Thank you everyone for joining us for the Neurogene Fireside Chat here at the 46th Annual TD Cowen Healthcare Conference. I'm covering analyst Ritu Baral, and joining me today we have founder and CEO, Rachel McMinn. Rachel, thanks for joining us today. Neurogene is developing 401 gene therapy for Rett syndrome based on your EXACT regulated expression gene therapy platform. For those unfamiliar, could you briefly walk us through the EXACT platform and how 401 is differentiated?
Sure. Well, I'll even do you one step further and just talk about Neurogene briefly first, and then we can get into EXACT. Neurogene is a genetic medicines company focused on the treatment of devastating neurological diseases. We take a disease biology understanding and approach first, so really trying to understand deeply the diseases that we're focused on so that we can develop life-altering treatments for patients with high unmet need. Our lead program, as you mentioned, NGN-401 is for the treatment of Rett syndrome, which is an absolutely devastating disorder affecting primarily girls, although there's some emerging data in boys as well that Rett syndrome is there.
This is a disease that robs children of their independence and unfortunately creates this dependence for, you know, being dependent on their caregivers for the most basic of needs for their entire lives. Really a very devastating disease with high unmet need. Large number of patients, 15,000-20,000 patients between the U.S. and Europe. You know, this really sets up a multi-billion dollar opportunity for genetic treatment in Rett syndrome. We are rapidly progressing towards potential commercialization of NGN-401. We are actively dosing, enrolling in our phase III registrational trial Embolden and look to complete enrollment of that study in the second quarter of this year, very high demand there.
We think the program has, you know, good de-risking has happened, going into this Embolden trial based on the very encouraging phase I/II trial results that we presented in November and were the basis for the Breakthrough Therapy designation that we received from the FDA, on top of other designations, but this most recent designation was based on some patient-level data as well as documented video evidence, really validating, providing that external validation on the phase I/II data on both the efficacy and the safety profile. You know, as we think about moving beyond that, Rett syndrome itself, you know, as we mentioned, large market, we're looking at payer work as well to really establish the commercialization pathway.
To answer your question, as we get to, you know, EXACT, and we'll get into points of differentiation, the EXACT platform technology was really designed scientifically to be able to control the levels of the gene of interest that is encoded into an AAV therapeutic. In this case, it's the MECP2 transgene, which we know if you have too little of the transgene, it causes Rett syndrome. If you have too much of that transgene, it can be toxic.
The EXACT system is, basically encodes a microRNA-based safety valve within the cassette, wrapped around the transgene, so that we know every cell on a cell-by-cell basis is able to have this restricted and constrained transgene expression that really allows us to avoid the harmful extremes that would be associated with an unregulated vector. Did I answer your question on-
Yes
more so.
On EXACT. No, that was perfect because we needed a background. Maybe we can actually start with one thing you alluded to, which was your Breakthrough Therapy designation, which I think you received just last week, correct?
We announced it just last week. That's correct.
Okay. You mentioned that it was based on recent phase I/II data updates, including video, and you've never released video before. Was the application based on data above and beyond, what has been presented to investors? Is the data set becoming even richer and more compelling?
Breakthrough Therapy designation does have a 60-day clock.
Mm-hmm.
You can think through the timelines here.
Mm-hmm.
It really is based on that October 30th data cut.
Okay. Got it.
I think the reason why we mentioned the video evidence is you're correct. We have not presented the videos publicly, but as you know, the video component is really important in Rett syndrome because it is part and parcel to our primary endpoint, right?
Right.
In the primary endpoint in Embolden, is video-based documentation of gain of skills and developmental milestones.
Right.
We have provided that data, and the reason we're mentioning the patient-level data is, you know, what's really incredible and one of the kind of the key messages around MECP2 restoration and what you would expect to see is that over time, as you're restoring these neural networks, that you would expect to see some gain in function, but that gain in function would occur over time. Indeed, that's what we're seeing in the phase I/II trial.
This consistent time-dependent multi-domain sort of improvement.
Exactly. You're taking the words right out of my mouth. Yeah, basically what you would expect to see is, you know, gain and function, and over time, and we are seeing, you know, in Rett syndrome, I, you know, I mentioned that it was a devastating disease, I didn't get an opportunity to explain a little bit further. You know, girls with Rett syndrome, they present normally at birth, the sort of first sign that something's wrong is developmental delay in infancy. For example, you know, instead of sitting up at six months independently, you know, at six months, you know, maybe it's at 10 months, or maybe it's at 12 months. Something is off.
Mm-hmm.
The parents are alerted, they're alarmed, they're going into the pediatrician's office, but really that heartbreak phase of the disease is during the regression period.
Where they lose skills. Yeah.
Where they actually start to lose developmental milestones. If they were using their hands to feed themselves or wave hello or just using their hands for any type of purpose, all of a sudden, you know, over a period of time, they lose that hand function, and they're no longer able to use their hands in a purposeful way. If they had words, if they were babbling, all of a sudden those words disappear, and they lose that ability. If they were kind of on the verge of walking, they just never quite are able to walk.
Mm-hmm.
They stop progressing. They stop progressing and gaining skills, but then they also lose those skills. Moving into the phase I/II data to answer your question, what we're now seeing is really that reversal, right? It's not just preserving a loss of function. We're actually improving upon.
You're not stabilizing disease.
We're not-
You're basically returning them to gaining skills which.
Right.
four or five, six-year-olds should be able to do.
...to be clear, it's not a cure.
Yeah.
We're not there yet, with this technology, but I think what we're heartened to see and what you would expect to see is that as the brain is starting to get rewired and the synapses are starting to function...
Mm-hmm
...more appropriately, that the girls are gaining these skills, and we're starting to see improvements that accumulate over time, and they're across both that hand function, that gross motor function and communication skills. It's really across the, you know, the full, you know, sort of spectrum of disease that we're seeing improvements.
Given the trial design, both the phase I/II and Embolden, how should we think about the occurrence, the rate of any skills gained, even the most basic, even the most small, in the natural history of Rett?
Yeah. As I mentioned in the natural history of Rett syndrome, you know, there's a very extensive database. Over 1,000 girls have been tracked.
Mm-hmm
...the Rett syndrome natural history study. There's been a number of publications on this data. you know, anybody who's seriously looking at Rett syndrome.
Mm-hmm
...to this data and interrogate it. It's a really rich database, and what we've been able to show, part of there's many things that are captured in this database, but one of the things that's captured is a developmental log, and it's really within that the clinicians are.
Mm-hmm
...and the caregivers are tracking, you know, when did a girl achieve a certain developmental milestone? Does she still have it? Has she lost it? If she lost it, when did she lose it?
Mm-hmm.
That data's available. We've been able to analyze it.
Is there a standard timeframe when a developmental milestone hasn't been seen that it's marked as lost?
When it's so if a girl, you know, had a pincer grasp, right?
Mm-hmm.
She was able to pick up a Cheerio for those who are thinking about...
Mm-hmm. Yep.
...what does a pincer grasp mean? you know, that's something where the clinician will ask the caregivers, you know.
Mm-hmm
...did your girl have this? Was she able to self-feed? Was she able to use a fork? These types of things. The answer will be like, they'll look at pictures. They'll, you know, kind of fill out this log of like, oh, yes, she did that, and then she lost it. In terms of that period of regression, for some patients, it happens very, very quickly.
Mm-hmm.
For others, it can be a more protracted process of it looks a little bit like a ping pong ball where, you know, things aren't quite right.
Mm-hmm.
She's not doing something consistently.
Yep.
Regression is defined really, once you're, the period of regression is over that six months from the time of the last lost skill.
Mm-hmm
...that they're stable, right? You're no longer losing skill. The girl has been stable for six months, so now you're considered post-regression, and you're in what's technically called that pseudo-stationary phase, but think about it as being kinda static.
Those skills have not been seen for six months plus.
Where the girls are like stuck.
Yeah.
They haven't been seen for at least six months.
Mm-hmm.
That's right.
Got it. In your phase I/II data, the increase from 23 to 35 developmental milestones gained across those eight patients suggested, again, as we discussed, the steepening benefit over time. How clinically meaningful are those 23 to 35 milestones gained in the context of in Rett natural history? What do you believe is driving the deepening of effect? You know, if the expression is not going up because EXACT tightly controls.
Mm-hmm
...expression, what's going on such that these girls are just gaining more and more?
Yeah. The way to I think just think about, you know, MECP2 biology is that this is a protein that is responsible for the health of a neuron over your lifetime. What we know from animal work, for example, is if you take an adult mouse and you remove MECP2. Those mice actually develop Rett syndrome.
Mm-hmm.
It's not like some other neurodevelopmental disorders where, you know, you can only express protein within a very narrow window, and then, like, afterwards, like, it doesn't matter. We know that this is critical for neuronal health. To your point is like, okay, well, if you give it, you know, shouldn't. You know, is there a world in which, you know, you just sort of gain all these developmental milestones within a few months of restoration? Why doesn't that happen? You know, the brain is pretty complicated. You know, think about stroke, think about traumatic brain injury. You know, it typically takes years for patients to recover from these types of, you know, brain injuries. In the same way, as you're rebuilding these synaptic circuits across the brain.
Mm-hmm
... you're rewiring the brain, right? You know, you think about these girls are starting to improve, but just like anything else, if they are practicing a skill.
Mm-hmm
... you can actually see deepening of a skill. You can see girls that are, like, learning. First they're following one set of instructions, and then it goes from, you know, for one patient, you know, first it was like, "Hey, give me a kiss," and you see the girl, like, lean over and give her mom a kiss.
Mm-hmm.
You're like, "Oh my gosh, that's amazing." It's like, "Hey, close the door, and put your laundry in this basket." Like, "You know, put your stuff in the trash," and, you know, "Come over here." You know, the more and more instructions...
Mm-hmm
You're seeing kind of like the girl engage, like, all the way across that, you know, from the house, and it's like she hears her name, and she's, like, coming over into the room. Like, that never happened before.
Mm-hmm.
Just like, you know, a regular child is developing over time, you know, it takes time for any child to gain skill. We don't expect the kinetics and the time course to be normalized.
Mm-hmm.
It certainly takes time, right? An infant is not born speaking. An infant is not born walking. Just in that way, over time, you know, you see this development as the brain is, you know, really growing and changing. We certainly see, you know, a gain in function. So far we have not seen any plateau.
Mm-hmm
... in terms of gain in skills. Even the skills that patients have gained, we're seeing even the quality of that skill deepen.
As in, like, they're getting better at it. Getting better.
They're getting better at it.
Yeah.
You know, for example, you know, one girl walking up the stairs, you know, the first time she achieved that milestone where she was walking up the stairs by herself, you know, she was doing it, but there was a lot of kind of coaxing.
Mm-hmm.
You know, you see her doing it again significantly later, two years later, and you're like, "Wow," like, that is fundamentally a different girl.
Mm-hmm.
She's gotten a lot better at that. It might not even show up in a number, but certainly the caregiver can, you know, can see it, and you can look at it from baseline videos and see the quality of that response deepen as well.
Rachel, it brings up a really good point, and especially one to, I think, investors keep in mind as we look at Embolden and maybe other studies, this element of encouragement and practice at home. How do you control for that sort of across families and across studies?
Because if these girls are entering or re-entering a period of neuromotor development, you know, just like we go to the gym and get strong in theory, if they are encouraged at home, if they're encouraged to try things, if they're encouraged to practice newly skilled skills gained, I think it's fair to think that they would do better with practice and encouragement than without. Is that something that can be controlled for or is a part of careful patient selection, I guess, or family selection?
Well, it's definitely both.
Mm-hmm.
As part of the trial, you know, these families are not provided with new types of treatment.
Mm-hmm.
If they have a certain physical therapy or occupational therapy regimen.
Mm-hmm
... that they are using. You know, they will continue those regimens. We are not implementing something new and trying to standardize it across all families. Everyone has different needs.
Mm-hmm.
You know, certainly the families that are participating and, look, Rett families in general, I mean, this is a very sophisticated, dedicated group of families that really want the best for their children. So they are already actively using PT and OT just to try to maintain, right?
Mm-hmm.
This is part of what happens when you have a girl with or a boy with Rett syndrome, is you're trying to do everything you can to preserve, you know, whatever muscle tone.
Mm-hmm
... and function they have. This is already being provided to these families.
To max, to probably-
The families are very committed, right? Somebody who's entering a gene therapy trial, like, they are highly educated. They want the best for their children and they are looking to try to maximize, you know, the outcomes for their children. That is... You know, whatever they had before will continue to be used and encouraged in the trial.
Got it. You mentioned no plateau seen so far.
Far we have not.
Could you encounter a plateau at one point with additional follow-up in Embolden's 12-month study so?
Look, so Embolden is a 12-month study. We certainly have not seen plateau at 12 months.
Mm-hmm.
We are gonna continue to follow these girls. Our first dose.
Mm-hmm
... will have her three-year assessment.
Yeah
This summer, that's very exciting.
Yeah.
We think that, you know, a number of stakeholders are gonna be very interested in that long-term data.
Mm-hmm.
Right? If you think obviously from a caregiver perspective, you are interested in the arc of disease, not, you know, what happens three months later.
Yeah
Really what's happening several years after treatment. We know that the payers are very interested, right?
Mm-hmm.
People want to see durability.
Durability.
The KOLs, of course, wanna be able to offer their families, you know, the most, you know, valuable treatment that they can, given the one-time nature of a gene therapy. You know, multiple stakeholders are gonna be interested even from a regulatory perspective. You know, you've seen durability become a question.
Yeah
... for certain gene therapies in the past. Following, you know, this phase I/II cohort over multiple years is gonna be really valuable information for the marketplace and for regulators.
Four or five patients, within that 12 months of phase I/II data achieved a CGI score of less than three. That's a less, less is better scale. How should we think about the relationship between milestones gained and CGI improvement?
Yeah.
I'm sorry. The CGI-I.
Yeah
stands for improvement.
CGI-I improvement.
Yeah.
Yeah. The Clinician Global Impression of Improvement, this is a scale that has been developed specifically for Rett syndrome with Rett syndrome anchors and has been employed across development of pretty much every treatment regardless of modality for the treatment of Rett syndrome. It is part of the composite endpoint of Embolden. We have both milestone gain, one of 28 milestone gains, and as well as a CGI-I improvement. What we see is that a Clinician Global Impression of Improvement, we tend to see that as either coming in concert with milestone gains or even ahead. You can have a CGI-I improvement that is observed before a full milestone has been achieved. We've seen that.
Mm-hmm.
It's always consistent with the milestone gains. It's just an extra level of rigor that allows clinicians to really, you know, weigh in on the totality of evidence of, you know, how a patient is performing in the clinical trial.
Patient number five has shown an SAE of abnormal nerve conduction findings in the past. I believe it was transient in nature. Can you elaborate what occurred clinically, how the patient actually symptomatically presented and how it resolved?
Yeah. This patient had grade II findings, so the nerve conduction test that you're talking about.
Mm-hmm
was transient and returned to normal levels. The peripheral neuropathy that is associated with that, this has been described very well, most recently in the Itvisma label.
Mm-hmm.
This is a neuropathy, that seems to be a class effect that is part of the, you know, the overall risk profile of AAV. There are symptomatic treatments for that. What I'll note with this patient.
This is, likely AAV related rather than payload related?
There may be some combination.
Mm-hmm.
we do see, you know, we've seen this across programs.
Mm-hmm.
Itvisma is the Zolgensma label, but kind of reformulated for an IT lumbar-.
Yeah. The
... administration.
The 50 call. Yeah.
It's the same, you know, the same payload that's in Zolgensma, but just, for the IT lumbar. We've seen it in ALS.
Mm-hmm
seen it in Pompe disease. We've seen it across programs.
Mm-hmm. Okay.
Not every program has it, but we're certainly seeing it across payloads.
Got it. have your safety checks to date seen any other cases? How did the clinician or family know to do a nerve conduction test? Was there, I guess, evidence-?
This is Yeah.
of this before?
This is part of the study.
Yeah.
... you know, following the 2021 FDA Advisory Committee Meeting, on AAV gene therapy, so that was some time ago. You know, going through that panel, there were a number of toxicities associated with AAV.
Mm-hmm.
You know, TMA was one of them.
Mm-hmm.
DRG. You know, there was a talk about AAV integration.
This is just a regular part of the protocol. This is not-
This is part.
Okay.
following that, you know, most programs in AAV-
Mm-hmm
... are required to have nerve conduction-
Mm-hmm
... studies.
As we look at your next data update from the phase I/II mid-2026, what would success look like to you in terms of say, additional milestones gained, additional CGI improvement response? Should we expect that responder rate to continue to increase with longer follow-up?
I mean, I think the way to think about it, we have a high responder rate already.
Yeah
right? In the first five patients, as we mentioned, we had an 80% response rate. I think, you know, most drugs don't have a 100% response rates.
Hence the ceiling. You know, at some point-
We're,
... you have to plateau 'cause you can't get past it.
Well, think about it like this. Response rate is really a gain of one milestone.
Mm-hmm
... plus an improvement on CGI-I. As we think about, you know, again, what's important to families-
Yeah
... what's important to clinicians, and payers, it's really, you know, some of the key secondary endpoints. For example, how many milestones-
Mm-hmm
... are girls gaining and are they across, you know, more than one domain? Are you seeing this, you know, really kind of global change? You know, for example, if I just kind of give you an example of, you know, patient one. You know, this is a girl at baseline where she couldn't hold on to an object for more than about two seconds. She would drop it. She could walk, but she would freeze.
Mm-hmm
... when she would walk. she couldn't follow any instructions from her caregiver. Two years out, she's gained 10 developmental milestones. we're like, "Okay, what does that actually mean?
What does it mean? Mm-hmm.
She can hold things. She can go shopping with her mom. She can pick up a fork and put it in her mouth and literally eat, you know.
Eat food
eat food off of a utensil.
Feed herself. Yeah.
and feed herself. That was unheard of before. If you would've put a fork in her hand before, she would've just dropped it instantly. She, you know, will get out of her house and go navigate a pretty complex path, stand at the car door and, you know, get in and out of the car by herself. Like, these are things that she couldn't do before.
Mm-hmm.
You know, she's able to follow these instructions, as I mentioned. The arc of who she is is totally different. Beyond the numbers, we think that's the profile that families wanna understand. Like, could that be my daughter?
Mm-hmm.
Well, what if my daughter wasn't walking? What did she look like, right? We have another girl who, you know, was not ambulatory, took two people to, like, really pull her in any way into a standing position. By nine months, she was able to stand with a lot less support.
Mm-hmm.
What does she look like two years later? These are the kinds of questions that families really have. I would encourage you to think about it like that. In terms of the data itself, just to level set, we presented data on the first eight patients.
Mm-hmm
... pediatric patients that were enrolled in the phase I/II . For this midyear update that we're gonna have, it'll be 10 patients. In that eight-patient data set, we had a minimum follow-up of six months, and one patient out to 24 months.
Mm-hmm.
Now as you think about the phase I/ II midyear, we're gonna have a full 12 months on all 10 patients.
10. Mm-hmm.
We're gonna have some patients with multiple years of therapy.
Between 24 and 36 months.
Yeah. As I mentioned, the, you know, that first patient, her third-year visit is coming up this summer, so she might not make the three year into this data set. Obviously we'll continue to follow-
Mm-hmm
and we'll have longer term data. There will be more patients going beyond a year, which, you know. What constitutes success? From our perspective, success is continuing to see the results that we're seeing, which is multiple you know, developmental milestone gains across multiple domains and just continuing to see that deepening of response over time.
We talked about Embolden, and we went through the primary endpoint of that responder analysis. How is enrollment going? You reiterated Q2 enrollment completion. As far as patient dosing, are all the sites open at this point? Are you sort of on track?
Yeah. What we've said is, you know, not only did we dose our first patient, but we dosed multiple patients before the end of the year last year.
Mm-hmm.
We were really focused on site execution, you know, getting 13 clinical trial sites active. That's really important for enrollment, but also think about that from a commercial perspective. We're 60% of the way there in terms of turning on, you know, the kind of 20, call it 20-ish centers of excellence in Rett syndrome. We know from a payer perspective and utilization perspective, if sites have experience in the registrational trial with a drug, they're more likely to be, you know, early adopters...
Mm-hmm
on treatment. That, you know, there are strategic reasons-
Yeah
... to both enroll as well as support for future commercial launch. We haven't commented further other than to say, you know, we continue to expect, enrollment to complete in the second quarter.
Mm-hmm.
The demand is quite high. You know, we're very happy with the level of enthusiasm that we're seeing from the Rett community for this trial.
How has safety with the dosed patients been? you know, investors continue to anchor on an early HLH event with a different higher dose. any Anakinra, any comments on messages from DSMB?
Yeah. Look, just to take a huge step back, we did have, you know, a very unfortunate HLH event in a three times higher dose level.
Mm-hmm
... when we were first exploring a higher dose. We did remove that dose. That was sort of step one. The second step in the process is that we included an HLH monitoring protocol as well as a treatment algorithm in the phase I/II trial. Because what we learned is that this hyperinflammatory syndrome, if it is detected early, that you can not only treat, but completely reverse any consequences of HLH. Left unchecked, it is potentially fatal.
Mm-hmm.
That was really important for us because while HLH has never been observed, you know, at lower doses that we're using now, we didn't wanna take any chances for patient safety. We've really been advocating for all gene therapy companies, not just. This isn't, you know, this is a systemic issue, meaning that we know that when gene therapy.
It's an AAV issue. Yeah
... gets into, you know, systemic circulation, that we really wanna make sure that every company is aware of this, and it's a very simple test to include in the protocol. I'm happy to report that no news is good news.
Yeah.
We have no cases of HLH. You know, we're very happy with the way things are progressing. You know, I think, clinicians and caregivers, you know, feel very well supported in this effort as well.
Another big controversy is around the fact that you have picked a conservative 12-month endpoint for your registrational study versus your competitors who indicate that they can do it with six months, that they have regulatory sign-off with six months. How do you see the evolution of benefit with Rett gene therapies? How do you see that informing the decision of month six to month 12, and do you have optionality on month six for Embolden?
Look, both companies, you know, anyone who's in gene therapy for Rett syndrome has a 12-month primary endpoint. I would start there.
Mm-hmm.
I don't think it's conservative. We have written FDA feedback saying that six months is not considered clinically meaningful. We specifically tested that, and the FDA, both in the Nicole Verdun era as well as the Vinay Prasad era, we've double-checked both sides. That has not moved.
Mm-hmm.
The FDA, as you've seen, is looking for more data, not less. Frankly, caregivers, clinicians are also looking for more data, not less. This is a disease that is lifelong debilitating. 12 months is a very reasonable endpoint in which to see change and to, you know, have an assessment of the benefit risk profile of any gene therapy for Rett syndrome. We feel it's really important to follow FDA advice on this. We feel very comfortable with the 12-month assessment.
Great. With that, we are over time. Rachel, thank you so much for the updates.
Thank you.
Looking very much forward to the midyear data. Just as a reminder to our clients out there, the IRSF Conference, the Rett Conference, is also midyear. Looking forward to seeing you there.
Thank you very much, Rachel.