Welcome back to our afternoon session of the first day of the Leerink Partners Global Healthcare Conference here in Miami. I'm still Marc Frahm, Senior Analyst at TD Cowen, and I have with me Rachel McMinn, CEO of Neurogene. Rachel, how are you doing?
I'm good. I'm good. Thank you for having me. Really appreciate it.
A pleasure to have you back. Before we go diving into nuances and data and trial design and timing, let's take a little bit of a step back in terms of where you are in Rett syndrome. From a stock perspective, essentially the single driver of the stock performance, although generally not the only thing you guys are doing at Neurogene, but the only thing for which we have meaningful public data. Refresh our memory on where we are in terms of number of patients, state of dosing, and disclosed timeline to pivotal data.
Yeah. Let's take a step back, as you said. Neurogene is a genetic medicines company. We're focused on devastating neurological diseases. We take a biology design-first approach to our genetic medicines with the goal of being able to have transformative outcome for patients and their families. Our lead program in the clinic, as you mentioned, is NGN-401 for the treatment of Rett syndrome. For those of you who don't know, Rett syndrome is an absolutely devastating disorder. It's primarily in girls, there are even more cases of boys being documented.
What's in common here is that these children, they're robbed of just the most basic skills that we all take for granted, whether it's the ability to communicate, you know, a lot of gross motor function, just being able to do purposeful movement with their hands.
As a result of that, these kids become dependent on their caregivers for not only the most basic needs, but for their entire lives. That is sort of the setup. There's approximately 15,000-20,000 patients in between the U.S. and major commercial markets in Europe, so this is a very easily multi-billion dollar market opportunity with very limited penetration when you think about premium gene therapy pricing. We are rapidly advancing towards commercialization, potential commercialization with NGN-401.
Our Embolden registrational trial, as you alluded to, is ongoing. We were able to dose not just one, but multiple patients before the end of the year last year, despite a record flu and cold season. We are looking to complete that enrollment in the second quarter, not just enrollment, but dosing in the second quarter of this year. Very comfortable with that guidance. The phase I, II data that we announced, we had data on an eight-patient pediatric cohort that was announced in November of last year, and we'll have a, you know, more fulsome update with 12 months+ worth of data coming midyear this year as well.
that's sort of like the high level, setup, and happy to kind of dive into more specifics on your question as well.
Let's dive in. I think there's been a lot of question around the variability of Rett patients.
Mm-hmm.
which is vast and not surprising given the length of their survival and the breadth and universe of their clinical outcomes. Talk to us about how we should think about the commercial implications of a success on the pivotal endpoint that you have settled on in terms of, in terms of milestone benefit for families, clinically and commercially. Like, how do we interpret an improvement of a certain number of milestones? Like, what does that mean for the individual patient and the individual family?
Yeah. You know, in terms of the data that we have presented so far, this was the basis for Breakthrough Therapy designation, which we announced very recently. Within that, we provided the FDA with patient-level data, not only all the individual milestones, but all of the the supporting video documentation, which is so important, because, and I'm sure we'll get into this, but, you know, part of the primary endpoint is being able to show a gain in developmental milestone. You know, one of the things that you're pointing out is really important. There's a question of, well, there's a regulatory bar and that's one thing, but ultimately, what's going to drive commercial adoption?
Really what we're hearing from, whether it's families, you know, thought leaders, you know, who care for these patients as well as, you know, payers who are ultimately going to reimburse, people are looking for functional gains of skill. Not just a single milestone, but really globally. What I'm pleased to be able to say is that in our phase I, II data, you know, we were able to show not just one gain of skill on average, but actually multiple gains of skills.
There seems to be today, so far, with patients followed anywhere from six months out to as much as two years of follow-up, we have not seen a plateau in gain of function, which is really incredible.
It is consistent with the biology of the disease and this idea that too little MECP2 drives disease, and if you can restore that, you can start to restore some of the, you know, neuronal connections in those neural networks. That over time, as those synapses are firing and wiring together, that you can start to get benefits, and that they would accrue over time and become durable.
And not just in one particular domain of disease, but really across the spectrum of disease. That's what we're seeing. We're hearing from, you know, the very best thought leaders as well as families. Like, they want as much as they can get out of a gene therapy. They're not looking for a gain in a skill, right? You know, can my daughter hold a pen or, you know, hold a fork?
Like, can she actually use that fork and feed herself? You know, can she move more easily? Can she stand, you know, with much less support? In some cases, you know, walk up the stairs unassisted? You know, is she able to follow what I'm saying? I mean, these are the kinds of-These are the kinds of skills that we're able to measure in the Embolden study and certainly within the phase 1/2 where we've seen really, you know, very exciting transformational benefits that are accruing over time.
Let's talk about that accruing over time dynamic exactly. You've given a pretty remarkable amount of durability data relative to the stage of the company on an individual patient basis. How should we think about projecting the possible trajectories of that improvement over time? Should we expect something more asymptotic?
Is there a good model to look at as we think about how much benefit these girls, women could gain if we continue to follow them for the one year, two years, et cetera? How age-dependent is that in terms of when you dose these patients?
A number of really good questions in there. I think, look, what we've shown in the phase 1/2 data is that we've dosed across the disease severity. Whether they have a, you know, a genetic mutation that's maybe associated with more mild disease or more severe disease, their clinical presentation was more mild in some domains, more severe in others, and we've seen benefit across the patient population. I think that's very encouraging.
In terms of, you know, how many milestones can they gain, you know, will that continue to accrue over time? When does this plateau? What does it look like? You know, every girl. The reason why this is a baseline controlled study, and you asked that before, but, like, going into a little bit more information, right? No two Rett girls are alike.
What that means is, you know, somebody might be non-ambulatory and be a four-year-old, and some other four-year-old is walking around. You're like, "Okay, well, how is that possible?" It doesn't follow the same trajectory. It's not a neurodegenerative disease. It's mosaic, where half of the cells are, you know, are normal and the other half are deficient, and depending on where that is, it's gonna result in a different phenotype.
In fact, There's some incredible case studies where you have identical twins that present entirely differently. One is very severe, and one is very mild. These are real-world people that I've met, you know, the grandparents of these people. The only way that's possible is when you start thinking about the mosaicism, right?
You know, if somebody has a very severe respiratory phenotype, it means they have more deficiency in the brainstem, just to give you like a sense of where that's going on. How can gene therapy then help? Well, the idea is that what we're seeing is the exact technology. We are delivering a very constrained level of MECP2.
We know that if you get too much, that could be toxic, that's solved for. We know that with ICV administration, we are maximizing the amount of MECP2 that we can get into individual neurons, right? That's really important. The other key design feature of NGN-401 is using the full-length gene, right? This is a gene that is highly conserved.
We wanna make sure that we are, you know, getting a fully functional protein, and so that's what we've baked in here. You know, to go back and answer the question, I don't know if there's like a certain time in which, you know, girls would, you know, kind of peak in terms of their ability to gain skills. We can say this is not a cure, right?
We're not gonna get into the majority of neurons with the current technology. That's just not on the table today. Certainly, the kinds of benefits we're seeing is that we're seeing, you know, this nice durable gain of skills that is continuing to grow over time, and again, that is consistent with the biology and what you would expect with MECP2 being restored through gene therapy.
I wanna dive in a little bit on delivery question. I think this is a debate that has swung back and forth and been a pretty violent pendulum amongst those who are following Rett. Talk to us about, for those here and also on the, on the listening or the audience, how routine is ICV administration in this patient population for other indications? Conversely, how complex is it in terms of number of time you're spending in facility, number of physicians who are trained to do it, et cetera?
ICV is a very routine common neurosurgical procedure. It is something that neurosurgeons learn as junior residents, and we are told, "Pick up the phone and call any neurosurgeon." They will tell you this is like bread and butter of neurosurgery. Very straightforward. It is a standard procedure. We are not pioneering anything new. It's not bespoke.
It's not, you know, an extensive procedure. All in, it's, you know, approximately one hour. It is performed by a neurosurgeon. Again, these are trained very standard. The feedback that we've received, you know, in terms of, you know, is this a barrier, is it not a barrier? We've heard over and over again, whether it's payers, patients and families who are voting with their feet, you know, KOLs who are voting with their feet.
You know, We have a lot of enthusiasm for the Embolden trial. We have no problems with enrollment and feel very comfortable with our 2Q guidance. You saw, as I mentioned, we were able to dose multiple patients before the end of the year last year when we had just opened up Embolden. So we feel very comfortable with this. Any site that is going to use this drug, assuming we were to gain FDA approval, would be using it in a center of excellence, right? Like, that is just the paradigm. Gene therapy is not gonna be used in the community setting.
It is going to be given by specialists who have expertise in Rett syndrome and then also get training in how to monitor for the toxicities that are, you know, part of the risk-benefit of AAV just generally. So this is going to be handled by expert sites. All of those sites will have neurosurgeons, and of course, as part of that education, they will be trained.
This is not really kind of the key barrier to adoption. At the end of the day, as I mentioned, efficacy is really the main driver. Families want knowing that this is a one-time treatment. This is a very sophisticated community. They all talks among themselves, and they want the best for their children, of course. They're going to be picking a treatment. Not focus on route of delivery, but really focus on outcomes.
That's what we've heard very universally. When you think about the monitoring then, once the neurosurgeon performs the procedure, these patients then are followed by their neurologist just like any other gene therapy for a CNS disorder, and that neurologist, and it's not just the neurologist, but the whole care team, will be looking and monitoring for AAV-related toxicities, whether it's the acute potential toxicities that occur in the first week or two where you wanna have that monitoring and make sure that you're treating with extra steroids if that needs to be done, or if there's other things that you're looking for a little bit later, like we've seen with some of the DMD drugs where, you know, there are liver enzyme elevations that can occur later in treatment, like two and three months.
Those are things that all need to be monitored regardless of what gene therapy and how you give it. It's just part and parcel of gene therapy.
I wanna drill down a little further on that. We talked about procedure. We talked about the variability of the clinical data set. I think there's been discussion about how long you should follow these patients up to have an approvable data set, the six-month versus one-year dynamic that has come up on occasion. Talk to me about how long you have to follow these patients up to show a clinical benefit that's convincing.
Both companies that are involved in Rett syndrome gene therapy development have a 12-month primary endpoint. There's a reason for that. The FDA has never approved a gene therapy treatment other than a topical, but like anything systemically administered, all have at least 12 months or more of data. There's a reason for that.
Again, it's a one-time treatment where you are making a decision to forego any future other gene therapy treatments that may ever be developed, at least based on the current technology. There's also a durability piece, right? If you go and look at, you know, Roctavian, obviously totally different indication, but there were questions on durability.
The FDA said, "I don't want one year, I don't want two year, I want three-year data." FDA has a very strong track record within gene therapy for asking for more rather than less data, given the importance of, you know, this one-time treatment decision. That's also true, again, of families and clinicians. To this point about, you know, is six months acceptable?
Anyone can put in an interim analysis. You guys all know the difference between an endpoint versus an interim. As long as a sponsor is willing to take alpha risk, right, spend part of your P value, and then make a scientific justification, you can include an interim analysis whenever you want. Many of you have seen great interim analyses. You've seen like alpha spending that like just gets spent and doesn't actually turn into anything.
We had a different question for FDA, which is: Is a gene therapy approvable on the basis of six months as an endpoint? Not an interim, but as an endpoint. The answer, w e asked twice, both in the, you know, the prior administration. Well, there's too many prior administrations. When Nicole Verdun was, you know, running OTP, we asked our review team, and the answer was, "Mm, six months is not really considered clinically meaningful," again, in the context of gene therapy Rett syndrome. We said, "Okay, let's ask again because there's a new administration." We got back like, "Hey, we already told you six months is not acceptable.
You know, stick with the program of 12 months. We have very clear written FDA feedback that is very supportive of a 12-month endpoint, not supportive of 12 months, excuse me, of six months. As a result of that, we're not interested in taking unnecessary regulatory risk as it relates to, you know, having a six-month, you know, interim or endpoint. That's really the debate. Whether somebody else has different advice, I don't know. I can just tell you what we have, and it's very clear, and there's no reason for us to take additional regulatory risk.
Let's zoom forward to a world in which you have pivotal data, filing, approval, launch in the U.S. for the moment. How much capacity is there to treat these? There's a lot of Rett syndrome patients across a wide range of ages. How do we think about ramping up capacity? What is the commercial reality of this, of a gene therapy with a one-time ICV administration look like in the U.S. for a population as vast and varied as Rett syndrome?
Yeah. From a planning perspective, we felt like it was really important to be able to control our own destiny as it relates to manufacturing. We have manufacturing in-house. We have a U.S.-based manufacturing facility in Houston, Texas.
You know, this is a team that has been producing material from toxicology through phase I into Embolden. That process has not changed, and we are looking to continue to support the commercial launch out of this Houston facility at the same scale, thereby reducing, you know, any potential comparability challenges as it relates to scale. And we are initiating, you know, PPQ campaigning this year in order to support the BLA. You know, not all material goes to inventory, but part of that would be used for inventory.
As we've said, you know, we are, you know, continuing to move forward. There's not some sort of big CapEx expense. I know that was one of your questions, there's no, you know, material CapEx expense. We're not building any type of new facility. We believe that we can launch successfully out of this facility at our current scale.
I'm gonna roll to what you knew was the next question which is so zooming out of the United States, how do we think about regulatory path forward globally? Separately, the commercial opportunity which, I mean, we have a sense of the number of patients globally, but the commercial opportunity is a little bit more about pricing, positioning, strategy in terms of partnering. Like, how do you think about that? 'Cause those girls also need therapy.
Yeah. Right now we're very focused on laser-focused on getting Embolden, you know, executed, which will, you know, is really a U.S.-centric trial and that will support the BLA filing. We are not slowing anything down as it relates to that. We do have PRIME designation in Europe, so that's a really, you know, nice thing and we have started to engage with European regulators. The question of, you know, we will provide updates when appropriate there. I, I think, you know, the question is, you know, what's the timing of that given that Embolden is already going.
You know, there's really the next opportunity as you, as you think about presenting them with data, they obviously can't come in and change the study design. We're not gonna be doing that. You know, you can think about the longer term arc of, you know, is this data robust, and can you take that to, you know, European regulators? That's.
You know, we do have Europe in mind certainly. From a pricing perspective, I think it's premature to talk about that. You know, we certainly would, you know, look like anyone else who's evaluating the pricing dynamic and making sure that, you know, the value to the U.S. is really accrued and that there wasn't a material discount, you know, outside.
I don't think we can provide more metrics than that other than to say U.S. is our target market right now. This is a huge unmet need and we will continue to make decisions that are appropriately scaled, you know, for an emerging, you know, with our first product at launch. You know, I don't think you should expect us to be, you know, building out a substantial, you know, European infrastructure, you know, anytime soon.
On that topic, I wanna talk a little bit about not necessarily building out European infrastructure, but to what extent we might need data specific to other geographies, and how variable is the spread of genotype amongst Rett syndromes between geographies. I know this is not a disease with a founder mutation.
Yeah.
it is one where it's a fairly complex universe of genotypes across many different women.
Yeah. There's not a one-to-one genotype/phenotype correlation. For the most part, Rett is spontaneously acquired. It's not inheritable. There's some rare exceptions where that is the case, but it's very rare 'cause there's a lot of things that would have to happen for that to be true. When you think about the variability, there's been some very good natural history data that has been done, performed in Australia, for example, and they show very similar things. You know, these girls do not gain skills. If anything, they tend to lose, you know, hand function. There's been some very nice studies that have been done by Jenny Downs and others in Australia with several 100 patients.
We're obviously in touch with European thought leaders as well, but there doesn't seem to be an ethnic bias in particular Rett. It just sort of occurs across the globe. The frequency and the mutations are sort of all there. There's nothing inherent. The one thing I would point out is that the standard of care can be different on different locations. As an example, you know, spinal fusion surgery is very common in standard of care in the U.S. If your spinal cord is bent by a certain amount, you will be eligible for surgery because it's horribly excruciating and it's more than that. You can suffer very severe consequences if you don't get that righted.
There are certain geographies where that's just not paid for. As a result, these girls are gonna progress even faster and really have much more severe consequences. I don't have good numbers in terms of whether, you know, what the survival differences are and quality of life, things like that. Those are all very important questions. Fundamentally, the disease is the same across geographies.
We've had some experience with a therapeutic for Rett, which is an oral from Acadia. I don't think anyone thinks Acadia's efficacy profile is particularly impressive. Some would argue it's not particularly notable. The tolerability is quite challenging. There's a pool of patients who have rolled onto DAYBUE, who have now rolled off. Churn is quite notable, and Acadia updates it every quarter. How do you think about patients who are DAYBUE experienced?
Mm-hmm.
Does that at all impact how you think of eligibility? I'm gonna stop there before this becomes a 20-part question.
There's no issues from an eligibility perspective. The only eligibility that we have is during a window in gene therapy when you are taking the immunosuppression, you don't wanna have concomitant trofinetide use because given the substantial diarrhea associated with that.
Right.
The immunosuppressants, if they were to be excreted, that would pose a substantial safety issue, right? 'Cause it's like all of a sudden you don't actually have the prednisone on board that you think you have. Other than that, if patients have prior experience of trofinetide, as long as they wash off, that's fine. If they want to go back eventually, like, onto trofinetide because they want to explore that, you know, if payers support that, you know, that's fine too. It's really just the window, certainly from a clinical perspective in that 12-month window. You know, as you think about into the marketplace, it's really, you know, that safety window that you would be most concerned on.
Certainly patients with prior experience with DAYBUE would not in any way be hindered of taking a gene therapy.
Something of a sort of ancillary question. Again, we're going into the future. Pivotal data filing approved and approved data from the U.S. To what extent is this a warehoused population pre DAYBUE experience or previously diagnosed? There's obviously a substantial demand, desperate interest by families for treatment. To what extent is there a first-mover advantage here, and how, and how durable is that?
Look, I think in terms of qualifying for gene therapy, there's a whole bunch of work that needs to be done. I think just taking a step back, you know, again, these families, they're very aware that there are two gene therapy companies. If there is a relatively short difference between, you know, one company's out at one time and then a few months later there's another company out, the feedback we're hearing is that that's not going to be a major challenge for families. Obviously, the longer that window is, then it becomes more of a treatment question of like, well, if you're feeling a very high sense of urgency, then that might influence your decision. On the order of several months is not considered material. There's only approximately 20 centers of excellence right now.
Obviously, we, you know, we hope and we know that there are advocacy groups working to credential additional centers beyond that, and that will be important because all of the patients will funnel here. I think I mentioned this, but this is not going to be a community-based drug. If you got your DAYBUE prescription from, you know, a pediatrician or a neurologist who's not going through a credentialed center, that person is not going to be able to prescribe any gene therapy. I think there's gonna be the question of like, okay, do I want to have a gene therapy? You're going to be if you're a family, and your voice is just as important as the clinicians. We've definitely heard that from the advocacy groups as well as the clinicians themselves.
This is a group of physicians that invites the family perspective. What is the best decision for you? They're gonna be looking at the data. They're gonna be looking at these videos. They're gonna be looking at, you know, what is the best decision for us. And there's just frankly not all that follow-up.
You know, it's not, it's not available yet, but certainly, you know, at the time of these, you know, again, I'm going into the future with you of potential BLA approval for both products. They'll be looking at this data, not just the proportion of patients who met the endpoint, but the, you know, following these patients from the phase one, two of like, what does that look like over years? What could happen to my daughter over several years?
Our first treated patient was treated in the summer of 2023. Just think about that. She's gonna be getting her third year assessment this summer. It's really exciting and all these patients coming behind her. Now fast-forward to, you know, BLA timelines and post-BLA, we're going to have years and years’ worth of data on this leading cohort of patients, and that's gonna be just as important as what proportion, you know, have met a response rate.
I think that's gonna be a big, a big driver as well. As you guys think about your models, you know, think about the numbers of centers of excellence. You can't throw all patients. You know, if there's 10,000 patients in the U.S., there's not gonna be 10,000 patients that go through 20 centers, you know, over the course of a few quarters.
It's just like that wouldn't happen even if it were an oral, but it's certainly not gonna happen in the land of gene therapy. Just keep that in mind as part of the way you should be growing your models. Also keep in mind that families are gonna wanna hear from other families of what their experience was, and then it'll kind of grow from there. We see there's plenty of opportunity for two gene therapies, and it's a really big market opportunity for both of us.
Awesome. On that note, we're out of time.
All right. Well, thank you so much.
Thanks, Rachel.