but for other diseases?
Yeah, there are several novel targeted therapies for cardiac diseases that require genetic testing. So it's been a big part of uptake in the cardiology community. Historically, cardiologists have not looked at genetic testing because there's nothing to do. It has no impact on how they would treat these patients. But now that's changing, obviously, with several agents that are already approved and several in development now. So we already have a head start here. The LAMP2 gene, as part of the cardiomyopathy panel, was only put on there relatively recently. So now it's going to start filtering through the ecosystem. And we're going to start hopefully seeing more and more uptake between the genetic testing as well as the ICD-10 codes. And finally, I would say that Danon patients are not just in the centers of excellence. There's a lot of rural areas and referring physicians.
So we're focusing on referral sites as much as we're focusing on the centers of excellence that do a lot of genetic testing. And this is a program that's very active at Rocket in anticipation of peak year for Danon. It also, of course, applies then to PKP2, BAG3, and other cardiology programs that we have in the preclinical portfolio.
Yeah, great. All right, let's shift gears again. Let's go over to PKP2. Probably a good question for this. How exactly do you think about target expression levels, given this is a heterozygous disease? Outside of just protein expression, should we look at other desmosomal proteins that kind of associate? How do we think about that?
Yeah, so we could look at protein expression, obviously, by Western blot. There's also ways to localize protein. That's something that we're trying to do with the PKP2 study. And the other corollary or related question, I think, is also how much protein expression do you need to see? No one knows the answer to that, but these are heterozygous patients. They likely need more improvement than you might anticipate in something like Danon, where really a little protein goes a long way. And that's why we've started this program at a dose that we think is actually potentially going to work based on preclinical data. And we may have the dose escalate, I don't know, but it could be that this dose, like the first Danon dose, is the dose that works at 8e13 vector genomes per kilogram.
Yeah. All right, that makes sense. Why don't you just lay out some of the different clinical endpoints in PKP2? And I guess one of the questions is, as we start thinking about a potential accelerated approval, are there one or two kind of markers that early on at this point you're thinking could support that? We've kind of heard PVC benefit or PVC reduction thrown out as one that could be a good leading indicator. What do you think about that?
PVCs as one, NSVTs as one, other EKG changes that are more nuanced, like T-wave inversions, all those go together. Those, along with right ventricular diameter and general heart function, form part of a predictive score for fatal arrhythmias for these patients. I wouldn't necessarily bank on any single one, but I think there's going to be a signature of improvement that we'll know it when we see it.
Do you have any early indication how the FDA thinks about that paradigm?
I think the FDA has been, on the clinical side, very supportive of biomarker-based endpoints. We've seen it in all of our other, I would say, four programs that are in pivotal studies now, right? And I would be surprised if we don't read through to the other programs as well. Obviously, we have not talked to them specifically about this, but I think it would be something that they would smile on.
And for the trial itself, you finished the low dose enrollment. Are you actively enrolling at the higher dose?
No, we're going to see what this looks like and then decide if we go higher or not.
Okay. So yeah, to be clear, when you show the update first half, only the patients that have been enrolled thus far, you're not enrolling anyone new. We'll see what it looks like.
No.
Okay, and have you said when biopsies are done in the trial?
There's a few different time points, obviously six and 12 months, but we've also decided to do one before that, so we'll be able to update all of that when we present.
Yeah, makes sense. How do we think about acute safety exacerbations in this population? Could we see some arrhythmias or other cardiac adverse events early on with dosing? And that's kind of where your dose level becomes important, of course, but.
Yeah, we could. And that's all information that we'll be happy to share. I will say that there is evidence that when patients are on steroids and other immunomodulators, sometimes arrhythmias can get worse before they get better, right? So in the early days, I would say that looking at protein, looking at safety are probably the two most important parameters. And then efficacy probably manifests over time between month six and 12, just like it does for Danon. Heart doesn't reshape overnight.
Yeah, that's fair. All right, let's briefly go over to the Lenti side. For LAD-I, what exactly is the status of CMC discussions with the FDA following the CRL? What's the next update we should expect?
The next update, so that work is ongoing. It just takes time to get the actual assays validated and done in a way that the FDA likes. We're working on that in close partnership with them. It is a question of when, not if. We anticipate submitting the response to those limited number of questions as soon as we can, and then we'll be able to announce a PDUFA date. But we do anticipate an approval in 2025.
Great. For Fanconi then, was the plan always to do a rolling BLA submission for this one? And do any of your conversations related to LAD-I have any read-through to Fanconi?
So we're a small biotech. The benefit there is that we can be nimble and agile. And we reacted to the LAD news by making sure that in Fanconi, we do it exactly the way that they want. So we decided to do this rolling submission once we found out about the LAD. Sometimes you have to go slow to really go fast. But Fanconi will hopefully also be a similar timeframe of approval as LAD at this point.
Awesome. That makes sense. And potentially with PRVs associated with those programs. Awesome. Let's turn it over for any closing remarks. What are you most excited about in 2025?
I think if we just look at the cardiac gene therapy portfolio that Rocket has built, three programs here, those three alone have a prevalence that adds up to over 100,000. With other three coming on the heels of those, we're getting to 200,000. And that's no longer a rare disease once you're 200,000 or more, right? So while each rare disease is rare, you put these together and it starts being a pretty common disease. So we're very excited about the cardiac portfolio, but also excited about getting the hematology portfolio out approved and in the market treating patients.
Awesome. Well, look forward to a lot of exciting updates in 2025. Thanks for joining, Gaurav
Thank you, Gavin. Appreciate it.