Camp4 Therapeutics Corporation (CAMP) Earnings Call Transcript & Summary

Good afternoon, everybody, and thank you for joining us for our first-ever analyst event to discuss CMP-002 for the treatment of SYNGAP1. We are going to be making some forward-looking statements today as part of the discussion, and I encourage everybody to visit our public filings for more information. We have a wonderful agenda for you all today. I'm going to take some time to make some briefly prepared remarks but then you'll have the opportunity to hear from Tiara, a parent and caregiver to their daughter Kasha, about their family's experience living with SynGAP1. This will be followed by our CSO, Dan Tardiff; and our CMO, Yuri Maricich, we're going to review our preclinical data and provide an overview of our CMP Phase I/II clinical study. Next, you're going to hear from the -- CEO of Cure SYNGAP1, [ Mike Gallia ], who will share his thoughts on the importance of our Phase I/II study and how we collaborated with Mike and the SYNGAP1 community. Finally, we are quite pleased to welcome Dr. [ Stefan Avi ] of leading child neurologists and epileptologists who will provide a clinical perspective on SYNGAP1 and his views on the potential for a disease-modifying therapy. I'm then going to close with an update on our preclinical pipeline. Many of you on this call today are familiar with Camp4. But before I provide a brief update of where we are today with regards to our ASCEND study, I want to talk about the ambitions we have as a company. We built Camp4 to be a product company with a platform behind it. One that is able to continuously generate life-altering drugs for patients in need. What we have learned over the past 5 years is that we believe we can continuously design ASO therapeutics that upregulate genes, underlying diseases, to promote healthy protein expression. Our platform is broadly applicable. However, for our purposes, we are building a pipeline of upregulation therapeutics to solve genetic diseases of the brain. And I'm quite excited to have the opportunity to speak later about our newest pipeline programs after the main focus of today, that being SYNGAP1. As many of you know, we now have the approval to begin our clinical study in Australia, Argentina as well as the U.K. and we have an additional regulatory filing underway and review in the EU. Site activities are ongoing, and we have begun prescreening patients in a few regions with the expected goal of dosing the first SYNGAP1 patient during the fourth quarter of this year. Yuri is going to spend a lot more time reviewing the clinical trial design data with you. But I did want to talk about our time line for the data readout as well as our overarching goal with this trial to get an answer to, does CMP-002 represent a disease-modifying therapy for this terrible disease. This is the first of its kind therapy for this type of disease as well as its first of its kind clinical study. We're going to learn a lot along the way in terms of how and when these patients may respond to our therapy aimed to increase the expression of SYNGAP1 protein. Now we expect these top line results to be available in the first half of 2028. We the design of our clinical study may also allow us an opportunity to provide safety and pharmacodynamic updates prior to the full data readout. Where we stand today, just starting this journey, we do not know what kind of specific meaningful updates we might be able to provide or when other than the top line readout in 2028. However, we will look to provide meaningful updates on our progress when we can for the benefit of all of our stakeholders, including the investment community, and importantly, our patient, caregiver and clinician community. We are excited to embark on this new clinical development phase at Camp4, and we appreciate your willingness to spend time with us today to learn more. Now before I transition, I want to again take the Cure SYNGAP1 community and all the entire patients for their courage, bravery and collaboration to help get us to this point. We are inspired by you, and we hope we can make a big impact on you and your lives. As CEO, I have the privilege of being able to talk about SYNGAP1 to investors and companies alike. However, there are, of course, times when words and pictures on a slide do not do the disease justice. Therefore, we felt it was important for everyone listening in to have the opportunity to meet one of these brave SYNGAP1 patients. So to kick us off today, I'm pleased to introduce Tiara, a loving mother of Casa to talk about her family story living with the disease.

My name is [ Bartha Tarashuk ] I'm most known as Kasha's mom. So Kasha is a 9-year-old Syngapian, a 9-year-old little girl living with Syngapian-related disorders. I want everybody to understand that SYNGAP1 is a devastating disease. She's 9 years old and compared to a typical 9-year-old She's very far behind. Her abilities are about 12-month old, sometimes 18-month old child. But she's in the body of 9-year-old little girl. She is not able to do anything for herself, and she needs assistance with all daily living activities. She does -- she's failing on verbal. She has no words. She has a way to communicate with us. and we can understand some of her communication, but it's a very simple communication, like I want this, I want that. It feels like those kids with Singapore, they do have depth to them, the depth of thought, but they can't truly communicate. And it's because you have daily seizures because procedures are -- before she was medicated, they were every 10 minutes on EG, we observed. So it's 150 seizures today that you can't really see, we couldn't see them back then when she diagnosed 3 years old. So she has daily seizures. They're changing now as it's changing. She is not able to feed herself. She is not able to go to the toilet by herself. She's fully diaper. She needs help 24/7 with all her daily living activities. And she has also GI issues, she suffers from gas pain and acid reflex because of all the medications. She's suffering and there's nothing -- I feel sometimes there's just nothing else we can do. And there's no way with the medicine that we have available today. There's really nothing else we can do well, the biggest -- we had to change our whole life to be with my children and take care of my children, but I never imagined that I will have to completely gave up my professional career. But in our situation, I did. We just don't have any other choice. Her needs are so great and my husband will continue his career. He's a physician. It made sense for our family that he will be the one to continue and support family financially and so we just don't collapse under the weight of this disease. Kasha has trouble sleeping. So we do -- and I have to sleep. I can't be on 24/7, so he does give me the time -- the certain time during the night that he stays out with Kasha and she watches her and she has trouble sleeping. He takes care of her and I can sleep during that time. And so he had to adjust his scheduled work. He had to give up some of the work opportunities and some of the career opportunities that otherwise he would probably be able to take on we don't have a regular home. Our home is open to caregivers and therapists and we have people in our home 7 days a week. So we never have any privacy in our home. But again, it's a choice we made, so we can have some resemblance of some normalcy in our life and our younger daughter can have some normal childhood...

Right. With that, we're going to hand it over to our CSO, Dan Tardiff.

All right. Thank you for the introduction, Josh. I think it's pretty clear in watching this video of Kasha that we have very, very much focused on being able to help this patient population. So today, before we get into the ASCEND trial and before Yuri describes what we're going to be doing, I'd like to walk you through the underlying biology and the target that we're going after as well as the preclinical data that is supporting our efforts moving forward to get CMP-002 to the patient community. So here at Camp4, we are targeting non-coding regulatory RNAs to increase gene expression. So what are these RNAs. These are non-coding RNAs that are transcribed from both promoters and enhancers of all genes, and they actually help regulate transcription and they do so by binding to both positive and negative acting transcription factors and helping maintain high local concentration of these factors so that they can interact with the DNA with the promoter to help regulate transcription. Again, all genes are generating these regulatory RNAs. And we have uncovered over the last number of years that we can target these noncoding RNAs with antisense oligonucleotides to increase gene expression. And what we have found is that by targeting these reg RNAs, we influence their structure and change the proteins that they're interacting with. Ultimately, what this means is that there is an increase in gene expression. Again, importantly, there's a couple of features here that are highly relevant. One, all genes make these RNAs, they also act very specifically. So when we are targeting a regulatory RNA within oligonucleotide, we're only having an effect on the gene of interest. And also, the effect size that we get is really well suited to haploinsufficiencies, for diseases where there is about a 50% reduction in expression, and we want to bring that back towards wild-type levels. So SYNGAP1-related disorders caused by haploinsufficiency or mutations in the SYNGAP1 gene that results in about a 50% reduction in activity. SYNGAP1 is a post-synaptic protein, it is involved in regulating the insertion of receptors in the postsynaptic membrane. So what happens when there is a reduction in Snap levels, there is a stabilization of the ampa receptor at the post-synaptic membrane. This results in increased signaling, glutamate signaling and neuronal hyperexcitability. So these synapses are too strong they've matured too quickly, and this results in hyperexcitability and leads to all the different neuro phenotypes that you have seen exhibited in the video of caution. So what we are doing is we're targeting the SYNGAP1 non-coding regulatory RNA with CMP-002. The idea here is that we will restore SYNGAP1 in the post-synapse. This will normalize receptors at the postsynaptic membrane, and restore proper neuronal activity. So the data that we have generated to date establishes that targeting the SYNGAP1 regulatory RNA is able to increase expression and that this has a physiological benefit. So the data that I'm showing on this slide on the left is looking at an in vitro system. This is patient IPS-derived neurons. So we're looking at control neurons or with a wild-type sing gene in black. And then in purple is the patient IPS-derived neuron. So these cells have a mutation in a SYNGAP1 gene that results in a 50% reduction of expression, and you can see this. When we add in our CMP-002 development candidate oligonucleotide, you can see that this SYNGAP1 levels are restored towards wild time. Now we've also been able to demonstrate a similar relationship in vivo. So how are we going to look at the activity of a human-specific oligonucleotide in mice -- to do this, we turn to a humanized SYNGAP1 mouse. So this is a model in which the human SYNGAP1 gene that includes the promoter and the regulatory elements that are transcribing non-coding regulatory RNA have fully replaced the mouse gene. So there's no more mouse SYNGAP1 remaining. There's only either 2 copies of human SYNGAP or a single copy of human SYNGAP1. And you can see that comparing the black bar to the purple that there's a 50% or more reduction in SYNGAP1 protein when there's only a single copy of the human SYNGAP1. Single-dose administration of CMP-002 by intracerebral ventricular injection or ICV injection results in an approximately twofold increase in protein levels, restoring it back to wild-type levels. So this nicely shows that both in vitro as well as in the animal system, we can administer an oligonucleotide and engage the regulatory RNA target and increase SYNGAP1 protein back towards wild type levels. So what's critical as we develop CMP-002 is also to show that the increase in expression that we're achieving is having a physiological benefit. So to do that, we, again, use this humanized mouse model and looked at a wide range of phenotypes that are both neurobehavioral as well as seizures. As we heard during the video, there's a wide range of phenotypes and symptoms that these patients have. an exhibit. And by restoring SYNGAP, we would hope that we can have some impacts in a broad way across the different domains of disease. So we looked at learning if memory and motor function in the hyperactivity as some neurobehavioral assessments and phenotypes. And you can see in each case that there is a significant difference or deficit comparing the haploinsufficient SYNGAP mice compared to their wild-type to copy syngas controls. And in each case, when we administer CMP-002, we're bringing these phenotypes back towards the wild type level. So we're able to have broad-reaching improvements in these neurobehavioral phenotypes in this humanized mouse model. We also wanted to explore seizures. So seizure is a significant component of the SYNGAP1 patient experience. These mice on their own, do not exhibit over accountable motor seizures. So to assess seizures we use an inducible seizure assay using a GABA antagonist. So SYNGAP1 haploinsufficiency results in neuronal hyperexcitability and by adding PTZ or by injecting these animals with PTZ, which is a GABA antagonist or an inhibitor of inhibitory neurons this further exacerbates or makes these as even more susceptible to seizures. And the way we run a study is we give repeated administrations of PTZ every 5 minutes and then count score whether those animals have a seizure or not. And you can see that the wild-type animals in the black line with repeated administration do not exhibit any seizures. However, the haploinsufficient mice not only had a single copy of SYNGAP1 are susceptible to experiencing seizures in this induced mode paradigm. And then you can see in the teal color that administration of CMP-002 results in a statistically significant improvement and reduction in the seizure threshold in these animals. So the data shown in this slide nicely shows across multiple different phenotypes, all caused by SYNGAP1 haploinsufficiency that by administering CMP-002, targeting the regulatory RNA, increasing SYNGAP1 that we're able to have a significant improvement in a number of phenotypes. And this helps inform our future study in the clinic where we will like to look at multiple different symptoms. So now I'm going to turn to a nonhuman primate study. So all of these studies in mice nicely show that we can increase in gap protein when targeting the human regulatory RNA that the effect on protein has a benefit. But this is all with ICV dosing or again, directly into the brain. When we are in the clinic with CMP-002, the clinical route of administration will be by intrathecal or IT dosing. So it's important to us to demonstrate that we get good distribution of CMP-002 to the relevant brain regions, and that we can achieve concentrations that are having some effect on SYNGAP1 protein that would be expected to be meaningful. In addition, there's been very strong translation of showing target engagement in nonhuman primate studies with clinical studies and biomarkers as well. So on the left, what we're showing are the dose-dependent and dose linear increases in CMP-002 concentration across a number of different brain regions, various different portions of the cortex as well as hippocampus, and these are all regions where SYNGAP1 haploinsufficiency can manifest in some clinical phenotypes. So we're getting the right -- we're getting high levels in oligonucleotide to relevant brain regions. Importantly, when we look at SYNGAP1 protein levels in these regions, we see a dose-dependent and statistically significant increase in SYNGAP1 protein. Shown on the right panel is face as well as hippocampus, these are 2 regions highly linked to a number of different phenotypes that patients exhibit. And we see a nice increase in dose-dependent increase in these regions. We also see increases in other regions as well. So this data nicely shows that with intrathecal administration, we're getting enough drug to the right places that should have -- that can engage the target, increase SYNGAP1 and this supports advancement to our clinical study. So just to recap what I've said, we've identified a new regulatory RNA that targets SYNGAP1. We have identified the candid algo CMP-002, this can engage the target increased expression in patient IPS-neurons. as well as a humanized mouse. The increase in SYNGAP that we achieved has a meaningful benefit in a wide range of both neurobehavioral as well as seizure end points. And we can also administer CMP-002 by intrathecal injection, which is the clinical route of administration to get good distribution of the algo throughout the brain and the concentrations that we achieve are able to increase protein levels. So this is the data that has really made us excited about moving CMP-002 towards the clinic. And we've been working very closely with Yuri Maricich, our CMO, who is now going to discuss the ASCEND trial in more detail. Thank you.

Great. Thank you, Dan. And thank you for everyone for being here today. I'm Yuri Maricich, Camp4's Chief Medical Officer. To frame our sharing about the SYNGAP1-ASCEND Phase I/II clinical trial I'll start with some background on SYNGAP1 as a disease and review some natural history. SYNGAP1 impacts a full spectrum of neurological function with key phenotypic elements being intellectual disability in all patients, generalized epilepsy and autism-like manifestations, which include severe behavioral problems. No therapies exist for SYNGAP1 patients with current care Limited to symptom control in the form of anti-seizure Medicaid, anti-seizure and behavioral medication. Importantly, we've heard very clearly from patients' families as well as their clinicians that any benefit across the multiple domains of disease highlighted here would be significantly meaningful. There's a growing natural history data set across multiple studies that informs our knowledge of the disease and is a valuable guide for endpoint selection as well as comparison for patients who received treatment with a potentially disease-modifying therapy. As the slide outlines, there are 4 sources of this natural history, including, first, a SYNGAP1 global census that's run by Cure SYNGAP, where they've been adding now approximately 200 new patients per year since 2020. Second is the PROMISE study, which is a prospective natural history study conducted out of Penn Chop, Children's Hospital Colorado and Stanford, and Camp4 is also a sponsor of the study. The third source is a retrospective EMR cohort that's conducted and held through Citizen Health. And then fourth is the European registry, so-called [ Foray ], which also has been seeing significant growth and participation. Collectively, across these, we see over 2,500 patients characterized from the census perspective as well as real-world and registering cohorts which provide insight for guiding subsequent development as well as potential comparators. The majority of Syngapians have severe protein truncating variants in Exxon's 5 through 19, which result in haploinsufficiency with approximately 50% functional protein which is the most homogeneous and also the largest population, representing roughly 80% of all syngapians. This is the ASCEND Phase I/II trial initial target population. There are patients with PTVs in Exxon's 1 through 4, who have greater than 50% protein level. They represent only around 1% to 2% of the population. Importantly, they provide a natural biologic proof of principle where even a modest degree of increased protein expression results in a milder phenotype. Here the patients are more verbal they have fewer seizures and many can, in fact, go to special schools. And then the remaining patients are missense, intronic and/or the U.S. SYNGAP1 impacts the majority of neurologic function. The natural history data and publications have in fact replicated the phenotype described earlier and here across multiple independent natural history studies and publication. This gives us confidence in the clinical manifestations, which we are also enriching for in our trial for homogeneity. We see amongst different data sets from different studies, a recurring prevalence of symptoms, which include intellectual disability in everyone. Most individuals have epilepsy, and a very high rate of autism-like symptoms, particularly behavior also in sleep. And when we have some contact SYNGAP1 severity is also similar or higher than analog diseases. In this important analysis, which compares SYNGAP1 natural history to RET, Angelman and a collection of 40 other epilepsies. As you can see in the graphs across a number of domains. SYNGAP1 is comparable to even higher. So importantly, SYNGAP1 has some of the highest frequency of seizures, which you can see on the top left, difficult to manage autism-like behavior in the top right and then intellectual disability, where you also see particularly in SYNGAP1 neuro arrest or this like developmental plateau. So the average cognitive age of 2, but you do not see neurodegeneration and then communication impairment, where many patients are nonverbal or speak a few words. The majority of SYNGAP1 patients have epilepsy with a high frequency of seizures. SYNGAP1 has one of the highest seizure burdens among genetic epilepsies, consisting of multiple seizure types. These are patients on background antiseizure medicine treatment. The Eluvia graph that's shown here is published data, and it uses a color coding of the severity score demonstrating the frequency with patients who are actively having seizures. And I want to highlight a couple of important points. In addition to the 85% of patients receiving an epilepsy diagnosis compared to other DEs, SYNGAP1 has some of the highest frequency of seizures -- the genotype of focus of PTVs 5 through 19 have the highest rate of daily seizures among SYNGAP1 patients. And then there are multiple seizure types with nonmotor seizures being the most common, such as abson seizures, seizure pie can vary by age and then finally, SYNGAP1-specific EG signatures include changes in the alpha-thala wave. Now for a description of our ASCEND Phase I/II clinical trial. But before I get into the trial, I think it's important in framing and to underscore that we designed this following clinical trial and our iron development plans with the world's leading experts in CNS neurodevelopmental diseases, including DEs who have experienced studying as well as treating patients with targeted therapy, such as ASOs and gene therapies. They are on the front lines in conducting clinical trials and other related diseases as well. The ASCEND trial protocol was developed in close collaboration with them as well as the SYNGAP1 patient community and early input through scientific advice from regulators. Furthermore, we've built relationships with expert drug developers experienced in ASO drug development and other diseases. Thus, this trial design, including our dosing approach has been cleared to proceed by 3 regulatory regions, which we'll discuss further. I think also it is important to keep in mind throughout that we are the pioneer in SYNGAP1 therapeutic development. And so thus, our trial is signal-seeking across multiple domains of disease. We are not preselecting nor committing prematurely to particular endpoints as we have the opportunity to learn and take a data-driven approach. The study goals are to demonstrate safety and tolerability to characterize pharmacokinetics and select an optimal biological dose and identify relevant endpoints that are applicable to SYNGAP1 patients to chart the path for regulatory approval. Categories assessed will include seizure, sleep, motor and gate, communication, behavior and development and cognition. The trial will be a randomized, double-blind controlled multiple ascending dose study with a 3:1 randomization and those receiving some CMP-002 will be via IT administration or a sham pinprick as a control. At the end of the study, open label extension will be offered to all eligible participants. As for the study population, we'll include a minimum of 8 participants per cohort and participants will need to be 2 or older, up to being under 18 years of age at the time of randomization with a genetically confirmed SYNGAP1-related disorder. All individuals will be required to have daily seizures and paired sleep and the inability to speak in phrases. The study periods will have 3 different stages, the first is screening and baseline period. There will then be a study treatment period with 3 doses and then a post-treatment follow-up. The study length per participant is 10 months. As far as the key eligibility criteria, key inclusions are the age, as we discussed, H2 to under 18, genetically confirmed SYNGAP1-related disorder with protein truncating mutations in Singapore 19 the haploinsufficiency phenotype, which includes intellectual disability as well as inability to speak in phrases, sleep disturbance that are consistent with affluent sufficiency. All individuals must have refractory epilepsy, which includes daily seizures despite at least 1 ongoing antiseizure medication in a prior trial that leased to ASMs and they must be stable on their ASM regimen at baseline. Key exclusions are non-truncating variants such as on Exxon's 1 through 4 or uncertain significance. Other CNS diseases that are unrelated to SYNGAP1, unsafe intrathecal dosing and any other clinically significant lab abnormality. This is a schematic that will help visualize the 3 periods of the trial. So you can see starting on the left, the baseline period where there's screening followed by a minimum of 4-week assessment to really help us set a firm baseline on which to make comparisons. Then those who are confirmed in their eligibility will go into the treatment period, where you can see 3:1 randomization with 3 doses given over a 3-month treatment period. and then individuals who participate will move into a follow-up period where there will be multiple time points of assessments over 6 months. In terms of transitioning from the first cohort to subsequent cohorts after 2 doses in a participants, all safety data will be reviewed. And upon review by the safety review committee, then the dosing can begin in the next cohort. Throughout the trial, there will be a daily seizure diary, side effect and medication review. There'll also be numerous safety and functional assessments across multiple domains disease that we'll talk about momentarily, and there'll be actigraphy prior to each study visit to help assess sleep. Now we'll double-click on some of the key assessments. There are multiple validated instruments that are going to be important for assessing categories of SYNGAP1, including behavior, development, communication and motor function. These are measures that have been used in other neurodevelopmental disease therapeutic trials and also utilized for regulatory decision-making. These assessments map to the domains of disease that have been found to be important in the natural history of SYNGAP1 and are themselves being utilized in one or more of the natural history studies, thus providing a potential comparator. So you can see, for example, that across scales, such as the Bayley, the Vineland, we actually are able to assess multiple domains. And so through this series of validated assessments, we're able to collectively assess across those domains that are important in SYNGAP1. We're utilizing the gold standard methods for assessing seizure and sleep, which include multiple methodologies. First will be Video EG, which is common across both domains. For seizure, there, we are also utilizing seizure diaries and the seizure-related impact assessment scale so-called Sirius. And then for sleep, there, we are using the children's sleep habits question here as well as actigraphy on top of the Video EG. So this will allow dual methods for measuring key sleep metrics. And you can see in the inside on the right that 4 EG measures will be assessing multiple parameters that will continue to provide deeper insights into the patient population as well as the impact of CMP-002. This is a global trial. With the goal to enable collaboration with the leading experts across the world as well as to support recruitment and agility in executing as well as moving beyond our Phase III. We'll have 11-plus sites across 9 countries and 5 regulatory regions. We have 4 sites in regulatory regions that are already approved to initiate the trial. And 7 EU sites that are part of the review by the EU. We already have a strong execution track record with those 3 regulatory regions cleared to initiate the trial, in the U.K., Argentina and Australia. Before I conclude, I would like to take a moment to share on a personal note, how excited and motivated we are at camp. Personally, I've had the true privilege to meet with the leading experts around the world and the SYNGAP1 community. I met SYNGAP1 patients now across multiple continents, with a multitude of different genotypes, where their families have invited me into their homes, share their experiences and struggles and just generously invited me to spend time with them and their Syngapian. You've heard earlier from Viana and Kasha story, and you'll hear shortly from Mike Gralia. I'm so grateful for the trust that the community around the globe has shared with myself and my camp for teammates. We become deeply knowledgeable because of the sharing. And we've requested and received feedback on our developmental plans, our protocol and how to set up and conduct a patient-friendly trial from the patient community. Camp4, we're on a mission to develop a medicine for individuals with SYNGAP1 and their families. As you've seen, this is a multifaceted disease. And so we've heard from the patient community and their physicians that they have nothing. And so even impacting 1 domain of disease could be transformative. In conclusion, as we've shared, Camp4 is pioneering SYNGAP1 development. We have clearly defined Phase I/II study goals. And as the pioneer, we're signal seeking with multiple domains of disease and multiple potential comparisons from baseline between groups and natural history to demonstrate signal and measure success. SYNGAP is a severe lifelong disease with consistent natural history data across multiple studies to guide our development. We've partnered with the leading experts, the patient community. We're signal-seeking across all the domains of disease where there are validated measures or assessments. We expect to have first patient dosed by year-end and top line readout is targeted for first half of 2028. With that, I would like to introduce Mike Gralia, who's the CEO of Cure SYNGAP1. Cure SYNGAP1 community has really played a pivotal role and so I think it's important to hear from him.

My name is Mike Grallia. My wife, Ashley Evans and I founded Cure SYNGAP1 8 years ago, on our son, Tony, was diagnosed with SYNGAP1 at the age of 4, today he's 12. When he was diagnosed, we called around, we went to all the usual places. There are a handful of great scientists working on SYNGAP1, but there weren't enough great scientists working on SYNGAP1. And there were no companies. There were 0 companies with SYNGAP1 on the pipeline. We created the organization and we tried to basically make SYNGAP1 tractable, investable and then try it already. But at the minimum, where we were starting with derisking the disease so that companies like yours could come along and bring your expertise and develop therapies for SYNGAP. So having a child brain never gets out of 2 years old, while having seizures and not sleeping, and et cetera, et cetera, et cetera, it is the whole family gets diagnosed and the burden is -- I'm not even going to touch the way the education system fails and the group housing, the failures just keep coming. And people just do not appreciate the burden on families day 1 when they're little in cute and you're trying to help them. But these things mount and grow as their bodies mountain and grow, and it's a huge -- the unmet need is endless, and I could talk about this for hours, but it really is important that we get a disease-modifying therapy, the kind that you are developing because sleep, seizures, behavior, intellectual disability, not diapering. You can't medicate all these things we have been working for 8 years to put the natural history in place, to put the EEG knowledge in place to identify scales that made sense. And we brought all that to help inform your clinical trial design as well as actively giving you feedback on everything from how the day should look to the level of support our patients require. And we've been grateful both that you asked in the first place and that you've taken on board what we said. People are jumping out of their seats. I get a call every week should I move to Australia. And I say, no, stay there. Just wherever you are, stay there. Any of the trial is probably coming to you. there's patients in Australia who are probably going to getting into that trial first because they know the PI. Like calm down is what I've been telling people, but there's tremendous excitement, right? It's our responsibility to our children and to all the kids who have yet to be diagnosed because we know there's thousands out there who haven't been diagnosed yet to contribute to these trials to take part if we're able and to make sure that we figure out if CMP-002 can work, it can help our kids. And so we are committed to doing whatever work is required to giving this drug a fair shake in a rigorous trial. And I think that starts with education, making sure people understand what's involved in the trial, what placebo is, why we need placebo, awareness, telling everybody, we're already kind of all over that, but we'll keep doing it. Support to families who are in process, giving them whatever they need through our own patient support people as well as making sure you guys have things in place and also expectation management. So we're excited for this partnership, both because we have a great working relationship with Camp4, and we want the drug to be successful, we need to be successful. And this is -- there's a much bigger opportunity here for SYNGAP globally to show that humans are rescuable.

Great. So before we go to the fireside chat, Dan and Yuri, we just have a question that came in through the webcast for you. So given that your initial ASCEND trial stops at age 18, what does Camp4's preclinical data show about whether this regulatory RNA upregulation can successfully reduce or control intractable seizures in a young adult brain?

Right. So I can start here. So we have shown in younger animals that we are able to engage the regulatory RNA target that we can increase in gap and we can reduce seizures, along with all of the additional neurobehavioral phenotypes. In terms of the age of onset. These children are typically diagnosed around the ages of 2 or 3, we're able to intervene at that point. And then there's also evidence that even later on an older animals in preclinical studies that intervening at older ages as well is able to reduce a number of different phenotypes. So it seems that they're across a broad range of ages there is an ability to intervene. But I think clearly, the data that we've generated and the -- based on the natural history as well, we're certainly going to prioritize administration of CMP-002 to younger patients.

I'll just maybe add very briefly that I think importantly, as Dan mentioned, there's no evidence at present that there is some kind of limited therapeutic window in SYNGAP1. And furthermore, the natural history does not show neurodegeneration. In fact, it shows more of a neuro rest or plateau with actually very gradual improvements over time. So you do see the ability to continue to potentially have new skills or learning. And so this, coupled with the preclinical data that Dan referenced gives us, I think, some insight that there may be the potential to intervene beyond pediatric population. The Ascend Phase I/II clinical trial is starting in individuals under 18. But we -- this is an area where I think as we get more natural history, we'll think about where do we go in the future.

Great. And just one more before we go to the fireside chat. What clinical outcomes do you hope to improve with CMP-002 and which endpoints will be used to assess treatment efficacy. For example, seizure burden, communication and language, cognitive function behavior, sleep or daily functioning.

Yes. I think importantly, we are the pioneer here. This is the first potential disease-modifying randomized clinical trial. And so we're signal seeking. And we've heard also very clearly that impacting any of those domains would be really transformative for the patients as well as the families. And clinicians have reinforced this view. So I think there's a lot of different places we can go, and we want to be data-driven. We don't want to pre-commit to any particular endpoints. And so that's why wherever there are endpoints we think, that are able to be assessed and are meaningful, and we're going to measure those. And lastly, I'll point out the things that we're assessing are also being assessed in the natural history data. So we have data that can support the use of those assessments and as well a potential comparator.

Great. Thank you, both. So, I think we can go to the fireside chat now.

Great. So it's my great honor to introduce Professor Stefan Avin, who is a pediatric neurologist and epileptologist. He recognized for his expertise in developmental and epileptic encephalopathies. His work really bridges translational neuroscience across clinical development but also regulatory science. He's co-authored more than 350 publications. He's advised over 30 pharmaceutical and biotech companies on developing innovative both anti-seizure and importantly, in relevant disease modifying therapies for rare neurological disorders. Professor Avin is also the Deputy Editor of the ILAE Journal, Epilepsia, and he served on multiple regulatory committees. And so it's my great privilege to welcome Stephan. So Stefan, thanks for taking the time to speak with us today.

Thank you. Very happy to be here.

So I have a couple of questions for Stefan that I thought could be helpful for everyone to hear. And I think we'll first kind of start broad. So Stefan, in your experience, how are new medicines and precision treatments impacting the landscape, both in neuroscience, but particularly genetic DEs. And do you think these treatment modalities seem to be increasing in clinical trials and as part of the resource for clinicians?

For a long time, I mean, in the epilepsy field and impact land, we were using treatment focusing on one single symptom that were the seizures basically. And now that we are accessing treatments that can target the mechanism of the disease, of course, we are hoping to have action not only on the symptoms that are the seizure, but what is the constitution of a meaning impact on the seizure and the nonsecure outcomes that could be behavior there could be a condition or sleep that is affecting the quality of life of these patients, there are a lot of preclinical work has been generated. But now as a clinician and investigator we are seeing more and more of this trial coming and it generates a lot of not only in the family, but also in the investigator and the pension community.

Great. that and it really has been exciting. You can kind of feel the enthusiasm at medical conferences and in talking with you and your peers. What is your experience with the ASOs? And you mentioned in terms of disease-modifying therapies, how large is the need and is there anything unique given the different modalities out there about Camp4's approach or upregulation?

What is interesting is like if you think about epilepsy and the -- a lot of the monogenic disorder, meaning they are accessible for targeted treatment targeting the gene other then is probably up to 10% of the epilepsies that we are talking here, and we are talking about the more severe one that are very important because you're not dealing with seizure and need, but also with announce outcome condition behavior and so on. There are different tools and what is kind of interesting in the Camp4 technologies like you are not switching on or off you are targeting the regulatory, meaning you can kind of do like a very fine-tuning about the change of the expression. And this change of expression is based on the normal gene. That is kind of a cool technology.

Thank you for that Stefan. So maybe let's zoom in on SYNGAP1 now. For the audience, investors, observers, what do you think is important for them to know about SYNGAP1? And then also, what are the learnings from other that you think has review to SYNGAP1?

Something that is interesting for SYNGAP1 and for all of these like needs now to what is the need of the patient and the need of the patient is based on the incidence and the prevalence of the different symptoms. What is kind of distinctive in SYNGAP1 comparisons -- like the fact that families, academia have generated a lot of naturality studies. And we are aware with a large number of patients, even it's a rare disorder what is the phenotype and what kind of symptoms the patient have to deal with and what are the priority for patient and family. Sometimes you have to run from 0, learned about like the disease and try to understand with natural history study. But the advent of data for Singapore is great, and it's very helping how to look for changing treatment, how to design a trial that is very helpful now.

I think that's something that I've been so impressed with and frankly to find you and your colleagues are doing an incredible job of encouraging participation in the natural history data, and we're seeing that in terms of the increase of people joining and participating in those types of studies? So we just talked through the first clinical trial, the ASCEND clinical trial, potential disease-modifying therapy for SYNGAP1. What are some of the important attributes about the clinical trial that you think for observers to be aware of?

I think what the important is the foundation is based on the symptoms and what are the prevalence and incidents per with key challenges because you are not developing the treatments that are just targeting figures, but you want to deal with the full disease based on the mechanism of the disease, meaning that the trial has been designed with that idea let's focus on the seizure and the nonseizures with different domain that will be assessed with different kind of validate scale and just aiming to understand the integrity, the complexity and what are the key symptoms that could merge and demonstrate that you have a signal for further demonstration of the efficacy of the content later on.

And maybe as a follow-up to that point, Stefan. So as we shared at the beginning of the presentation and time together, Snap-on's completely devastating impacts basically all aspects of neurologic function. How do you think observers should think about the proposed trial end points. And what do you think might be successful for patients in the pediatric neurology field?

I think the way to look at the trial is like the design and the different end point has been done in a way that we are not giving the chance to not capture a signal for treatment that could work just because we are not using the right endpoints. That is we are covering that in a way with -- if there is any chance that we have a signal will capture it. That is probably important I think at the stage we are -- I mean, this is the first time that we might have at this modification treatment for Snap meaning that any clinically meaningful change will be a success I mean we are in a landscape that we are -- nobody worked before, and it's probably something that is key here, any progress, any clinical significant progress will be a win for patients and the community.

Great. .And maybe I'll just ask 1 final quick question because I know you've had experience from other related trials. And you've also had first-hand interaction with the SYNGAP1 community. What have you seen that might be helpful in understanding interest and participate interest around participation and in trial and enrollment?

There is a lot of excitement both from the patient community and the investigator here at some point that sometimes I say, oh, slowdown. The expectation should not be that high. We are doing clinical trial. We are not expecting like it's a magic period. It could be, hopefully, but also this enthusiasm is meaning that the community is only aware is fully dedicated to the participants. And I mean, not taking the example of the SYNGAP1 trial because it didn't start ready. But I'm part of several Phase I/II studies. I'm receiving mail every week for family looking for giving -- having the spot in trials. And this is a landscape of the modification treatment, for targeted treatment. We receive a lot of solicitation because the family want to be part of it to move the science and like positive outcome later on.

Stefan, thank you so much for your time. It's really great. Really appreciate you sharing your wisdom and experience with myself and with everyone here today. All right. With that, we're going to turn it over to Josh, right?

Thank you very much, Yuri and Stefan. I don't think I could have said it better myself. Before I move on, I want to once again thank the Cure SYNGAP1 foundation as well as all the patients. We hope to make a big difference for you and your families. As I previewed earlier today, we have bigger ambitions at Camp4. And I want to conclude today with a sneak peek of our future pipeline, where we are focused on haploinsufficient neurodevelopmental disorders to expand on the expertise we have gained through our SYNGAP1 program. Feeling McDermott Syndrome, PMS or Shank 3 is a severe neurodevelopmental disorder caused by mutations or deletions of the Shank 3 gene, resulting in a true haploinsufficiency, making it a sweet spot for our platform technology. Just a bit about Shank 3. It encodes a postsynaptic scaffolding protein, which is critical for synapse development, maturation and maintenance. As it is a haploinsufficiency, 1 of the 2 copies of Shank 3 gene is either deleted or contains a pathogenic variant. As a result of this mutation, patients suffer from profound developmental delays, intellectual disability, autism and milestone regression. They have limited to no speech, often nonverbal and have severe motor impairment in hypotonia. Like SYNGAP1, patients have behavioral challenges and elopement behaviors. Leaving them in danger and under constant supervision. There are no approved treatments addressing the underlying cause of BMS and the standard of care is limited to symptom management. There's a notable caregiver burden and patients require lifelong constant supervision and care. It sounds quite familiar and is very similar to SYNGAP1 situation. We estimate there are at least 45,000 Shank 3 patients in the U.S. alone, including a multisite, multiyear ongoing natural history study and global registry with more than 3,500 patients included. Like SYNGAP1, it has validated disease-specific clinical scales we can leverage once in the clinic and a strong SYNGAP1 overlap in terms of KOLs and centers of excellence. Based on emerging data, we are pleased to be able to announce Shank 3 a new pipeline program that we're intending to advance towards DC nomination in 2027. Behind that, we have 2 other DEE haploinsufficiency programs that we look forward to talking to you in the coming year. We will also talk more about the Shank 3 program and share data in the coming months. And with that, I'd like to conclude today's prepared remarks and open it up to questions from our analysts. Thank you very much.

Thank you, Josh. Yes. So at this time, we will be conducting a question-and-answer session with our 4 speakers. To our analysts joining us live, we kindly ask that you limit yourself to 1 question and then 1 follow-up. So please hold for a brief moment while we poll for questions. So our first question comes from Anupam Rama at JPMorgan.

Thanks for hosting this Analyst Day, super informative. I have a question for the company as well as Dr. Stefan the KOL on the line. I know everyone is going to be looking at the totality of the data as you get kind of data from the ASCEND study. But what level of seizure decline do you think is clinically meaningful? And have you heard anything from regulators on what's a clinically meaningful threshold? Or are there comps that we should be thinking about in other developmental spaces?

Thanks, Anupam, and I'll definitely after sharing my thoughts on the question, pass it over to Stefan. I think as we shared earlier, really because this is the first, we don't know what the potential magnitude of impact is, I think, also in Stefan as well can speak to this, that see impact and how it might forecast other changes that are disease-modifying can vary across different genetic epilepsies and particular DEEs. I think where the regulatory discussions have been just as an aside, have really been more around do we have all the right ways of assessing any change. And are we going to be looking at multiple ways of also kind of measuring that as well? And I think what I feel really good about, and Stefan can speak to this now, but he also mentioned as well is making sure that if there is a change, we're going to be able to assess that adequately in a reliable way that both the clinical community, but also regulators want to see. Stefan, anything you want to add?

Yes, I think -- I mean, this is also a new landscape, even for the regulatory because when you look for this most of the time, a lot of the DEE, so change in the seizures was based on motor seizures, while in SYNGAP, it's a lot of non-motor seizures, and if you look at the protocol, there are like multiple way clinically and also easy with stimulation to make sure that we are capturing the type of seizures and on motor seizures, meaning absences or myoclonic leisure or absence with myoclonic seizures that is kind of very common these patients. Coming back to my research in other, the day without seizures at something that has been associated frequently with increasing quality of life. And it's probably something that we have to think about. It's part of the assessment that has been put in the protocol, but it is the only way to measure it. Then difficult to give a number, but all the instruments are in place to show like the significance. And after that, of course, the association with changes in quality of life or daily burden will tell us what is clinically meaningful or not.

Great. Thanks for the question, Anupam. Next question comes from Steve Seedhouse at Cantor Fitzgerald.