Everyone for joining. So I'm joined today with the Rocket team. So we have Gaurav Shah, CEO; Kinnari Patel, COO; and then we have Jonathan Schwartz, the chief gene therapy officer. So thank you for joining us this morning. So I guess we'll just dive right in. So speaking on the cardiovascular pipeline, so starting with, of course, the Danon program. So enrollment is ongoing in the pivotal study. So I was wondering if you could give us maybe an update on how enrollment is progressing, in terms of the pace of enrollment of patients, but also in terms of the cadence of dosing.
Things are well, going well, on track. We're not really providing patient-by-patient updates-
Mm-hmm.
But, yeah, we're happy with the progress.
So how about dosing? So what's the cadence of dosing? Or do you need to dose the first patient, wait a little, dose the second one, or is it kind of just more?
Well, the first two were like that.
Mm-hmm.
Otherwise, it should be open parallel dosing. So, you know, moving forward, we're not... There's not staggered anymore, so.
Mm-hmm. And so since the beginning of the trial, what has the—I would say, kind of, the feedback you've gotten from the physician, the patient, and also the level of interest that you've seen?
You know, the phase 1 data. I'll start, and you continue this.
Yeah.
Phase 1 data were so remarkable, with some of the updated data showing that all appropriately treated patients were improving across every single parameter.
Mm-hmm.
You know, LV mass index, protein expression, Troponin-
Mm
... even how they function and feel, we saw improvements, and it's, it's hard to ignore.
Mm.
I think patients and physicians and families see that and are quite encouraged by it. So there's a lot of interest to get onto this trial and then potentially get the therapy, if it's potentially approved as well. Almost like a clamor. There's a clamor. It's our responsibility to make sure that it gets to patients. Otherwise, they have to get a heart transplant or pass away.
Mm-hmm.
Yes. I was just gonna say that, what's interesting is, being in this cardiovascular space, gene therapy, you know, when we started, they said, "Oh, it's not gonna work." So there was not a lot of interest. So over the 5+ years or 6 years that we've been doing this, it's great to see so many cardiologists that we talk to are now like, "Oh, we should do genetic testing because there could be therapies available," and they're starting to recognize Danon patients. So to me, that's a great success for rare diseases, is the step number one, having a diagnosis, and then two, when they look at the data, they were really impressed by it. And even the LVMI, 10% delta. All right, like, that's meaningful.
Mm-hmm.
If we can prevent transplant and transform the heart and shrink it, this is gonna be really big. So I think having those kind of feedback really helps us keep going, plus the patient interest.
Yeah. And so with, you know, that many patients interested in it, N of 12 in the study-
Mm
... how should we think about the distribution between the pediatric patient and more of the adult patients in the study?
Yeah. So our distribution is less age dependent 'cause we're looking at the type of severity of the disease, and sometimes we see that a 13-year-old could manifest a disease similar to an 18-year-old. But I think the distribution that we're more conscious about is, because this is a global study with U.S., EU, and U.K., we wanna make sure at least majority of the patients, 60% of patients, are treated in the U.S., and the remaining patients get strategically treated in countries where we, in Europe, that needs payers. For example, Germany is gonna be a clinical site, and having at least one patient there could just help us get access post-approval for commercialization.
Right.
Do you expect then a broad label in terms of the age range of patients?
Do we think so?
Yeah. I mean, the eligibility for this male pivotal phase 2 is age 8 and above. And, you know, I think we anticipate that the majority of the patients will be between the ages of maybe 10 and 15, 10 and 16. There may be a couple on the older side who are in the late teens or even very early twenties, similar to some of the phase 1 patients that we had. I don't think you're gonna have many much older than, you know, 18 or 20, simply because by past that time, most of them are likely to have experienced heart failure or calamitous events that would prevent them from participating.
Whether or not we get a label younger than the lower limit is, I think, a question, probably a little bit at the end of the day. But the rest of that would be to be determined.
Given the potential differences in disease presentation as well as the disease progression, are there any points that are more maybe relevant or important for various age groups?
So, in general, we just thought, you know, BNP, troponin, LVMI, they're all such great endpoints. I think our phase 1 was designed so we can actually figure out what's more meaningful for these patients and how do we capture in an accurate, consistent way and see that. So I think what was beautiful about phase 1 data is BNP, troponin, LV mass, LV mass index-
Mm
... NYHA classification, and KCCQ also. All of the endpoints that we had, improved in a, in a dramatic, way, which was quite meaningful. So when it came to discussions with FDA, you know, we're like, "Oh, we could just do BNP troponin," right? And I think the component of regulators as, as a hardcore regulatory person is this... They want to make sure that the biomarker and accelerated approval pathway is available for diseases that are devastating like Danon, but it's not to set a precedent for other drugs, in a way. So I think BNP and troponin have never been used as a primary endpoint. And to set that precedent made the conversations a little bit like, "Hey, there are so many endpoints.
Can we take something specific to Danon disease?" And as you know, Danon disease is a disease that with the, I think, there's a record that the largest heart ever discovered to date is a Danon heart in the world, right? So it's about the heart thickness. So seeing LVMI come down by 10% compared to patient baseline just made good sense for us. I think that plus the fact that for the boys, they don't have LAMP2 expression. It's very negligible. So to see any change in LAMP2 expression, we've seen result in a clinical benefit. So I think that's how we were thinking about the endpoints.
What's the fastest way, surrogate-wise, that we can clearly see benefit risk consistently across the patients, whether they're young boys or in their teen, like 8 or 10, or if they're 16 or 18, right? I think we saw the commonality of the disease, disease manifestation.
We've talked earlier a little bit about the eventuality of potentially going younger in age. Would there be any rationale for newborn screening coming as early as possible?
Yes.
I think-
Yeah.
Very, very much. And there will be initiatives to work on that. I think the field in general is starting to recognize that many, many of these inborn errors, whether they be cardiovascular, metabolic, hematologic, or neuromuscular, are gonna be more definitively addressed before there's irreparable damage, and that the technology to enable an accurate genetic diagnosis continues to become more accessible and more affordable. So one way or another, that's where we're headed.
Which would be great, 'cause we see this as a treatment option right now, but in the future, why would you wait for any manifestations to happen? Especially because Danon disease, it's a—the heart's the reason that they have heart failure or need a transplant or die, but they have secondary manifestations, neurological, learning, et cetera. So if you can treat these patients as early as possible, then you prevent all of that and give them a hopeful full life. I think that's how we're thinking about it holistically. But it won't be initially at the approval. It'll be a life cycle management type of an activity.
Yeah.
All right. So also thinking about kind of expansion to a broader patient population. Could you talk about maybe your development plan in female Danon, and also what the regulatory path may look like?
So female patient population are quite interesting, and actually, you know, when we're talking about male pivotal study with FDA, they're like: "Hey, females we've heard are devastating, and we've seen in your documents. What about females? And you see the..." So, we absolutely think there's an unmet medical need. There are a lot of female patients that reach out constantly for treatment option. I think the way we're thinking about it is, let's treat the males first, because the urgency there-
Yeah
... is really significant.
Yeah.
Females, there's a population that has urgency, but there's a broad range and a little bit of heterogeneity. So we are doing a natural history to understand the female population better, because we wanna make sure the endpoints that we see relevant for the males also translate equally to the females, and if not, have that specific conversation. 'Cause I think our drug development experience in totality between the three of us, we've learned is, you have to design the clinical trials, where you can see a benefit for the patients as quickly and consistently as possible. So I think we're just trying to get our better understanding of the females.
That said, I think it's clear that the spectrum of the disease in the Danon female patients is broader than the males.
Yeah.
Within that spectrum, you clearly have some adolescents and girls who present at an age range and with a, with an aggressiveness and a hypertrophy that's very resemblant to the disease in males.
Yeah.
Whether that's 10% of the disorder or some other percentage in the females is something that we'll hopefully be able to define over the coming months and years. For that subset, a study with endpoints extremely similar to what we're doing now in the boys and young men is going to be appropriate.
Yeah.
And then for that more classical or typical group of women who present in their twenties and thirties, and then have end-stage complications in their thirties and forties, there may be some different endpoints. And that's likely the sequence that we'll move in. Even for those women with the more , "indolent," cardiomyopathy, it's still one of the most aggressive-
Yeah
... and rapidly fatal cardiomyopathies that's been described, and we wanna make sure that we're able to address that need hopefully soon.
Thinking about addressing the need, you know, it's first in one population and then potentially extending through life cycle management. How should we think about manufacturing capabilities as of now, in terms of, the pivotal trials or beyond?
... So for manufacturing, we're really proud of the fact that five or so years ago, our board of directors supported us in trying to bring manufacturing in-house. So, you know, when you're a company of 30, 40, each saying, "Oh, I'm gonna bring it in-house," sounds great, but it takes a lot of learning. I think we've learned a lot. But we're really proud of our facility. We have a facility in Cranbury, New Jersey, near Princeton, and in that facility alone, about 100,000 sq ft, we have everything from small scale, 2 liters, all the way up to the 800-liter bioreactor activities. And what we've shown is-- We've done comparability, and we've done the data analysis and showed it to the FDA. And what we're seeing is basically the phase two material is locked down for commercial grade.
So I'm really excited that bringing it in-house, not only do we have better controls, better COGS, better quality of the product, but also the Cranbury facility itself can actually support the Danon launch as a whole. Now, we do have a pipeline, so if RP-A601 or PKP2 and BAG3 come in, we're gonna have to build a second facility for sure, or work with the CDMO. But for Danon, we're very comfortable with the current facility.
Great. So actually, this is a great segue to my next set of questions. I kind of wanted to talk a little more about, maybe things that are a little earlier in the cardiovascular pipeline, especially the PKP2 program for arrhythmogenic cardiomyopathy. So, maybe you can give us, you know, a little overview of the, the disease and the current standard of care.
Sure. So for PKP2-mediated ACM and ACM in general, that's a disorder that we estimate a prevalence of somewhere in the 50-100,000 range. There are different numbers out there. We've tried to be conservative. And this is a disorder that predominantly presents in young adulthood and affects young adults and middle-aged men and women. And it is a very significant cause of sudden cardiac death events and serious ventricular arrhythmias. So one of the things that you'll often people read about or hear about a young person, an athlete, physically fit, sometimes you know, competitive college or similar athlete who then has some life-threatening heart event.
One of the frequent causes of such an event is this disorder, which is also called arrhythmogenic right ventricular cardiomyopathy, but more recently, it's just been called arrhythmogenic cardiomyopathy. This is a disease that predisposes to very significant arrhythmias, but then over time, also causes a cardiomyopathy that initially affects the right ventricle and then eventually the left ventricle. At present, the standard of care therapies include any number of antiarrhythmic agents, which have not really, for the most part, been demonstrated to prevent very serious and potentially fatal arrhythmias. The other standard of care is an implantable cardioverter defibrillator, an ICD. Many of the more serious cases will get that ICD.
Many of the patients will have frequent ICD activity, which includes basically a shock that is life-saving but also highly traumatic and is something that provokes a great deal of fear and anxiety and is not uniformly-
Yeah
... effective, and sometimes it can happen inappropriately, which is also unfortunate. Our preclinical results in a very relevant mouse model showed that we were able to affect both the electrical and the structural component of the disorder, and markedly extend the lifespan of the affected mice, and for the most part, really prevent the arrhythmic activities. So that's really our goal. We started the phase 1 study-
Mm-hmm.
And we'll continue to work with the patient community and the broader expert community to think about the most relevant endpoints that would enable us to design an efficient phase 2 program.
So I know it's, it's very early, given that, you know, that it's just the beginning of phase 1, but, you know, there are several companies that are going with gene therapy approaches, using different vectors for the same target. How should we think about potential differentiation? What are some of the factors that we should be looking at in terms of, you know, trying to understand how the program could be?
Well, it's not our place necessarily to comment on other programs. rh74 has a lot of experience in humans with Sarepta and others, where we can push the dose to the E14 range without a lot of publicly known toxicities.
... I think in a population where most patients are heterozygotes, maybe have 50% expression, we want to be able to improve on that expression to make a meaningful difference in the disease. So do we have to go to E14? I don't know. Maybe. But if we do, then I think Rh74 is a highly de-risked vector in the clinic. So that's why we picked it. We also compared it head-to-head with AAV9 neuro models, and it appeared safer and more effective. So that was our choice. We're also starting at a dose of 8 E13. These kids have one chance at cure, so you have to start at the right dose. You can't really have a safety running phase, right? You have to start at the right phase, right dose.
So hopefully, we'll see something soon, and we'll be first in class.
All right.
I respect a lot of people, but I'm slightly competitive.
As we should all be. So, I guess moving on to the hematology pipeline. So, we're, you know, waiting for the upcoming PDUFA. So, maybe if you could speak a little bit in terms of, like, the nature of the delay and whether you see it potentially having impact on other, you know, assets.
So I think the nature of delay, when you're at late stage in the middle of BLA, getting through the inspections and everything, getting excited, and then a slew of questions coming just to better understand. Because, as you know, FDA has done an amazing job over the last two years with Dr. Peter Marks, really building up the organization. So with the building up comes new team members, new resources, and I think honestly, we got caught up in the organization, in the growth at FDA. So the questions that the new reviewer had asked, we didn't have to do any new experiments or any new activities, but we just had to get him up to speed on what tests we do, why do we do it, and just all the details, and I think the clock was just running out.
So the only way the regulators can extend the clock is by three months, so I think we're there. If we were a one-drug-focused company, could we have said, "Hey, this is not okay?" Probably. But I think for us, the way we think about this is, what is the impact? And I love the question we ask: What is the impact to other products, right?
Mm-hmm.
We're about to file FA, US and EU. So if the same CDMOs, the same reviewers at the FDA, get a really good, detailed understanding on LAD, which is manufactured at the same place as Fanconi anemia-
Mm-hmm
To us, spending that time now for LAD will pay dividends for FA and BLA review. So I think we said, "Hey, there's a lot to be doing, and et cetera," but I think collaboration can go a long way to help the lentiviral pipeline. And then PKD, as you know, also uses the same CDMO. So we figured we can just keep adding to the experience, knowledge, and the relationships built with health authorities. So we're disappointed personally for the patients, but it's a matter of time.
Mm-hmm. So it will, it will also benefit other assets in the hematology pipeline in the long run?
Yes.
Great. So in terms of the launch, how are the preparations going, and how should we think about the commercial launch, maybe in the first year?
Mm-hmm
... within, you know, different geographies?
Well, I would say that this is a launch light. A soft launch, right?
Mm-hmm.
This is not our biggest launch. Sorry, I have-
I can-
post-inflammatory wheezing, but I'm okay.
Yeah.
LAD is not a lot of patients.
Yes.
Mostly inbound to our two centers of excellence. We have the QTC set up. We have the supply chain set up, the distribution channels, working on pricing and reimbursement. But we're not doing a lot of marketing, not doing a lot of... Certainly not a sales effort, even not a lot of medical affairs or MSL efforts. So whoever is out there with severe LAD, we want to make sure that they're treated, and there's a very clean supply chain, and their experience is very positive. But it's not a revenue-generating first launch, right? It's a PRV opportunity that sets up the infrastructure for Fanconi and Danon and beyond. So that, that's the general outlook. But it's, it's good.
Yeah.
It's going well.
Yeah. And I think the other thing I'll add in, then Jonathan, 'cause this is our baby, right?
Mm-hmm.
The PID community is really close-knit. So the work that we've done over the last eight years at Rocket, of building relationships with PIs that treat immunodeficient patients, LAD patients, all over the world, in partnership with Jeffrey Modell and other foundations, has been really great. So I think because of the network, we also don't have to invest as much upfront, and I think that's a great way to just get us started. And as we think about Fanconi, learnings from this, in whatever we have, we can apply to Fanconi launch, and hopefully, whatever learnings we have from Fanconi, then we can apply to Danon. So that's. We're thinking about de-risking, adding, learning, and growing.
Yeah, and I think in terms of that, you're, you're probably talking about, each successive launch potentially being an order of magnitude greater-
Yeah.
Yeah
... than the predecessor. So this way, we can kind of get our experience with launching a commercial gene therapy product-
And build-
-in a relatively finite setting, and then expand, and then further expand when it, when it comes time for Danon.
Great. Yeah. So with Fanconi anemia being next up, how should we think about regulatory timeline there? Any update in terms of, the timeline?
... I think I'll just say first half of this year, we're gonna file in the U.S. and Europe. We're trying to do it as parallel as possible. We're very excited because this program has been in development beyond and before Rocket-
Yeah
- for 20-plus years. So to see this come through, and I think the cool thing about Fanconi, as you know, is without conditioning, it's the why not drug, right? As the patient advocate says. Without any reason for conditioning, if Fanconi works, if gene therapy for Fanconi works, great. If not, they can always have a transplant backup option.
Mm.
I think the safety profile with that conditioning is beautiful. The efficacy is so promising. We're very excited about that.
All right. And so how should we think in terms of, you know, same question that we have for Danon in terms of the interest that you've seen so far, the pace that we could expect, you know, uptick within the first year of launch?
So uptick first year of launch. So we've identified quite a number of Danon patients just for the clinical trial, and I think a lot of those could be ready for the first launch. We're not giving exact numbers yet, but at some point, we will. Probably, probably publish it in a peer-reviewed journal at the right time, but this is a case where, genetic screening wasn't done for Danon until pretty recently. And now that it is, there's, there's really a lot, that are sort of coming out of the woodwork in terms of physicians and families who are being tested.
I think for Fanconi launch as well, we're not giving numbers or guidance, but the Fanconi foundations in U.S., Europe, all over the world, are very connected, and they're awaiting the therapy. So I think for us, we're focused on just bringing good product to the patients that have the urgency, and hopefully the numbers in itself will show over time.
I guess we're kind of coming up on time, but maybe just if you could kind of give us just maybe a little bit on the PK PKD program and potentially what we should expect there. Maybe like one minute that we have left.
Sure. So 1-minute synopsis. I think we are really excited, not just the Danon RP- Phase II pivotal design, but the partnership. I've done hundreds of meetings with health authority. To end a meeting in 20 minutes where everyone's fully aligned-
Yeah
... on the primary endpoint, 10 patients, 1 year, readout, and hemoglobin change of 1.5, right? And as you see in the phase I data that's publicly available, patients that have been treated more than 2 years have nearly doubled. They went from a range of 6 or 7 or 8 to 13, 14 and became transfusion independent. So we're really-
Yeah
... excited about the potential it has. And so right now, we're just focused on execution of getting the study going and getting the patients treated. But it was a huge win in collaboration both with FDA and EMA because they recognized the disease, the endpoint, and the benefit-risk is very clear.
Gene therapy cures.
Curative intent. There you go.
Well-
PKD is an example.
We are up on time. Thank you so much for your time.
Thank you
... and, we look forward to all the upcoming commercial launches.
Appreciate it. Thank you. Thanks for your support.
Thanks so much.
Thanks, everyone.