Morning. Thank you for joining Guggenheim's 2026 Emerging Outlook Biotech Summit. I'm Debjit, one of the therapeutic analysts, and my next presenting company is Neurogene. From Neurogene, we have Christine Mikail, President and CFO.
Good morning.
Thank you for joining us.
Good morning, and thanks for having us here today.
Awesome. So let's start with an overview of Neurogene and key milestones for 2026.
Sure. So Neurogene, for those of you who do not know us, is a genetic medicines company that is developing therapeutics for rare neurologic diseases. We take a biology-first approach to the designs of everything we bring to the pipeline. And so by that, what does it mean? What it means is we take a really deep understanding of the underlying biology of the disease. Why is that important? We need to know what we're shooting for in order, in order to develop treatments that are gonna be clinically meaningful and truly impactful to patients. Our lead program is NGN-401 for the treatment of Rett syndrome. Rett syndrome is a multi-billion dollar market opportunity with 15-20 thousand patients in the United States and the major European markets. It is really a devastating neurologic disease, where children, primarily females, are impacted, and they...
You know, generally, they develop normally on a developmentally delayed basis, and in fact, it's that developmental delay that brings them into the pediatrics office and then eventually ends them up into the neurology office. Because what happens to them is developmental delay leads to some developmental milestones that are reached, but eventually, those children lose those milestones around the ages of 18 months to 2-3 years, and they so they regress, and then they have a stability of disease. Essentially, imagine your child being static in areas where they cannot use their hands, they cannot communicate, whether verbally or expressively, and they have severe, you know, gross motor impact. And so, when you're developing a treatment like NGN-401, that's actually the area that we're looking to make the most difference in, in those those key domains that impact Rett syndrome.
Right now, NGN-401 has started a pivotal study. We started dosing patients in Q4 of 2025, and we announced earlier this year that we've dosed multiple patients. We're on track to complete enrollment and dosing in Q2 of 2026. And, you know, we think we have a pretty clinically de-risked program at this point. We presented phase I and phase II data last year in 8 participants, where we showed, you know, 35 milestones gained across those 8 participants, which generally implies about 4 skills per patient. They were multi-domain, as I talked about, which is really important for the disease. They were durable over time, and they just continued to deepen. So we're really encouraged by what we're seeing, and we think that provides, you know, minimal risk into the pivotal study.
As far as catalysts go, right now we're heavily focused on getting that enrollment and that dosing done. We expect that that catalyst will be completed in Q2 of 2026, and then we'll be presenting data from the phase I, phase II in all 10 patients that were dosed, and that we'll have at least 12 months of data and more by then.
Great. So there are two AAV gene therapies in the clinic. Can you sort of walk us through the key differentiation between yours versus your competitors?
For sure. I mean, it goes right back to that biology design principle. We were really pretty serious on taking an approach that allowed us to develop a best-in-class gene therapy for Rett syndrome. So what does that actually mean? To develop a best-in-class gene therapy for Rett syndrome, you need to do a few things. Number one, you need to be able to make sure that you're delivering the drug to the key areas of the brain that impact Rett syndrome, and we know for sure that that is in the brain. You know, it's really important to express the gene of interest, which in this case is MECP2, and that you need to be able to control that level of expression because Rett syndrome and the MECP2 gene itself has a very narrow therapeutic window.
So we set out with that in mind to ensure that we accomplished those parts of the problem statement. So our construct encodes for the full-length human gene, and that means: what are you guaranteeing? You're guaranteeing translation of functional protein. A truncated protein does not guarantee full translation of the protein, so we wanted to ensure that we could do that, and that's extremely important in the disease. The second thing that was really important was to develop a technology to allow us to constrain and regulate the expression of the transgene. Again, that's very important. MECP2 itself is a highly toxic gene, and so it's a very narrow therapeutic window. It's very dosage sensitive.
So Stuart Cobb and his team at Edinburgh, who's been researching Rett their entire career, developed this Neurogene proprietary technology to solve this problem, and this way, we can avoid overexpression toxicity. Then the last thing we did was we chose a route of delivery that ensured that the drug got to neurons in the brain, because if it doesn't impact neurons in the brain and translate MECP2 protein, there is no way to guarantee a functional benefit. It's those three things that we did that ensures that we believe kind of reads through on the phase I, phase II data that we're seeing today.
The route of administration, ICV.
Mm-hmm.
Do you think that's a barrier to utilization or shouldn't be a problem, it's the overall efficacy?
We tested this actually, because I think this has been a concern of ours and even those in the industry. The reality is, when we've talked to caregivers, we've done market research on this, caregivers actually know that the cause is in the brain, so they are looking for a treatment that gets drug as close to the cause. So we haven't seen caregivers have any sort of barrier to entry there. We then tested it with KOLs. They actually agree that, at least from a theoretical perspective, you need to get drug into the brain, and out of all the routes of delivery, that is the route of delivery that can guarantee drug into the brain.
Then the last thing is, you know, a drug that works matters, but if you can't get it paid for or reimbursed, it doesn't matter. We went and tested the same thing over with payers, and what payers have told us is, you know, the route of delivery is truly agnostic for them. What they're looking for is an efficacy profile for a disease-modifying therapy that is easy and objective to see, and so they love the milestone gain, part of the endpoint, so they feel like they can actually see a difference in these patients.
... Got it. A little over a year ago, you had a little bit of a stumble at the 3E15 dose.
Yep.
You're now operating at the 1E15 dose. How confident are you the 1E15 dose will be clean?
We're pretty confident to date now. Like, we have not seen any signs and symptoms in any of the patients that we've dosed in relation to the, you know, what we're talking about is HLH. And, you know, the reason that we're confident is, one, we believe it's very much dose dependent. So the 1E15 dose, that is the dose that we're carrying through into the pivotal study, is 3 times lower than the dose where we saw this patient experience HLH. And then lastly, we put in a monitoring plan so that we can actually track what's happening to these patients and to look for the key diagnostic markers, the immune markers that would be implicated.
In this case, beyond all the other gene therapy more immune markers that we look for, all we did is add ferritin to that test. So it's no different than any other blood draw that we're doing for monitoring these patients. And we look for ferritin, you know, hyperferritinemia, we're looking for cytopenia, and we're looking for fever. Those are the hallmark diagnostic criteria. What we've learned is, as long as you can detect ferritin early, fever and cytopenia early in the course of this, it's fully reversible, and it's reversible leveraging, you know, steroids as a first-line treatment, and then even as a second-line treatment, if we needed it, we could use anakinra, which is an IL-1, you know, readily available agonist. So the data that we've followed, the data that we've presented suggests that we haven't seen anything at this dose.
We've already dosed more than the 10 patients and haven't seen it, and frankly, we haven't even had to intervene. So we feel pretty confident as a result of the monitoring protocol, that, you know, we don't think we'll see anything in the 1E15 dose.
Was there anything unique about that patient or was it purely a dose? Typically, what's the time course, or what, what do you think would be a time course, and once the patient has passed that time course, you don't have a problem?
Yes, that, I mean, that's an excellent question. So in regards to the patient, you know, unfortunately, we were not able to really do any sort of autopsy or really understand. The reason that that's an important question is there are patients who have a primary disposition to HLH, just from a genetic perspective. So we don't really know exactly, because we weren't able to really do any work to figure this out. But as it relates to being able to detect and monitor for this, we know that this is very early in the time course, within the first few days, and frankly, by day five, the patient hasn't seen, you know, any of these hyperferritinemia concerns or the fever. We don't really grow as concerned.
I mean, it's within that complement pathway, right, Debjit, where in those first two weeks for every gene therapy, we're all hyper, you know, focused on the monitoring, but as it relates to HLH, it's more in the first five days.
Got it. The nerve conduction issue that you had, in patient five-
That's correct.
Could you sort of elaborate on that and any sort of sequela?
Yeah, that patient we reported in November timeframe, that one of our patients had an abnormal nerve conduction finding. That patient, you know, the finding itself was transient, and that patient actually has come back with a normal range from a nerve conduction perspective. We actually think this is just a class effect of gene therapy, generally speaking. Neuropathy is really that symptomology that you'd be looking for. And in fact, you know, an IT was just approved, which is Zolgensma, essentially the AveXis product, prepackaged now into an IT lumbar injection. And if you look at that label, you'll actually see incidents of neuropathy. So then again, this is not sort of very specific to NGN-401, but more so, it's just this is part of the risk-benefit profile that goes with AAV.
So we've seen it here, or we're seeing it in, in an IT, you know, Zolgensma. We saw it in a Pompe program, it was reported. We see it in SOD1 . So to us, this is just part of the risk-benefit profile of AAV, generally speaking.
So this is not necessarily an ICV-driven or route of administration-driven talks on the DRG, but general AAV, doesn't matter whether it's intrathecal, IV or ICV.
You're, I mean, you're absolutely right. That's what an IT will tell you. I mean, it's an IT lumbar injection. We do think the pathology is likely, you know, around the DRG pathology, but it doesn't matter if you use ICV. It seems to not matter if you're using IT lumbar, because it really is, you know, are you transducing the DRG? And AAV does that. So that's really what we think is the cause.
Time to market comes up a lot, given it's basically a one-time therapy, and, you know, once you treat a patient, that patient has gone from the pool. So do you think this is gonna take all market, or it's gonna take-- the market's big enough to support multiple players here?
No, I really appreciate the question, 'cause I think this is something that's not really well understood, you know, by the market. This is a pretty large market opportunity for a genetic medicine, right? I mean, if you use a $2.5 million net sales price, which is the general price that we can take, measuring to comparables, and it becomes a multibillion-dollar market opportunity. It's very similar to DMD and DM1, where there is no winner-takes-all approach, and multiple players could be seen in the market. So we think this is more a large opportunity, and adoption will take some time. To your point, Debjit, I think these caregivers are actually very, very...
I mean, they're very intelligent consumers as it relates to this, and they're very much paying attention to the fact that once their children take this product, they're not gonna be able to take another gene replacement. We haven't figured out redosing. So I don't think adoption is gonna look like, you know, a complete hockey stick out the door for anybody who's on the market. It's going to take some time, generally speaking. And then more importantly, it's a gene therapy. The infrastructure in and of itself to administer a gene therapy, whether it's intrathecal lumbar or it's ICV, it takes, it takes some time, right? So there'll be time to make sure that the adoption is, you know, something that can be seen with more than one player in the market.
So at our market cap of about, like, I looked it up, it's like $300 million right now on a fully diluted basis, we get zero credit for the efficacy profile that we've seen with this drug. That implies a winner-takes-all approach, you know, given our competitive dynamic, and we just don't see. We don't even have a comparable for that. Like, who has come out on the market, been first to market, and taken every single population, you know, available, prevalent person in the first six months to a year? Like, we just don't see even an example of that today.
Let's talk about the regulatory landscape here. This has been a challenging, call it, 12 months for cell and gene therapy. What are you doing as a company so, you know, you don't stumble on deliverables?
It's a fair question. I mean, we saw what happened yesterday. We saw what happened with REGENXBIO. The regulatory environment is volatile right now. I think for us, you know, we are part of this START designation that we received a couple of years ago, which has been... You know, in my experience, I've been doing this for 25 years, I've never seen the level of engagement with the FDA that we see. We have quarterly set-up meetings, you know, that are on the books, where we talk about the development program from all perspectives, not just clinical. We've had CMC conversations. So we think that regular interaction on a quarterly basis allows us to really draw as much information that we can from the FDA to make sure that we're taking their counsel into effect.
So to us, that regular engagement helps reduce the potential for a stumbling block. And we, again, we've used it on all aspects of what would be part of the BLA submission, CMC, clinical, and so we feel pretty confident that we're doing everything we possibly can, you know, in this volatile regulatory environment, because that program has been very, very helpful for us.
How can the Street be confident that the interactions that you're having with the FDA rank and file doesn't get overruled by the director of CBER, which we just saw happening?
Well, I can't guarantee that Vinay Prasad isn't going to wake up one day and decide he doesn't want to do one thing or another, for anybody, not for me or any of us in this space. But what I can say is, by having those frequent interactions, you know, we don't only have frequent interactions where we're on Zoom with the FDA, taking live discussion into play, we're getting written feedback from the FDA, and we're taking it really seriously. I mean, a lot of people have asked us: "Well, why, you know, why you-- why don't you have a 6-month interim analysis?" Well, we have written feedback from the FDA, where they told us that 6 months is not sufficient enough for registration purposes, right? It's not about an interim analysis, because anybody can put that in their SAP, right?
It's about listening to the FDA when they give us counsel on what they think will be acceptable. We didn't get that feedback only in the, you know, the Nicole Verdun, you know, era, and the Peter Marks era. What we went and did in September is we went back and said, "You know what? This is volatile now. We're gonna ask the design questions on the clinical trial all over again," which, in my whole career, you don't disturb, you know, a sleeping lion, right? You leave it alone. No, we went after it and said, "Hey, let's check again every single design element." The FDA came back to us and said, "Look, we have questions, but, you know, do this, do this, do this-
Hmm.
- and, you know, we'll feel comfortable." And so it's that asking the second time during the Vinay Prasad, you know, era, where we took their feedback, and we're taking it very critically and not changing the course. No, there's not an investor and/or a competitor that is gonna change our course, because we have written feedback that's telling us what we should do, and we're taking it very seriously.
One of the things you mentioned in terms of your dialogue with the FDA is CMC. How much control do you have on your CMC, purity of the capsids, et cetera? Any thoughts or, you know, let's say, empty-to-full capsid ratios, any clarity on that would be helpful.
Yeah, so we have our own manufacturing process. We have a facility in Houston, where we developed our process ourselves, and so we feel very comfortable that we're controlling the quality. Our full to empty ratio is, you know, we have a very highly pure product. It's very consistent with the industry. It's better than what I've seen other, you know, others advertise, so we also feel very, very comfortable about that. And, you know, in relation to where we are, I mean, we've had frequent discussions with the FDA. You know, we're manufacturing for commercial at the same scale that we did for phase I and phase II to reduce any sort of concerns as it relates to comparability with scale up. And, you know, we're starting PPQ, we're getting ready for commercialization already.
Because it's in our control, because we control the process, we're having conversations with the FDA, we feel pretty comfortable that we won't, you know, have a stumbling issue for CMC.
Got it. Now, you've got the 12-month data coming up sometime in Q2.
Mm-hmm.
Internally, how do you think, or what would be the best case scenario?
So we expect to be able to disseminate that data in the middle of 2026. For success, really, it's really duplicating what we've seen in the phase 1 and phase 2. We have, you know, made pretty significant strides with the 8 patients that we've presented. So we'd like to see that duplicated again. We want to see a multi-domain response and hand function, gross motor function, and communication. We'd like to see more than one, right? These patients. It's not about getting the drug approved with one skill or not. It's about getting a change in these patients that caregivers will feel comfortable is showing a difference for their parents, for their families' lives. So multi-domain, durable improvements that are consistent and accumulate over time would truly be success.
Because the threshold for success has been set with the FDA to be seven out of our 20 patients, we feel like with an 80% response rate that we have right now, that we'll be able to easily duplicate that for the phase III study.
So let's talk about that 35% response rate that's agreed upon. How did we come to that and the assumptions behind that?
So what it really, really, you know, translates to is seven out of 20 patients just translates to 35% of that population. The key to this is our sample size is 20 patients. So what does that translate to from a powering perspective? What I can tell you is, with 20 patients, and the way that the study is set up, this, this study is powered at 99%.... so we, we are powering it with a sample size to allow us to detect a benefit and feel comfortable about that.
The seven out of, I mean, seven out of 20 seems like an arbitrary number, but there's got to be a reason why seven?
I mean, there is. We have a non-intervention response rate that we leveraged in order to be able to have this discussion with the FDA. We haven't disclosed that non-intervention response rate, but I think to give confidence to people, like, to understand, that goes to the powering, right? It helps you to interpret what it is. 35% is just the minimum threshold of what you would need, seven out of 20, but when you take the non-intervention response rate, you translate it for the sample size, you can kind of come up with the powering, and what I'm just telling you is the answer is we've powered it to 99%.
So the clinical hurdle is 35%. What do you think is the commercial hurdle?
That's a great question. I think if we were just trying to get the drug approved, it's great that we have a lower threshold, but, you know, we really believe, as I said before, that caregivers are looking for profound efficacy. We know that with the profile of AAV9, no one's curing the disease, but if you only had, you know, a situation where a patient had one skill, and it wasn't a very clinically meaningful skill that you're reporting on, I don't know that caregivers would take the drug. What I'd really like to see is the same profile that we have right now.
You know, our patients are multi-domain in their improvements, and they're, you know, gaining significant skills, and what I'd love to be able to publish, you know, in the future, at the time that the drug is approved, is, you know, following these phase 1 and phase 2 patients. Our first patient is coming up on three years here this year, and of course, right below her, there'll be other patients in that three-year timeframe. What do these patients look like three years, five years out? What has changed in them globally to show us that the drug has had its full impact? That, I think, is really gonna be instrumental for the, you know, the commercial differentiation, because it's not just about getting the drug approved, it's being able to demonstrate what's happened to these patients over time.
And so, those 10 patients that we're gonna disclose, you know, what's happened to them in 12 months and above, we'll continue to follow them, and I expect that we'll be publishing on them over time to show that kind of clinical benefit.
Got it. The registration study is expected to complete enrollment in the second quarter.
Mm-hmm.
It's gonna be a 12-month follow-up.
Mm-hmm.
But, are you at a liberty to disclose the safety profile, to de-risk the program before you get to the actual pivotal readout?
I mean, yeah, I think also as a public company, it's pretty easy, right? If there's no news, it's pretty good news, right? If we had a material event from a safety perspective while we were dosing patients, we would have to disclose that. You know, there's no way to get around that. It's a one-product company where all the value is situated in that. So we might not be providing, you know, regular safety updates. You know, I don't think anybody's really doing that. But if something were to happen to a patient, we would have to disclose it.
No, but, I mean, there's likely to be a defined time course when the HLH events happen. Once you've passed that, after the last patient enrolled has gone through that time course, why not put out a press release on the safety, which kind of de-risks the program, actually?
It's something that we can consider. I mean, I'm standing up here in front of you today, and I said from the very beginning when I talked about HLH, to date, I haven't seen any signs and symptoms of HLH, so in a way, I've just sort of provided you with that update. So it really, like, to me, it's really about making sure that we're filling our obligations and not, you know, preventing disclosure. So today, I sort of did that, and the reality is, we'll be able to do that every time we get up on the stage. It's really hard to dose a patient and be able to say, "You know, you are where you are," without being able to at least detect that.
Just remember, it takes a full 5 days to know, so you don't know the day that you're dosing anybody. But again, I feel very confident, based on what we're seeing, that we don't have any concerns.
You're very close to being a commercial company.
We are.
Can you sort of give us a handle on the scale of the commercial organization? What are you doing to operationalize the whole thing?
Yeah, I mean, the good news is this is a rare disease, you know, company as it is right now, so the ability to commercialize a product in... You know, that's really, truly a centers of excellence type of product, is not gonna be the, the kind of heavy lift that I would have had when I worked in oncology or I worked in, you know, some of these other diseases. So it's something that is finite and containable. So what we're doing right now is, number one, the clinical infrastructure that we've put into place, where we are dosing patients in the pivotal study, there are 13 sites that we're utilizing. That was very purposefully done because that's about 60% of the centers of excellence for Rett syndrome in the U.S.
You can kinda see that becoming a quick conversion for Tier One sites for the commercial launch. So that we feel very, very good about. In addition to that, we've already talked about CMC. We feel very comfortable about the ability to, you know, launch out of that facility at the scale that we're in and cover the demand for the market. We have modeled this at NGN, and we feel very good about that as well. And the last thing is just preparing payers, and ourselves to be able to deal with the reimbursement. You know, we have to have a patient hub. We're gonna have to be able to have a reimbursement, patient-cent, patient-centric, organization to be able to do that, and that's already is part of the plan.
You know, we have our T-minus 30 plan already underway, so we're getting prepared, and we feel comfortable that we'll be able to commercialize the product.
Is there-
In the U.S., I'm talking about right now, to be very, very clear.
So that leads me to the next question: Is there a life in Europe for NGN-401?
We think so. I think the European regulators are a little bit more. You know, we think the regulators here are complicated. I think the European regulators are even more complicated, especially as it comes down to single-arm trial designs. So we're gonna work through that with the regulators, you know, over time. We do think that the strong efficacy profile of this drug, it's not unheard of that sometimes you get a drug, you get it approved, and then you bring the file over to the European Union. And so right now, all eyes are on the U.S., developing a very strong, you know, file for the U.S., the BLA submission, and working with the regulators in the background in Europe to be able to determine how to bring that file forward.
Awesome, and unfortunately, we have run the clock. Thank you so much, Christine.
No, thank you. It's good to see you.
Looking forward to the data, and hoping for a very productive year ahead.
Thank you, Debjit.
Thanks so much.