Great. Thanks very much, everybody. It's my pleasure to be moderating this panel with Rachel McMinn, founder and CEO of Neurogene. The vibe of Rachel's background seems to align with the current biotech market, getting us all in the mood. Maybe to start, Rachel, you can maybe give us the couple-minute update on where things stand with Neurogene and the Rett program, and then we can dive into questions. Thanks so much.
Yeah, thanks, Paul. Thanks for hosting. You know, just to kind of take it very high level, you know, Neurogene is a clinical stage gene therapy company. Our lead program is NGN-401, and we're in the clinical stage development for Rett syndrome. Rett syndrome is a rare, devastating neurodevelopmental disease. It primarily affects girls and has a global incidence of approximately one in 10,000 females. Rett syndrome is associated with severe impairments in hand function, gross motor function, and communication. In addition to those core hallmark features, patients experience seizures and autonomic dysfunction such as breathing abnormalities and GI dysmotility. There are no treatments approved that address the root cause of Rett syndrome, which leaves a substantial unmet medical need in this population. NGN-401, just for background, uses EXACT. This is our platform technology that's able to control the levels of transgene expression on a cell-by-cell basis.
This is really critical for Rett syndrome specifically because we know that too little expression actually leads to the disease, but too much expression is toxic. We designed the EXACT technology to co-express a microRNA along with the transgene RNA that also contains complementary recognition sites specific to that microRNA. When the two match together, this limits transgene expression, leading to a consistent and therapeutic level of the transgene on a cell-by-cell basis. We presented encouraging interim clinical efficacy data from the first four patients dosed in November of last year from our ongoing phase 1/2 trial. You know, our key catalyst for the first half of the year is a regulatory update on our registrational trial plans, and I'm sure we'll talk about that, as well as the second half of the year, our key catalyst is additional clinical data from that phase 1/2 trial. Maybe I'll pause there, and I'm sure you have a million questions, Paul.
Sure. I want to, I mean, definitely the regulatory stuff is important, and I want to get to that quickly, but I think it's still like important to level set, right? We got data last fall on the efficacy front. It looks promising, but there's no placebo arm, right? I think we've dealt with this in neurology a number of times where you have this signal, but there's no control. You know, there ends up being this debate on the investment side as to whether or not it's a real drug effect or a placebo effect or something in between.
I just think in the context of all of that, can you talk about the data you generated, and what would you point out to someone as the couple key data points that make you feel like unequivocally this is really a true drug effect and not anything else driven by expectation bias of getting a novel gene therapy?
Yeah, absolutely. I mean, maybe just to start with, I mean, we did observe concordant clinically meaningful improvements across multiple clinical domains and multiple clinical assessments in those first four subjects enrolled. You know, the other sort of level setting piece I would say is that this population just doesn't tend to improve. I will go through some specific examples, but they tend not to improve. We can look at other data sets. We can look at the natural history. We can look at other, you know, clinical trials of Rett syndrome. This idea that there's like spontaneous improvements to the level that we've seen is really just not consistent with what's been observed in either clinical trials or in, you know, in the natural history. Let me just give a couple of pieces of data.
You know, one of the key findings is that the first four participants received a two-point improvement or much improved on the CGI-I. This is the Clinician Global Impression of Improvement. For reference, a one-point improvement is considered clinically meaningful. In addition, we did see improvements across the core clinical domains of the disease. For example, all of those participants, those four participants, experienced improvements in hand function. We also observed improvements in gross motor function as well as receptive and expressive communication. If I give some examples, one participant, you know, who gained, you know, the skills of using a utensil to feed herself, walking up and down the stairs without support, and following a command without a gesture, these are complex skills that really typically are not ever learned in Rett syndrome.
When you compare that and contextualize that against the natural history of the disease, it's unanticipated. If you look at another participant, she had no hand function at baseline, and she gained the skill of being able to feed herself. She also began to use words with meaning such as mama and dada. She gained improvements in gross motor skills such as being able to stand from a seated position independently. These types of improvements are well beyond what is expected in the natural history of disease. Finally, just, you know, a brief mention on the autonomic domains of GI dysmotility. The participants who had constipation at baseline all experienced improvements, as was assessed by the modified Bristol Stool Form Scale.
One participant who had dysphagia at baseline and was unable to drink clear liquids had improved to the point of being able to chew and swallow an apple slice and actually feed herself. You know, when you kind of put all this together, we're observing developmental milestones that were either lost during the regression phase of disease or were never learned, and those were actually gained. We saw these responses deepen over time, meaning the girls gained these additional skills over time. Hopefully that at least provides you kind of like a holistic picture of, you know, why this is, you know, why we don't think this is a placebo effect.
Yeah, I think that all makes a lot of sense. You know, I mean, this feeds into the regulatory conversation, but as you now have data on these patients and you've obviously looked at trials across this space, like what do you think are the best endpoints or measures in a future clinical trial to confirm benefit?
Yeah, I mean, look, I think we've talked about the various measures in our trials. You know, I think if we take a huge step back and say, okay, you know, what are the two, what are the key pieces of a registrational trial, right? The two key elements are defining your control strategy, and the other one is, you know, the primary endpoint. If we just sort of start with a control strategy first, if you'll allow me to go there, I mean, we definitely get questions, and I know you get questions, Paul, on, you know, do you need a placebo?
You know, in this disease and the methodology in which we're giving drug, both, you know, ICV administration as well as the use of corticosteroids to, you know, control the, you know, immune profile of giving AAV, you know, it really, you know, we don't believe that a placebo is warranted. It just wouldn't effectuate what a placebo would be intended to do. In other words, families would be unblinded because they're going to figure out that their child, you know, either got the gene therapy or didn't get the gene therapy. I just wanted to start off by saying we don't expect a placebo. When you're in that realm, you then have to ask yourself, okay, then like what are your available options, right?
Like if a placebo doesn't work and do, you know, ultimately deliver the scientifically rigorous goal of a well-inadequate controlled trial, then it kind of comes down to, all right, there's a single-arm study that you could do, right? If you're going to do a single-arm study, then you're really relying on your analysis, you know, and our analysis of the natural history data and having that discussion with the regulators to, you know, get their buy-in of, you know, the changes that we see, you know, and again, this is intertwined with the endpoint, but if you're running that single-arm study, then you have to get that buy-in that the changes that we see are above and beyond what would be expected, you know, as a placebo, right? Like in an untreated population, that's really what you're buying into.
If we can do that, then that's a single-arm study, right? If there's additional information that is required to supplement that, then that puts you in the land of, you know, some form of a delayed start, right? Where you're randomizing patients, you know, one portion gets treatment, the other portion, you know, doesn't get treatment, but goes through the assessments, and you're kind of monitoring those patients over time for the study duration. Does that make sense just to tackle the control element first?
Yeah, yeah, yeah, absolutely. Do you want to touch upon endpoints too? I mean, you've talked about different iterations that you're considering, right? I mean, one could be some sort of CGI-I responder thing. One could be based on milestones. Like what are the different things you're kicking around?
Yeah, I mean, again, I think we don't want to kind of go into piecemeal or provide sort of like half updates, but you know, I think the good news here is that we do have a number of endpoints from which to choose from, right? CGI-I is one, developmental milestones, you know, RSBQ is also positive. Really the way this works is that, you know, under the START pilot program, we have a very clear cadence of meetings, and it allows us to have these discussions with FDA without going through a formal like end-of-phase meeting, like one would typically do, right? You have an end-of-phase, and then you have this big back and forth, and then, you know, it's kind of this single meeting. That is not happening and doesn't need to happen with us.
This communication allows us to kind of go through, but basically, you know, the onus is on us to, you know, get information from clinicians, what's clinically meaningful, get information from caregivers, think about the payer landscape, think about the differentiation, you know, and differentiated profile that we would want to have with our drug. All of those different factors and basically putting that together to come up with a design that would give us, you know, a broad treatment label, you know, in something that we feel is reflective of the data that we've been able to demonstrate. That's at least conceptually the way that we're thinking about it.
Yeah, yeah, okay. It feels like much of the gene therapy space right now is trading in a correlated fashion based on the premise that how do we know a lot of the regulatory flexibility that certain companies have announced or others are looking forward to is going to be real and is going to persist? You know, it feels like biotech stocks right now are about as driven by macro and politics as I can like ever remember. I throw it back at you, right?
Like what has been your, what can you say about your engagement with the FDA in the past months, the consistency of it, and like the inclination again towards flexibility and working with you and like all the ways that you've kind of guided people all along and that you expect as a company that has this special designation?
Yeah, look, I think, you know, again, I think we all live in this world where we see these headlines that there's, you know, absolutely a period of uncertainty, and I appreciate, you know, sort of the chaos as everyone looks at that. That being said, from a day-to-day perspective, if I never read a headline, for example, we are not feeling a negative impact from any of this at Neurogene in our ability to communicate with the FDA. I have to say that, you know, we're very pleased with, you know, the professionalism and the focus that we're seeing. Additionally, I would say there really does seem to be broad support and alignment for the advancement of important medicines for devastating diseases. That does require some level of regulatory flexibility.
Senior officials in our review team at CBER continue to remain very enthusiastic in their support of the START pilot program. You know, and as you know, Paul, this is really designed to enhance communication, as we just talked about, with sponsors that have promising therapies targeting devastating diseases. You know, I appreciate, you know, like everyone's like on this hair trigger of like what's the next shoe to drop. I can say from a Neurogene perspective, we're absolutely pleased with the level of communication and interactions and responsiveness that we've had with the agency.
Okay. Can I ask you one question that as an analyst, you might have been had to answer, you know, 10 times a week, and as a public company CEO, you might not answer. I will not blame you if you want to answer. You know, people ask me this, like, what if Peter Marks leaves, right? What if this and that? Like maybe I will not ask you that exactly that way, but like from your perspective, when you think about your, and I guess you do not have firm regulatory alignment yet, but your, you know, alignment of being on the same page with the FDA towards a phase three or pivotal study that is not going to have a placebo arm, that is not going to be a huge sample, right?
Like to what degree is that alignment deep and deep across, you know, lots of people that you're engaging with and, you know, not dependent on one, you know, figurehead who is highly visible? Does that make sense?
Yeah, absolutely. I mean, again, what we experience is very strong alignment across, you know, all layers of the agency. And we see multiple people, you know, and just for, I don't know, it's, you know, it's not like Peter Marks is sitting in like review team meetings. Like I know, you know, Wall Street thinks he's like sort of everywhere all the time, but, you know, he obviously sets a vision and there's many, many people across the agency. You know, these people don't get paid. They don't get paid the level that we all get paid, you know, to be in industry. And they're really there to, you know, help forward the mission of approving, you know, treatments that are treating, you know, devastating diseases. So they're very mission-oriented and, you know, we're certainly, you know, again, feeling that from, you know, across all layers of the organization.
You know, I can't speak to, you know, what happens, you know, in government, but I do feel that, you know, what Peter Marks has been able to establish and Nicole Verdun and others in the agency, that there's, it's a different FDA on rare diseases than it used to be from a long time ago, and that's been suffused throughout the agency. I guess I'd be surprised if we saw worsening flexibility. That just doesn't seem to be where they're headed.
Yeah, okay. That's all fair. How, like at least like qualitatively, like how far along are you at this point in firming up the pivotal trial design? Like it sounds like you've continued to have conversations. Yeah.
Yeah, I wish I could answer that for you. I think that my best answer, Paul, is, you know, we have guidance in the first half and it's March 19th. I think we're still very much in the first half, but, you know, we're obviously working to, you know, provide as much of a thorough update as possible in the first half.
Okay, fair enough. From a safety perspective, can you talk about, you know, maybe help us think about it from a number of ways, right? One, precedent for AAV9, right? What we know about these rare severe events from a dose relationship. Two, the margin for your low dose versus your high dose and, you know, where those kind of sit. Three, some of the protocol modifications you made to mitigate risk. You know, sort of altogether your confidence going forward, right? That we're not going to have, you know, another awful severe immune reaction and that the risk-benefit here is going to remain favorable.
Yeah, thanks for the question, Paul. I mean, look, I think, you know, if we just go specifically to our case and what we saw at the 3E15 total dose, you know, we saw a very severe hyperinflammatory reaction. You know, this has been observed in the setting of cellular therapy, but much more rarely following AAV gene therapy. You know, at the time that the case was evolving for us in November of last year, we found limited published case reports on this, you know, reaction, which is called HLH. What we did find is that what was consistent is that they were all associated with higher systemic doses of AAV9 therapy. Translating that into the 1E14 vector genome per kilogram range or higher.
You know, if there's a silver lining in all of this, what we learned is that if you recognize this early, HLH can be mitigated with high-dose steroid treatment or the use of anakinra, which is an IL-1 receptor antagonist. We have not found HLH cases associated with AAV9 doses lower than 1E14 VG per kg. I think part of the math that, you know, people struggle with a little bit, but it's really simple math. A 1E15 dose, and that's what we're, you know, currently enrolling and what we're taking forward into our pivotal trial, that does translate into the E13 VG per kg range.
While it was not required from regulators, we did obviously remove the 3E15 dose, but we did make a decision not only to move forward with 1E15, but to modify our protocol as you alluded to, so that we could monitor for markers, you know, using the HLH diagnostic criteria such as ferritin. Again, since HLH may be reversible if it's detected early and treated early. That was sort of the rationale for modifying the protocol, right? Just not, you know, like step one, removing the high dose, but then also making sure that if we did see something that, you know, we would be in a position to catch it very early and treat it. I don't know if that answers all of your questions on dosing, but that's how, yeah, we set this up.
My next question is the natural one, which is, have you dosed more patients?
Yeah, so what we've said is, look, the updates to the protocol were submitted before the end of last year, and the trial is currently enrolling. We do plan to provide additional clinical data from both previously dosed patients as well as data from newly dosed patients in the second half of 2025.
Do you think you'll tell us when this next cohort of newly dosed patients has all been treated and they're, you know, essentially the no news is good news update?
I mean, I think what we've committed to is, you know, is making sure that we're providing folks with, you know, transparency on fulsome updates. You know, with regulatory, it's the first half of 2025. You know, with clinical data, it's the second half of 2025. You know, if there's anything else that we would need to share prior to that, then we would do that.
Okay, I understand. All right. In the meantime, we're going to get more data from the Taysha program. Do you have an expectation for that data? Like as they dose higher, would you be surprised if they were able to show the same level of efficacy that you've shown? Like it's obviously hard to compare across trials. I know you have points of differentiation for 401, but what are your expectations there?
I mean, I'm not the analyst anymore. Paul, I'm going to.
I have just as many opinions.
I'm going to, obviously, I have my own, you know, personal, you know, views. I think, look, we'll have to see what the data look like. Let's, you know, let's just talk through the differentiators because I just want to make sure that's appreciated. You know, the key differentiators for us is that we're using the full-length MECP2 gene. You know, and the goal here is to really maximize restoring the full gene function. When you use a mini gene, you're not necessarily getting to that, you know, full genetic, you know, function. In terms of, you know, route of delivery, as you know, the delivery aspect is really important because, you know, the virus doesn't magically go where it needs to go.
Using ICV administration with our program is really designed to maximize the biodistribution to the key areas of the brain that are affected by the Rett pathology. Finally, we're using this EXACT regulation, which, you know, sounds somewhat similar if you just use some of the same buzzwords, but they're really quite, they're really quite different when you dig into the science. Collectively, you know, we do believe that the combination of these factors are going to drive a best-in-class profile. I think the best I can give from you is, you know, we have our own clinical data that we presented in November.
You know, Taysha has, you know, presented their clinical data, and it's really, you know, up to investors and the community will, you know, be able to do their best to, you know, compare across studies, even though you're not supposed to do that. You know, we'll make those judgments, but we're, I think we're very confident in our profile.
Yeah, yeah, yeah. Okay. I feel like I've written cross-trial comparisons come with caveats and then made all of the cross-trial comparisons like one to two hundred times probably.
Yeah, nobody can help themselves, right? That's just part of the nature of the beast.
Yeah, okay. All right. We only have another minute left. Is there anything else you'd like to highlight, Rachel, to wrap up? Maybe comment a little bit on cash runway too.
Yeah, so cash runway, we do have cash into the second half of 2027. That allows us to put our heads down and operate during this very volatile biotech tape. We're going to do that. You know, lastly, I would just say, you know, this is a big year for Neurogene, and we look forward to advancing NGN-401 for Rett syndrome.
Okay, great. Well, best of luck, and we look forward to some updates soon.
All right, thanks, Paul. Thanks, everyone.