Good afternoon, everyone. Thank you for joining the 25th Annual Needham Healthcare Conference. My name is Joey Stringer, and I'm one of the biotech analysts at Needham & Company. It's my pleasure to introduce our next presenting company, CAMP4 Therapeutics. Joining us today from CAMP4 is CFO Kelly Gold. For those of you joining us on the webcast, if you'd like to ask a question, please do so at any time. You can submit a question using the chat box feature at the bottom of your screen. With that, we'll get started. I'll turn it over to Kelly for the presentation.
Great. Thanks very much, Joey. As Joey said, I'm Kelly Gold. I'm the CFO of CAMP4. CAMP4 is, in short, using antisense oligonucleotides to upregulate gene expression. We are doing this by targeting a relatively newly identified species of RNA that we refer to as regulatory RNA. We are interested in engaging this species of RNA because it can be used to up and down regulate gene expression. We are more interested in the upregulation characteristic of this target space. Because of that, there is a universe of about 1,200 or so diseases that we can address with our platform. These are haploinsufficient diseases, so diseases where we have one healthy allele expressing a normal amount of protein and one mutated or unproductive allele. In these disease states, the patients have 50% of protein that an otherwise healthy individual would have.
What we are doing is essentially asking more of the healthy allele to produce more mRNA, enhance protein, and restore protein to a wild-type state. There are a number of areas throughout the body that we can apply the platform. We're most directly focused in the CNS right now, and our lead program is in a rare genetic epilepsy called SYNGAP1-related disorder that we'll talk about more today. We are positioned to be the first in the clinic with this program, so we're very excited about the opportunity here. More broadly, we have a CNS-focused pipeline that is looking towards expanding our opportunities into other genetic epilepsies. Just a couple of notes about the underlying biology on which our platform is built. As I said, we are targeting regulatory RNAs.
These RNAs are short, non-coding pieces of RNA that are transcribed from either enhancers or promoters during active transcription. They've been found to play a very critical role in controlling transcription by recruiting positive and negative acting factors, and as well as other factors in forming sort of a kinetic trap, if you will, to control the concentration of transcription factors in the area. What we have found is that if we can engage the regulatory RNA in a key binding site with an antisense oligonucleotide, we can actually change the tertiary structure of the regulatory RNA and interrupt the binding of a repressor element. We're essentially taking the brakes off of the system and allowing transcription to continue for a longer period of time, hence increasing the amount of mRNA produced. This is the foundational insight on which we've built our platform.
Just a quick note on how the platform works. The first step is the most important step. This is where we actually map all of the regulatory elements controlling transcription of any given gene of interest. We do all of this work in primary human cells wherever possible. We do all this work, importantly, within the four walls of CAMP4. We are not mining external databases or public databases. This is all proprietary data generated at CAMP4. Once we have identified the regulatory elements that control the expression of a particular gene of interest, we then can screen that regRNA for the most optimal binding site on the RNA and generate an ASO sequence. This is how we come up with our ASO leads. The third step is optimizing chemistry.
This is where we'll look at different backbones or conjugations depending on where we want to deliver our oligos. We are focused in the CNS at CAMP4, and so right now we are not putting conjugates on our oligos, and we're intrathecally delivering a naked oligo. Quick note on the pipeline. As I said, our lead program is in SYNGAP1-related disorders. It is still in the discovery stage, but we believe that we can enter the clinic as early as the second half of this year with this program. We also have early discovery programs in the developmental epileptic encephalopathy umbrella, of which SYNGAP is one. We have a deprioritized asset for urea cycle disorders that has completed phase I/II studies in healthy volunteers, for which we are seeking a partnership. Finally, we announced late last year that we have a discovery stage collaboration with GSK.
This is a multi-target collaboration looking across a couple of different therapeutic areas to apply our platform. We're very pleased to be working with that group. Jumping into the SYNGAP1 patient journey, we like to start off talking about what it is, what these patients and families experience. This is Tony. He was first diagnosed with SYNGAP when he was four years old after presenting with symptoms. He's now 11 years old, and, as we'll talk about, this is a really complex disease. It typically does initially present as developmental delays or seizures, but as the patient grows older, the burden on the caregiver does become quite a bit more substantial, particularly related to challenges of behavior and aggression.
SYNGAP itself is a true haploinsufficiency, so this disease is characterized by a mutation in one of the two SYNGAP alleles, and so patients present with only 50% of an otherwise normal individual's protein levels. We believe there are over 10,000 patients in the United States and about an equal amount through the rest of the world. This disease presents with intellectual disability. Seizures are a hallmark of the disease. They're certainly not the only symptom, and we'll talk about more than that. Then this disease is actually relatively newly cloned. It's been cloned in 2009, and so its awareness of the disease is certainly increasing. It's had an ICD-10 code since 2021, and so it is a newer disease, if you will, in terms of awareness. But that is certainly changing by the day. And most importantly for these patients, there are no approved disease-modifying therapies.
As I said, developmental delays and generalized epilepsy are the two sort of most significant hallmarks of the disease. However, there is a very significant burden of behavior and sleep problems. And again, as patients get older, the management of behavior issues and physical aggression become, can become very challenging for the caregiver. Many of these patients, the majority, are categorized as severe. These patients will have limited to no communication and will have a very challenging overall phenotype of the disease. There is no disease-modifying therapy on the market. CAMP4 hopes to be the first one. These patients end up being on a cocktail of drugs to manage seizures, to manage sleep, to manage mood and behavior. As you can imagine, the polypharmacy aspect of managing this disease can become very very challenging and can itself lead to secondary side effects for these, for these patients.
Because this is a rare disease, we've done quite a bit of work to map out what the diagnostic journey looks like. Because awareness is emerging, that diagnostic journey has changed quite a bit recently, but still, still is emerging. If we were to speak to patients who are older now, their caregivers will typically tell us that they take anywhere from three - five years or more to be diagnosed. This was really due to a lack of awareness and also accessibility to whole exome or whole-genome sequencing, which has become more accessible, cheaper in more recent years. What we are seeing today is that the journey to diagnosis can be, on average, about a year. This is typically starting in the early years of life. These patients will present with either seizures or developmental delays, or both.
Based on these phenotypes, they will be referred for a genetic epilepsy panel. Now, as I said, more quickly for whole-genome sequencing, which is really the gold standard for identifying, for identifying its, for identifying this disease. There are some other diseases with which these patients have historically been misdiagnosed, Fragile X, Angelman, Dravet. Again, with better awareness and more rapid testing genetically, we are able to to better identify these patients in a rapid manner. In terms of the opportunity, as I said earlier, we believe there are over 20,000 patients globally and certainly a possibility for more. I think a key hallmark of of our approach here is going to be looking at how we increase this diagnosis rate.
That will be through a combination of awareness, access to testing, and then we're seeing very influential groups start to recommend testing more rapidly in the cases of intellectual disability, autism spectrum disorder, and developmental epileptic encephalopathies. A little bit about the biology of SYNGAP itself, SYNGAP is a postsynaptic protein, and it helps control the concentrations of AMPA receptors on the postsynaptic membrane. On the left side of the slide, we're looking at the disease state, and you'll see we have a higher number of postsynaptic AMPA receptors, and it actually results in a tightening of the synapse and a more rapid firing. The baseline state for the diseased patient is a sort of higher level of neuronal excitability. CAMP4's approach is actually very very simple. We are aiming to upregulate expression of the SYNGAP protein.
By doing that, we can restore the postsynaptic AMPA levels to normal levels and result in a less excited or more normal state of synaptic excitability. There's a fairly significant opportunity in SYNGAP1, and we have become very excited about this opportunity in the last year or so. I'll go into some more details about this data, but I'll first just talk about the various genotypes of the disease. As I said, there are milder and then more severe subsets of these patients. The majority are severe. They will have mutations in exons five through 19. There is a smaller subset of patients with mutations in exons one through four, and they present with milder symptoms, albeit mild is a relative term when we're talking about a severe disease like this. Milder patients will have better communication, slightly better intellectual ability.
They may have the ability to attend special schools. There certainly is a sort of phenotypic difference between these mild and severe patients. We actually think of this milder patient population as a nice proof of concept for CAMP4's approach because they do present with higher than 50% SYNGAP protein levels. It helps validate to us that higher SYNGAP protein expression can result in an improved disease state. We have some data in a SYNGAP mouse model that I will go into shortly, as well as some data in wild-type monkeys with our clinical candidate and the clinical route of administration. This is looking at a couple of our preclinical data sets. First of all, we looked at some iPSC-derived SYNGAP patient neurons. We looked at the patient neuron versus a familial control. Here we're showing on the left-hand side, mRNA expression of SYNGAP.
You can see that the patient in the gray is expressing at 50% of normal levels. You can see that the familial control in the purple is expressing at 100%, or typical levels. You can see this turquoise line is where we applied our clinical candidate, CMP-001, and you can see that the concentration of mRNA is increasing in a dose-dependent manner. We then took this into a humanized SYNGAP mouse model. This is a mouse model in which both mouse SYNGAP genes have been taken out, and one healthy SYNGAP gene human SYNGAP gene has been introduced. This is replicating the disease state in a humanized manner. You can see here on the purple bar on the right-hand side of the slide that our homozygous control is expressing SYNGAP protein at 100% normal levels.
Our haploinsufficient mouse in the absence of our drug is expressing it actually slightly less than 50% of protein level. You can see again, if we look at the turquoise bars, that we were, in introducing our drug, able to increase SYNGAP protein production in a dose-dependent manner. We were very excited about this, but said, all right, if we can increase SYNGAP mRNA and protein, does this actually result in an impact to the disease presentation? What we found last year, which was really sort of a turning point for us with regards to this program, was that we indeed can. We looked at these humanized SYNGAP mice across a couple of different measures. We looked at learning and memory, cognition, we looked at motor function, and we looked at hyperactivity.
We can see that for each one of these measures, the gray bar being the homozygous or healthy mouse, if we look at the heterozygous in the purple, this is the diseased mouse. If we look at the corresponding turquoise bar, which is the diseased mouse with CMP-002, or clinical candidate introduced, you can see that we, in each case, were able to restore the phenotype to wild-type levels. This was really the core data set that got us really excited about investing in the program. We then went and put our oligo into wild-type monkeys through the clinical route of administration, which is intrathecal administration.
We were able to first show that at low, mid, and high doses, we reach nice concentration across multiple cortexes and the hippocampus, which are the areas that we believe are most directly implicated in the disease state, and we can increase this in a dose-dependent manner. We were also able to show that SYNGAP protein levels across the frontal cortex and the hippocampus as an exemplar here, but across other portions of the brain as well, were also increased in a dose-dependent manner. This is a nice set of data as we embark on our clinical study, hopefully in the second part of this year, where we show that we are, first of all, introducing an oligo that is well-tolerated in the wild-type monkey. We're able to achieve broad ASO distribution to the areas of the brain that we believe are most relevant for the, for the, for the disease.
We are able to increase SYNGAP protein in each of those regions of the brain. CAMP4 is positioned to be the first in the clinic for SYNGAP1. We are the most advanced in the field when it comes to exploring potential therapeutics for this disease. As I said, there are no disease-modifying therapies currently approved, and most of the disease is managed symptomatically, which is a very significant challenge for management that evolves over time. There are a couple of natural history studies. There is one in Europe, there is one in the United States, and there's also one in Australia. Across these natural history studies, there are over 1,200 patient years of data obtainable, and so we're very thrilled that so much good work has been done to establish this natural history baseline, and we certainly do intend to leverage that.
There are global centers of excellence, some in the United States, many ex-U.S. This is a very small but well-organized patient population with a very sophisticated advocacy group behind it. There is a very nice network of individuals with whom CAMP4 works closely to learn more about the disease and to partner on preparations for global studies. In terms of our path to the clinic, we have completed the in-life portion of GLP tox studies, and we believe that we can initiate a clinical study going directly into patients in the latter half of this year. In terms of our path to approval, we are right now giving a lot of thought to what endpoints can look like for this disease. While this is a seizure disorder, it has quite a bit more to it than just seizures.
We are thinking about opportunities to look at enhanced endpoints for this phase I, phase II study that would include seizure measures, but also go beyond looking at sleep measures, motor, communication, behavior, development, and others. We look at a couple of different exemplars in terms of thinking about our own regulatory path. On the seizure plus potential, we look at precedents across Dravet and other diseases. There have been some nice examples recently in Rett, Angelman, and other diseases where we've been able to think about how we might incorporate measures beyond just a seizure to show potential efficacy for our drug. Our development path, we plan to go directly into a phase I, phase II study in patients. We expect that we will be able to go directly into a MAD study. We will be looking at a population that is more severe in nature.
We believe that we can start in pediatric patients, and we are corresponding with various regulators right now to determine what those age ranges will be. We would like to be able to go as young as possible there and have defined a preclinical toxicity package that we believe can allow us to do just that. We will be doing comprehensive assessments across all of the major measures. We will be supplementing that with our learnings from the natural history study. Finally, as these patients roll through the study, we will have them rolling into an open-label extension study. That's important for two reasons. One, to offer a treatment regimen for those coming out of a placebo arm. Two, in order to be able to follow patients longer for those endpoints that may take longer to play out, such as cognition.
Again, CAMP4, we're very excited about what we're doing in SYNGAP. We believe it is a very significant market opportunity, still SYNGAP is very SMA-like, in terms of size. We're quite thrilled to be moving forward with the platform right now, not just in SYNGAP, but also in the future, working towards a larger CNS pipeline focused specifically on genetic epilepsies.
Great. Well, thank you so much, Kelly, for that excellent presentation. Once again, if you'd like to ask a question, you can use the chat box feature at the bottom of your screen. Kelly, we'll start with a few from me, if you don't mind. You mentioned the initial phase I, phase II trial, first-in-human -
Mm-hmm.
Going directly into pediatric patients.
Mm-hmm.
A bit unusual, typically, we'd go into adults first and then transition into peds. What gives you the confidence that you can do this and go directly into peds?
Mm-hmm. Yeah. Without saying too much, we're looking at a number of geographies for this study, and so we've interacted with a handful of regulators now. We are working with regulators in multiple jurisdictions to explore what would enable us to do that. We do believe that like many of these diseases, intervening earlier can be important, and so we do want to have the ability to do that. I think that this is definitely, as I was saying, an extremely well-organized patient population that has really done a lot of work to help people on their diagnostic journey earlier. I think that there are probably a lot more patients that we're going to start seeing identified in those earlier years of life, and we would like to be in a position to help those patients.
You mentioned the intrathecal dosing-
Mm-hmm.
Could you give us a sense for how you think the frequency of administration relative to some other ASOs that are in development or have been-
Sure.
Are marketed? Yeah.
Sure. We're actually using the same backbone chemistry as Spinraza.
Yeah.
We expect that we will be on a very similar dosing regimen to that drug. There is the loading period with three doses, and then once quarterly thereafter is sort of the standard regimen that we think of. I know there's a lot of work being done now.
Yeah.
At Oligo is about extending those periods of time and making them more durable. There is always opportunity to think about extending the period of time between dosing. Right now, we would imagine utilizing the regimen for which there is quite a bit of data from a safety and durability perspective for the chemistry that we're utilizing.
You mentioned there are no approved drugs.
Mm-hmm.
I'm curious, how well do these patients do on the background anti-seizure medications? Maybe as a follow-up, what is their typical baseline seizures per month relative to some other types of similar disorders?
Sure. I think probably like you've heard for a lot of diseases, or seizure-related disorders, I think anti-seizure medications sort of work until they don't. There's sort of this constant modifying the formulary, if you will. I think there is quite a bit of that sort of it seems to work and then it doesn't. We hear a lot of that from families. We also, I think, hear quite a bit about, yes, the seizures matter, but this is so much more than a seizure disease.
Mm-hmm.
That's what really matters to families. I think the sleep and behavior aspect of this disease are really significant. I think that families are really, they would love to have seizures better managed. They would really like to see other measures impacted that would improve the quality of life for the entire family, including the patient and the caregiver. In terms of number of seizures a day, there can be some variability. Certainly, we would say 10+ is not uncommon, but certainly have met families that are seeing their patient have 25 or more a day.
Yeah.
There's quite a bit of variability, but we would think of it as a fairly significant burden seizure-wise.
This particular disease, based on your mechanism of action, do you have good reason to believe that by up-regulating-
Mm-hmm.
You could improve the non-seizure aspects of the disease, such as the intellectual disability and some of the behavior aspects? Is it a matter of you have to intervene early on?
Mm-hmm.
Or, what are your thoughts on that in terms of the non-seizure-
Mm-hmm.
Possibilities there?
Yeah. No, it's a good question. Actually, our CMO actually always says this very nicely. He likes to remind us that this is a disease that is a neuroarrest disease as opposed to a neurodegenerative disease. These patients, we believe can be helped at any age with the introduction of more protein. I think we typically would think for any disease, though, particularly one of the CNS, that earlier intervention would be better. There's certainly no reason to believe that we couldn't have some sort of an impact on older patients as well.
Got it. Last question or two-part question for me is that you talked about the development path forward, given there are no approved drugs.
Mm-hmm.
What's your current thinking on a potential registrational-type endpoint?
Mm-hmm.
You mentioned it could be seizure, but maybe a composite type of-
Mm-hmm.
Endpoint. What are the pros and cons of looking just at seizure?
Mm-hmm.
Versus some of the non-seizure aspects? As a follow-up to that, what is the natural history data telling you?
Mm-hmm.
If you've had a chance to look through that on some of the best candidates for a registrational endpoint?
Yeah. We're spending a lot of time thinking about this as you can imagine. I think in terms of a path forward, I think first we really do want to think about giving this program the best opportunity for success. In our phase I, phase II study, that is the reason we'll be focusing on the more severe patient population. More broadly, I think, we're watching others. There are other very notable names right now going through this exact sort of decision-making process, if you look at the work that's being done at Stoke and Praxis. We're doing that same thought exercise. I think that a seizure endpoint is a more well-trod path from a regulatory perspective, but we certainly don't want to limit the opportunity for this potential therapeutic.
I think a lot of what we're going to be doing in the phase I, phase II study is introducing a number of exploratory measures so that we can better understand the impact of the drug and the course of the disease on those non-seizure measures. I think the outcome of the phase I/II will very strongly inform what a registrational study looks like. We also will think about post-phase I, phase II how we address mild patients. We certainly do want to address all patients.
Yeah.
Patients have a severe burden, and they really, really do in this case. We want to make sure that we're designing a development path and a regulatory strategy that will allow us to get a label to support all patients. I'm sorry, your second question, oh, the natural history study.
Yes.
The natural history study is very interesting. We do see that seizure burden sort of increases with age and then persist at a high level. That's certainly something that does not ameliorate over time. Again, that I think allows us to think about seizure as a potential endpoint. There's quite a bit more that we're seeing in terms of the natural history study. These other measures really don't improve, and in many cases, they get worse with age, behavior and sleep in particular. I think these are areas. Certainly cognition and things like that can just take more time because that's the nature of that particular endpoint. The variability on days that you measure will sometimes result in a somewhat nonlinear data set. I think that's probably been shown in a lot of diseases clinically.
If we think about sleep, for example, that's not something that would necessarily take nine to 12 months to show. That's something we believe we could see a little bit more. Right now, we really are just very eager to start our study and look at a number of these exploratory measures and get a better understanding of where we can set the program up with the highest probability of success and the broadest label in a pivotal study.
Great. Well, Kelly, thank you so much for the excellent presentation and discussion. Thanks everyone for joining on the webcast. Have a good day and good rest of the conference.
Great. Thanks so much for having us.