Let's focus on 401, developing 401, and gene therapy for Rett syndrome in scurrying phase I and II study. Can you talk about the unmet need in Rett, given that there is a fairly small diffuse mechanism that addresses the disease and what patients and families still need? Then we'll get to.
Sure, absolutely. Thank you very much for the invitation. It's a great pleasure to be here. Thank you, everyone, for attending. Look, Rett syndrome is a devastating, rare neurodevelopmental disease. It is rare, but not that rare. The global prevalence of the incident population is about 1 in 10,000 adults. When you think about the disease itself, the core cardinal features of Rett syndrome are severe impairments in hand function, communication, and gross motor function. There are also autonomic disturbances, including severe mood abnormalities, GI dysmotility, and there's also a seizure burden in this population. The approved treatments for Rett syndrome really do not address the mood levels. As a result of that, there's just a substantial unmet need in this population to really address the most important features, including communication, hand function, and communication, gross motor function.
These are all kind of the defining features of the disease. There is no treatment approved today that really substantially alters the disease.
Nice. Thanks, Sarah. What was the Exact platform and what sets your gene therapy approach in Rett and beyond?
Yeah. We developed the Exact platform to be able to control the amount of transgene that gets expressed in an AAV vector. Why would you want to do that? In a disease like Rett syndrome, it's really critical. Oh, yeah. It's really critical because in Rett syndrome, too little of the protein that is critical for the disease, when that happens, you get Rett syndrome.
Because in Rett syndrome, too little of the protein that is critical for the disease, when that happens, you get Rett syndrome. We also know when you get too much expression of the transgene, that is also toxic. Exact works as following. It's a platform technology that is designed to control transgene levels on a cell-by-cell basis. How does that work? There is a microRNA that is co-expressed along with the transgene. Within the transgene RNA, there is a series of recognition sites specific for that microRNA. When the two meet and the microRNA matches with the recognition sites on the transgene, that limits the ability of the transgene to be present and, as a result, delivers on a consistent level, a therapeutic level of protein on a cell-by-cell basis. Obviously, as you know, the lead program for Exact is NGN-401.
Got it. You presented very compelling interim phase 1, 2 efficacy data from the low-dose cohort 2015 last November showing consistent, durable, and what was notable was time-dependent improvements across the CGII, key CGIS severity subdomains, and the RSBQ. Before we discuss your registration plan, can you maybe highlight some key data points that were part of that presentation and the importance of those endpoints? I think that's been an investor focus, the CGII versus CGIS.
Yeah, absolutely. Let's just give a high-level overview. In November of 2024, we presented data on the first four patients enrolled in the trial. Two of those patients had 12 months or more of follow-up. To your point, there was long-term follow-up in some of these patients. As you noted, there was concordant, consistent improvements across multiple clinical domains as well as multiple clinical assessments, right, some of the scales that you are mentioning. For example, on the CGII, this is a metric that has been used historically in Rett syndrome clinical trials. CGII stands for the Clinician Global Impression of Improvement. It's where the physician is really asking, relative to a child's baseline, is she a little bit better? Is she a little bit worse? How is she doing?
All four of those subjects that we presented data on showed a much improved or a two-point improvement on the CGII. And just for reference, a one-point improvement is considered clinically meaningful, right? That just gives you a sense of what did the CGII look like. When you then go and look specifically across some of these cardinal features of diseases that we're talking about, right, the hand function, gross motor function, receptive and expressive communication, we also saw improvements there as well. If I give you some examples, right, in one of our patients, she started to begin to use a utensil. She started climbing up and down the stairs. She started following commands without gestures. These are complex skills that most girls with Rett syndrome never learn.
This skill development, and it was time-dependent, as you mentioned, this is well outside of what would be anticipated as a spontaneous change in an untreated population. If you look at another girl, she had no hand function at baseline. Following treatment, she learned the skill of being able to feed herself for the first time. On gross motor function, she was able to get up from a seated position. She also was able to follow command without gesture. You are starting to see, and on communication, she was using words with meaning, saying mama and dada. Again, something well outside of what would be anticipated in the natural history. When you go beyond that to some of the autonomic domains, all of the girls at baseline who had constipation saw that improve.
That was measured by a standard measure that's used in other clinical trials to assess constipation called the Bristol Stool Scale. The one girl who had dysphagia, which is known as somebody who has very difficulty swallowing, this girl at baseline could not swallow clear liquids without choking. On study, she was able to chew soft foods, even learned the skill of being able to feed herself for the first time. Beyond that.
Is this the patient that used the utensil?
This is Lodos 3 that I'm referring to. This is a girl who couldn't swallow, and now she's eating meatballs, soft carrots. She's able to see clinical improvements in her swallowing and then even able to feed herself an apple slice. It was thought that this girl would never even be motivated to feed herself because she had always been spoon-fed by a caregiver because of her dysphagia. When you sum all of that up, we are seeing all girls had improvements in hand function. You saw this time-dependent deepening of responses. In that way, despite the varying presentations that these girls had at baseline, I think we were encouraged to see these improvements over time.
As we think about that CGIS subdomain, what's the most important, again, not just to patients, but also families insofar as caregiving for?
Yeah. CGIS, just to kind of separate it out, CGII, we talked about it's a seven-point scale. As we talked about it, two is much improved. When you go to the CGIS, what gets confusing is it's also a seven-point scale, but it's different, right? This is the Clinician Global Impression of Severity. It's a way that a clinician is able to determine, you know, how severe is this girl? The three major.
Sort of like a static scale, versus the dynamic scale.
Yeah. CGII is much more sensitive to change because it allows the clinician to ask the global question of, is this patient, on a global basis, has she improved? You're not saying, does this specific thing improve? Whereas CGIS is much more rigid. It's not a linear scale, right? You can have somebody who has substantial gains in function, but if the girl is required to draw with a pen or have a bilateral pincer grasp, then the numerical change on the CGIS is not going to capture that type of improvement where you would capture that on the CGII. Excuse me, I just confused the two things. CGIS is not linear. It's not as sensitive to change. It's not really designed to kind of measure changes as sensitively as a CGII.
Without making promises to your pivotal design update later this year, your current discussions with FDA on what that primary endpoint or primary analysis is going to be to support approval, what you've described is qualitative. You can measure achievement of skills that are rare to achieve. However, I think we're all familiar with FDA just sort of thinking about scales with established precedent, established acceptability, established validation, whereas what you're describing is a much more sort of dynamic collection of clinical improvement data points driven by the heterogeneity of the disease, first of all, to be perfectly clear. How is FDA approaching that heterogeneity and sort of the dynamic aspect of the data versus what they're used to doing, which is scales and stats and whatever?
I think the onus is on us as a sponsor to present a credible plan. You asked a minute ago of what's important to caregivers, right, and what's important overall to the community. Maybe if we start there and then get into then, right, the FDA is interested in understanding what's important to families. We've obviously spoken to families. We've done research. There's an externally-led patient focused drug development meeting that happened a number of years ago at the PFDD. You can see in there that these families view they don't need substantial improvements for them to be. Is reasonably low because the burden of disease is just so high. This is a community that really would appreciate even incremental gains in some of these cardinal features of the disease, such as hand function, such as gross motor function, such as communication.
With that feedback and the support of KOLs as well, right, they understand what's important for this disease. It's our job as a sponsor then to kind of collate all of this information that we've gathered, collate the perspectives of the families, and present a credible plan, right? I don't think we're not going in there and just sort of throwing spaghetti at the wall. We're going in with a very clear sense of how we would analyze data, how we would measure it. In terms of the FDA process, and I think this is one of your questions, but START affords us with a clear cadence of meetings, right?
A really dynamic.
It's a dynamic set of communications, and it allows us, right, we have very clear visibility. The whole goal of START is to accelerate programs that are promising for these absolutely devastating disorders, of which obviously Rett syndrome is one of them. We're sorry, go ahead.
This is I did not tell you I was going to ask this, but it's of such importance to the investment community. Given your close communication with FDA over the past couple of years, ever since you got START designation, which was.
We announced it in June.
Yeah, right about a little over a year ago. Has that changed? With all the changes at FDA, with all of the disruption, has your cadence of START communication been any different than last year?
No. I mean, I think we're incredibly pleased with the way the program is progressing. Honestly, we couldn't be happier with.
Still no disruption to what you said.
Look, I mean, the reality is there is disruption at the FDA. I mean, I think you can see it. There were public meetings ongoing when there was a short period of time when the executive orders came out.
Right. Celia Witten has left.
Yeah, there's been some departures. Look, I think we're very pleased with the way FDA has been communicating with us. We believe that this is a program that's important. This is an area of priority for the FDA and that there is an infrastructure to be able to support this. I don't have any greater crystal ball than anybody else in this room or listening to this webcast. I think we're very happy with the program and we're happy with the.
You do have the START program, and you do have data points for interaction that I think investors don't. I think your input has been helpful.
Yeah, we're not seeing the level of disruption that I think sort of stirs this, I don't know, panic within the investment community of like, "Oh, gosh.
Or would impair your ability to keep this program moving forward at the clip that you want.
Again, I can't make any promises to what's going to happen, but certainly based on what we're seeing, we don't have any corporate impact to what we're doing.
That's very helpful. Okay.
I figured you would ask that question.
I did. I wasn't here. It comes up in every single fireside chat. It's so important for anybody working with the FDA closely. The next phase one two update, 401 update, when can we expect it? Have you commented on dosing new patients at the low dose? And if so, how far along are they?
Yeah. We haven't commented. What we've said is we did amend our protocol. I'm happy to talk about that. We amended our protocol in December of last year. We submitted that. The trial is currently enrolling. Our plan is to provide a substantive update. Just taking a huge step back because I don't think we actually got to this part of the conversation, we do plan to provide a regulatory update in the first half of this year with additional data in the second half of next year.
Got it. Will the regulatory update include updates on additional patient dosing, potential low-dose patient dosing?
So.
New patients.
Yeah. No, I mean, the way that we're thinking about a regulatory update is really just that. I think everyone who talks to Neurogene is interested in Neurogene is trying to understand what is the path to a registration trial and what does that look like. When we say regulatory update, that's what we're talking about as regulatory update. We can kind of break it into two buckets, Rachel, right? One is control strategy. That's a really important discussion of what does control look like. The other one, obviously, is primary endpoint, right? When you think about control strategy, a lot of people ask, "Are you going to run a placebo-controlled site?" Right? That's sort of the number one question.
What we've said historically and we're going to continue to say is we do not believe that a placebo design is warranted in this population. The reason why I can say that is the route of administration of delivery of our drug is ICV. On top of that, we give immunosuppression.
You can't change that.
Both of those.
You can't change to a sham.
Are either difficult, if not impossible, to blind. If you can't blind a placebo, then it doesn't actually effectuate its intended design. If you remove placebo from the conversation, what does that leave you with, right? You have two options, basically. One option is a single-arm study. The other option is some form of a delayed start trial design. Let's kind of talk about what would have to happen for either one of those. For a single-arm study, that's where the natural history analysis is going to be absolutely critical, right?
Because what you're trying to do in that case, what we're trying to do, if we were to be proposing this to the agency, would be to say, "Look, the kinds of changes that we're seeing are so outside of the realm of natural history that you're basically agreeing and negotiating with the FDA that whatever that response rate is would be relatively low and that you would be agreeing that treatment effects above and beyond that are truly drug-derived, right?" That is what is required. Because if you can't get alignment on that, then you're not going to be able to do a single-arm study. That is sort of the most aggressive case you can come up with a single-arm study and how it would work. If we're in a situation where it's like, "Look, we appreciate the data, but we need more," right?
You are in a situation of delayed start. Because in that case, just to explain to the audience what that is, you're talking about a group of patients that get randomized to treatment, another group that gets randomized to the delayed arm, meaning they come in for assessments over that period of time, and then they would get treatment after the study endpoint. It would allow you to compare treated patients versus untreated in a contemporaneous way. Either way, the whole goal is to develop a well and adequate controlled study. Either way, depending on the endpoint that you pick, you're obviously looking for that untreated group to have some sort of low response rate, if you will, right?
Historically, yeah.
That's how it feeds in. Then from a primary endpoint perspective, you guys have seen the data. We've talked a bit about the CGII data. You've seen various subdomains within the CGIS. You've seen developmental milestones. You've seen RSBQ. There's also.
Do you still report RSBQ? How do you feel? Right now, snapshot in time, how do you feel about the RSBQ?
Yeah. Just to finish up, obviously, when those endpoints are refined, then that is part of what we will be obviously discussing. In terms of the RSBQ itself, I believe the reason why you're asking is there are others. Another company in the space has said, "Look, we're not reporting RSBQ going forward." Let me just give a little bit of context. Rett Syndrome Behaviour Questionnaire, that's what it stands for. It is one of the co-primary endpoints that was used in the FDA approval of Daybue, right? The only drug of the.
The other one being the CGII.
With the other one being the CGII. From that perspective, there is precedent. What is it? It is a caregiver assessment where the caregivers are rating numerically whether their children have certain symptoms and certain behaviors. Without going into a lot of detail, there's some motor, there's some autonomic, there's some emotional. There's a bunch of different things in there. We did see improvements in the RSBQ. There are challenges with it as well, though, because it doesn't cover sort of the full suite of some of the cardinal features that we talked about. It's not without its challenges. Again, as you think about a first-in-human study, the goal of a first-in-human study, obviously, is to establish a safety profile and get a sense of what are the different endpoints that could be used as a primary.
From there, you refine that and you present that plan. I think that's really the way to think about it. Obviously, we'll talk more about what are the relevant endpoints when we're ready to talk about that fulsome update.
Let's back up a little bit to your protocol amendment. For the last update, you're moving forward with the 1E15 dose. The high dose was almost immediately discontinued after that SAE of HLH, hemophagocytic lymphohistiocytosis. You have added additional time point monitoring to your protocol. You have added ferritin, which is, I don't think I'm using the word correctly, but practically pathognomonic for this SAE. What else have you added? For those unfamiliar, maybe we'll start. For those unfamiliar, can you describe HLH, how it looks when it's occurred in Zolgensma, at least, because it's occurred a few times with Zolgensma, and how that's been managed in real life with Zolgensma and what it means for 401?
Yeah. HLH is a rare hyperinflammatory syndrome. It has been seen in a number of indications, whether it's idiopathic. It has been observed in the setting of cell therapy and much more rarely, but it has been reported in association with high-dose systemic AAV treatment.
Also post-viral infections. I think there was a NEJM article about Epstein-Barr post-Epstein-Barr.
Right. There is a broad umbrella of these hyperinflammatory syndromes. We will not get into the unique differences between different presentations. I think the point is that there have been rare cases associated with high-dose AAV treatment. At the time of the SAE, when it was ongoing for us, there were a very, very limited number of case reports. Obviously, we have done substantial work beyond that. In all cases, HLH has been associated with doses of at least 1E14 vector genomes per kilogram or higher. I know that is a mouthful, but I just want to make sure that is clear. I am going to explain why that is important in a moment. It really has not been observed at doses lower than that. There is something about this kind of higher level of dosing in the systemic circulation that is associated with these rare cases.
The silver lining on all of this, and you sort of were able to get at it, is that if you measure ferritin early, it happens to be a very sensitive marker that escalates very quickly, literally within days.
With HLH and none of the other side effects seen with gene therapies. This is what I heard at World when I was there.
Right. So ferritin is, in general, I mean, all of us have gotten our ferritin measured, right? We do not really think too much about it unless you are an older woman and you are trying to figure out whether you are anemic or something. In the setting of gene therapy or in the setting of some of these other cases in cell therapy, ferritin numbers, just to give you a sense, in the case report from Galletta et al. in 2022, the baby's normal ferritin level was 80 nanograms per milliliter. Within 48 hours of dosing, that number went to 3,000 nanograms per ml, literally 48 hours later. If you look in the HLH literature, it goes into the tens of thousands. We have even heard upwards of 40,000, 100,000. This is not a little tiny subtle thing that you are looking for.
The other thing that's really critical here, and to your point, is that it's actually reversible. If you catch it early, you can treat with either high-dose steroids or with an IL-1 receptor antagonist called anakinra, both very well tolerated, very effective. What did we do as a company? First off, we took out that 3E15 dose where we saw this case. This is where the math comes in. For those of you who are brilliant at math, if you take 3E15 VGs and you divide it by the kilogram, the weight of the patient, you're going to get into the 1E14 plus VG per kg range. We're not taking that dose forward. The first protocol change we made was take that out. The second thing that we did was say, "Okay, we're going with 1E15." Again, do the math, folks.
When you do that, you're effectively in the E13 VG per kg range. That is really important because, again, we haven't seen any cases reported or heard of or otherwise at this lower dose range. We think that is sort of the big change. Beyond that, because ferritin is such a simple, cheap, easy thing to do, we decided as a company we think it's the right thing to do. We determined that we want to have daily monitoring. Typically, within gene therapy, the first two weeks, it's pretty intense, right? There is a lot going on in gene therapy, and you want to make sure that your patients are safe. You're already drawing labs pretty regularly.
You're expecting a little bit of blood that's already being drawn.
Now, again, you're adding in a couple of extra days, two extra days in the first week to make sure, God forbid, if you started to see some sort of big jump, that you would catch it early. Because, again, everything that we've learned from talking to experts and from our own case and other cases is that if you can get in early, you're possibly reversing it. And we've certainly seen that with others. That's really the substantive change in our protocol. It's like, "Okay, we're unlikely to see it because we're at this lower dose. But let's not just leave it to chance. We want to make sure we have these extra.
You catch it.
We catch it. We treat it. All of that's baked into the protocol.
Got it. In our last minute, I want to talk about your plans to advance another product candidate from Exact. How are you thinking about that in 2025? Do you plan on remaining focused on neurodevelopmental programs? What's the strategy on picking indications going forward?
Yeah. The things that are important for Exact as a platform, as I mentioned at the very beginning, Exact is a technology that allows you to really control the level of the transgene that is being expressed. As a result, we would want to make sure to employ it in indications in which transgene overexpression is something that you would want to avoid, right? Something similar to Rett syndrome. There are indications that exist like that. Another important filter for us as a company is to make sure that these indications are commercially attractive, right? Because you can find certain indications where there's a very, very five people or something that's really rare. Those are huge needs. I don't want to disparage that. It's difficult as a company, as you know, to really make that work.
Having a commercially attractive indication is equally important as a filter.
Great. With that, we are at time. Rachel, thank you very much. We really look forward to your regulatory update because I think you'll be setting some breaking new ground and setting precedent for some of these ultra-rare diseases with heterogeneous natural.