Great. Thanks everybody for continuing on here. Happy to be moderating this discussion with CAMP4 Therapeutics. With me is Kelly Gold, the Chief Financial Officer. I've asked Kelly to give us maybe a 10-minute overview of CAMP4 and where things are at, especially with the CMP-002 program, and then I have a bunch of questions. Kelly, I think you have some slides. Please feel free to walk us through and then we'll do Q&A. Appreciate it.
Great. Thanks very much, Paul. We appreciate you having us today. I'm gonna give a very quick background on the company, and then I'm gonna dive in to talk about our 002 program for SYNGAP1-related disorders. CAMP4, for those who aren't familiar, is using oligos to upregulate gene expression. We are focusing on upregulation because there is a very large number of diseases or genetic diseases in which underexpression of a protein is the cause of the disease state. These are haploinsufficiencies in which we have one healthy allele and one non-productive allele. What we are doing with our platform is asking more of the healthy allele, if you will, to try to restore protein levels to wild type. Our lead program is in SYNGAP1-related disorders, which we'll talk about more in a moment.
It is a genetic epilepsy, and it is a very compelling opportunity from a commercial sense and also because there is very little available to these patients. We are very interested in SYNGAP1 as an anchor point for a broader DEE franchise in our CNS-focused pipeline. I'll speak a little bit just about the foundational biology of our platform. We are targeting a non-coding species of RNA that we call regulatory RNAs. These are RNAs that are transcribed from either enhancers or promoters, and they play a very direct role in essentially recruiting, activating, and repressing factors within a sort of kinetic trap, if you will, during active transcription.
What we have found is if we can engage certain important elements of the regulatory RNA with an antisense oligonucleotide, we can either evict an activator or a repressor from binding to the regRNA, and we can tune up or tune down gene expression. We, of course, are more interested in tuning up gene expression, and what we really like about our approach is that this is not an on/off switch. This is truly a tunable switch, so we can really fine-tune how much or how little of protein is being expressed. Our platform itself is done all within CAMP4's own labs within the four walls of the company.
We work in primary human cells wherever possible, and we use a suite of next-generation sequencing techniques to create terabytes of genetic data for any gene of interest that is expressed in the human body. We create these catalogs to basically understand all of the genomic features of what is being done and regulated during the active transcription process. With this very large set of genetic data, we are then able for any gene that's expressed in the human body to go in and determine, first, which regulatory RNA most directly controls expression of that gene, and second, where within that regulatory RNA we should be engaging with an oligo. For a sense of scale, regRNAs are 2-3 kilobases long. The oligos that we design are typically 19-20 base pairs long.
Once we have identified the sequence of the ASO that we would like to develop, we then go into chemistry optimization. That would be modifying backbones or putting on conjugates, depending on where we want to deliver. We, again, are primarily focused in the CNS at CAMP4, and so our oligos are intrathecally delivered naked oligos. A quick note on our pipeline. Our lead program, CMP-002 in SYNGAP1- related disorders, is currently in GLP tox studies. We believe we can move that forward into a clinical study by the second half of this year, so we're very excited about that. We do have a clinical program in metabolic disease, urea cycle disorders that we are actively out-licensing.
We also have a discovery program with GSK that we inked at the very end of 2025 focused on neurodegenerative and kidney disease. Jumping into SYNGAP1-related disorder, this is a disease that was identified really only about 15 years ago, and there's still a lot of very good work being done on this. This is a true haploinsufficiency, so these patients are generating only 50% of the SYNGAP protein that an otherwise healthy individual would. From an opportunity perspective, there are about 10,000 patients in the United States, and we believe an equal number in the EU5, and so globally, this has the potential to be a very compelling opportunity. Characterization of the disease, it's primarily intellectual disability and seizures, but there are a host of other symptoms we'll talk about in a moment.
This only received an ICD-10 code about five years ago, so still relatively newly identified from that perspective, and there are zero disease-modifying therapies for these patients. It's very easy for us to think of genetic epilepsies as being, you know, primarily diseases of seizure. Seizure is certainly a hallmark of this disease, but there is quite a bit more. As I said, developmental delays and intellectual disability in 100% of patients. Very significant behavior issues actually for these patients. The majority of them have significant sleep problems. We've spoken to parents who say their children don't sleep at all night long. Many of these patients are very limited in their communication. A number of them are completely non-verbal.
You can imagine this leads to a significant amount of frustration for the patient and for the caregiver. These kids tend to be on a host of different medications, usually some combination of anti-seizure medications, often something to regulate behavior, usually some sort of a sleep aid. The cocktail of drugs is itself quite burdensome, and the side effects just from the drugs alone can be very difficult. A quick note about identification of patients, which of course is always, you know, a challenge in rare disease. Historically, it was a very long diagnostic journey for these patients. That is starting to change quite a bit.
It now has an average time to diagnosis of about one year, and that is typically through either a genetic epilepsy panel or the gold standard, which is whole genome screening. Access to whole genome screening, of course, is becoming better and better with costs coming down and it becoming more of a standardized recommendation once a patient presents with intellectual disability. Quickly at the synaptic level, the underlying biology of the disease is we have, you know, 50% of the SYNGAP protein we should otherwise have. That results in greater expression of AMPA receptors on the postsynaptic membrane. We have tighter firing, more frequent firing, and so that results in a sort of elevated excitability at the baseline neuronal state.
Our approach is quite simple. We are restoring SYNGAP protein expression to healthier levels. This reduces the number of AMPA receptors on the postsynaptic membrane and restores neuronal excitability to normal levels. Just a couple of quick slides on the preclinical data that we found very compelling and you know caused us to really double down on developing this disease. First, preclinically in both patient lines and in humanized SYNGAP1 mouse models, we have been able to show in a dose-dependent manner that we are able to increase both mRNA expression and protein expression with our clinical candidate. More importantly, we wanted to make sure that we could actually have a phenotypic impact with this increase in protein.
In a humanized SYNGAP1 mouse model that is haploinsufficient, so this replicates the disease state, we were able to show that we can rescue the phenotype across learning and memory, motor function, and hyperactivity. This was really the key preclinical data set that caused us to sort of sit up and say that we were quite interested in moving forward with this study. Intrathecally, just a quick note, we reach very strong distribution across the brain for intrathecal administration, which will be the clinical route of administration. We also see a nice dose-dependent increase in SYNGAP protein levels in the relevant brain regions. As I said, we're moving toward the clinic in the second half of this year. A couple of notes about how we're thinking about our clinical positioning.
First, the standard of care, no disease-modifying therapies. There are a couple of really well-funded, very broad natural history studies, one of which CAMP4 will be a partner of. There's one in Europe, one in the United States. These are multi-site studies. There are over 100 patients in them. There are a very significant number of patient years of data available. These are being operated at a number of centers of excellence across the United States and Europe. As I said, we are completing our GLP tox studies right now for this program. We've completed the in life portion of this study, and we are now having regulatory interactions in service of moving forward with a phase I/II study globally. Last point about endpoints.
You know, we really do look to some of the companies that are on the leading edge of the broader genetic epilepsy field. We look at Stoke, we look at others, and certainly seizures will be, you know, a primary endpoint for our phase I/II study. We are also looking at other developmental disorders like Rett and Angelman, where we've seen regulators being very favorable in terms of looking at seizure plus. You know, seizure reduction plus some other measure, be that motor or gait, communication, cognition. Or in some cases, you know, we've seen some favorability from regulators in terms of looking at a couple of different measures on a much broader panel. We are having those conversations right now with regulators. My last slide, and then we'll pop over to you, Paul.
I think I'm right on time. Our phase I/II study that we believe we can start this year is going to be going directly into patients. We intend to start with a MAD study, so we believe there's precedent for moving straight into a MAD. We will be looking at the more severe portion of the population, which is the vast majority of the SYNGAP1 population. We plan to start in pediatric patients, ideally as young as two. Again, that is pending regulatory feedback. We will certainly be monitoring seizures, and we're thinking right now about how we're gonna monitor those seizures because some of these seizures are not easily diarized. They tend to be something that could be better monitored through 24-hour EEG or perhaps even video monitoring.
We're thinking about that right now. This will be a placebo-controlled study. We will have an-
Yeah
Open label extension study that these patients will roll into.
Okay. Great. Awesome overview. I was looking at my question list and I can nix like five of them, but.
Okay.
No, it's great. I mean, I think maybe just like one thing to start.
Mm-hmm
Seizures are their own endpoint, right, where you can have like a baseline number and look to reduce. For other clinical measures in this condition.
Mm-hmm
like a cognitive measure, for example.
Mm-hmm
Would you expect the placebo arm to improve over time? Like do these patients get better, just not in a developmentally typical way? Or like, do they
Yeah
Actually decline? Like how does that vary by age?
Yeah. No, it's a good question. You know, you know, we often describe this as a sort of neuro arrest, so it's not degenerative, but it's also not sort of delayed development. You know, typically, these patients are not going to develop intellectually past a fairly young age. You know, we wouldn't typically expect to see improvement, and I don't believe that's been seen in the natural history data as these patients get older. But, you know, there, it's, you know, there's always a possibility to see a signal in a placebo arm, as you well know.
Yeah, right.
It's not something that is sort of characteristic of the disease, natural history if you will.
Okay. Do you, from like a neurocognitive perspective, do you?
Mm-hmm
Expect to leverage a lot of the endpoints that we've gotten to know from Angelman?
We're certainly exploring those. Angelman and Rett are, we think, particularly relevant here in terms of endpoints, and so we have you know done a fairly deep dive into that study. I think we're also following Stoke very closely. I think they've had a lot of news lately, not around-
Right
just around data, but their own regulatory interactions. We think of that as a really close comparable to what we're doing.
Right
... understand, we don't just think at the end of the day about what kind of label we're going to get, we're also thinking about what's meaningful to the patient population. I think the burden here for caregivers and for patients is very significant beyond just seizures.
Yeah
You know, that's really what we're thinking about.
For sure. Okay. What about measuring sleep?
Measuring sleep is a, you know, that's a challenging one. You know, there are a few obviously wearables and things like that. We're looking at-
Can't get everybody like, oh, cool Oura Ring or something like that?
I know. I know. It's, you know, it's actually not a bad idea and probably less expensive than the other things we've been looking at.
Yeah. Yeah. Yeah.
No. It's, I think sleep is really significant. I mean, we've had a, you know, patient and caregiver come in and talk to us and, you know, this parent was talking about how one of them has to stay up all night every night. I mean, if you can imagine the toll it takes on a family. I think-
I mean, anyone who has kids can imagine that like.
Exactly
for a very short period and it's like torture.
Yes.
So.
Yeah.
Yeah.
If you can imagine that sustaining over the course of your child's life into adulthood, that alone is very significant. You know, sometimes
Right
When we talk about these measures, they sound small when we list them compared to intellectual disability or seizures, but they're quite meaningful.
No, it makes sense. Obviously sleep is like correlated with development too.
Exactly.
What do you as it relates to the like the mechanism here?
Mm-hmm
Like, if I contrast this disease to Rett.
Mm-hmm
One of the nuances with Rett that I think everyone asks the companies is, like, one, like, do you have to transduce all neurons, right? To kinda fix the genetic issue.
Mm-hmm.
and two, what's the risk of overexpression? That's with MECP2.
Mm-hmm. Mm-hmm.
Do we have answers to those questions with SYNGAP1? Like, is there risk of overdoing this mechanism?
Mm-hmm.
too, maybe touch upon a little bit more of like the biodistribution data.
Sure. Yeah. Actually I think we've explored this sort of concept of overexpression very extensively, not just with this program, but you know, we've mapped dozens of genes at this point, and we are always looking at overexpression. It seems to actually be a very nice feature of our platform and of biology, if you will, that the risk of overexpression really is very, very low. There seems to be some sort of a physiological ceiling, if you will, when it comes to engaging these regRNAs to upregulate gene expression. I think because we're leveraging sort of natural biology, there's some sort of feedback mechanism within the cell that just doesn't allow you to express tenfold what a healthy individual should.
You know, we've typically seen that we can get back up to close to or at wild type levels, but we are typically not able to get any higher than that. I think the risk there is just sort of a, I guess a, the bug is a feature, as our CEO likes to say.
Okay
... and then with regards to biodistribution, we believe, and if you think about the disease phenotype, the more relevant brain regions for this are gonna be the cortical regions and the hippocampus. You know, we can, if you were to go to our corporate presentation and look at our biodistribution data, we have really nice biodistribution throughout those regions. We're using the same chemistry as Spinraza and Tofersen. Those similarly I think have nice biodistribution data, you know, that have been published and, you know, also nice to be using chemistry for which there is a very well-established safety profile. I think overall chemistry-wise, we're quite comfortable and confident in the development candidate.
Yep. Okay. Makes sense. As you think about, like, seizure burden, and I guess it is something easy to focus on, right? Because it is, like.
Mm-hmm
measurable and more objective.
Mm-hmm.
Is this the kinda thing where most all patients have high seizure burden that would be enriched for showing a benefit, or is it, like, a separate population?
Yeah, no, I think seizures, you know, almost 90% of patients have 20-25+ seizures a day. They are quite significant. They do vary though. These aren't necessarily drop seizures that a parent would be able to observe and diarize. You know, sometimes these are going to be, you know, sort of more subtle seizures that you would certainly see on an EEG, and there's actually some interesting work being done at one center of excellence here in the United States where they're looking at EEG signatures and thinking about them as a potential biomarker. A lot of good work being done here. Yes, I think going back to the question, I think seizure reduction is the most well-established regulatory path, certainly would be meaningful for patients.
That will be the primary focus endpoint-wise, but we are looking at quite a bit beyond that.
Yep. Okay. Do you envision yourself, like, trying to power this study statistically for these endpoints, or is this gonna be more of like an exploratory trial?
I think, you know, it's a phase I/II study. We primarily just wanna show safety, some potential efficacy and, you know, understand the optimal biological dose. We're not statistically powering this as a registrational study. You know, again, we're following the field in terms of regulatory interactions and we're seeing a lot of interesting things happening, you know, in this area. You know, that's sort of the primary thinking right now, but we do believe that, you know, we'll try to work in a number of exploratory measures that will allow us to inform a registrational study post the phase I.
Okay. You, I think you said that this disease was just codified 15 years ago. Is that right?
Yeah.
Maybe talk about, like, how you've arrived at your prevalence estimates, and what do you think the diagnosis rate is right now?
Sure. Yeah. It's funny. With any rare disease, when you start trying to triangulate into a prevalence rate, you could really justify a very small number or a very large number. This is no different. In fact, there's one widely cited paper that implies that up to 1% of intellectual disability is related to SYNGAP1 disorders, which would imply a very large patient population. We've done a lot of work with external groups, looking at you know, a number of different measures that we'd sort of triangulated ourselves and validated working with a third party. You know, as we said, a little over 20,000 between the U.S. and the E.U., but of course we have been hearing from patient organizations from all over the world.
We certainly know that there is, you know, a significant opportunity here, particularly for something that's disease modifying if we sort of forecast forward and think about potential pricing for a label like that. In terms of diagnosis rates, they have been improving. You know, if you talk to a family with a teenage SYNGAP1 patient, many of them have terrible stories of no diagnosis and misdiagnosis. Autism is a common-
Yeah
misdiagnosis.
Right.
Fragile X, Prader-Willi, Angelman, these are the kind of common ones that people have been misdiagnosed with. Diagnosis rates now are kind of about a year. Typically, when a child presents with either seizures in the first couple of years of life or intellectual disability, missing milestones, they're typically referred for a seizure panel, and this does appear on an on the genetic seizure panels, or, as I said, whole genome sequencing, which I think before used to be less accessible than it is now. I think with costs coming down and it becoming more of a standard diagnostic tool, particularly in pediatric cases, we're definitely seeing diagnosis rates increase.
Are there any registries out there that give us an idea of the prevalent population right now that's under care?
Yes. Yeah. There are registries in the U.S. and the E.U. I think, you know, we find in rare disease registries are sort of a lagging indicator. You know, if you were.
Yeah
We went back and looked at the number of patients on the SMA registry when they were starting phase 1 versus how many patients are actually on drug today, and it's, you know, orders of magnitude higher. I think that we do see registries as important and, you know, but we don't look at them as a sort of a benchmark of the patient population.
Yeah. Okay. Yeah, maybe just the last thing. I wonder, are you just honing in on the phase I/II a little bit more? Like, you know, are you gonna have to really try to find a specific homogeneous population?
Yeah. Yeah. It's a good question. The majority of the patients are very severe patients. These are non-verbal kids who, you know, have all of the sort of most severe phenotypes of the disease. There's a small proportion of the population that has their mutations in exons 1 through 4, and they tend to have, like, 75% of a healthy individual's SYNGAP protein as opposed to only having 50%. They actually present as somewhat milder. They will be better able to communicate. Some of them go to special schools. You know, they. If you were to meet a severe versus less severe patient, you would see a very stark contrast. In order to set up the study for the greatest chances of success in phase I/II, we're gonna be focusing on that severe population.
We do want to ultimately be able to expand to sort of that milder population. Of course, mild is a relative term in this case. I will just also note that mild population is interesting to us because it's sort of a genetic proof of concept, if you will, that greater protein expression can ameliorate some of the symptoms of the disease.
Right
We're very interested in studying that group as well.
Yeah. Yeah. Okay. Great. We only have about 30 seconds left, but anything else you'd like to add?
No. Just that we've got, you know, some exciting milestones on the second half of this year. We're excited to come back talking to the market a little bit more about, you know, finer tuning our clinical plans and, you know, letting you all know when we've initiated.
Right. How long's your runway? Cash wise.
We have cash runway into 2028, and that excludes a $50 million PIPE tranche that we're eligible for later this year when we initiate the study.
Okay, great. All right. Well, thank you very much, Kelly. Appreciate it.
Thanks, Paul. Appreciate it.
Okay