My name is Ted Tenthoff. I'm a senior biotech analyst at Piper Sandler, and before I begin, I'm required to point out certain disclosures regarding the relationship between Piper and our next presenting company, CAMP4, which are presented at the back of the room and also at the registration desk, so, as you may know, CAMP4 is developing a novel modality called regulatory RNAs, or regRNAs, and what they do is they design antisense oligos, excuse me, that target these regRNAs in order to bind them, and in that process, upregulate gene regulation to treat haploinsufficiencies. Here with us today from CAMP4 are my good friends, Kelly Gold, CFO, and also Josh Mandel-Brehm, who's the President and CEO. Thank you, guys, for being with us, so maybe you can start out by describing this.
I did like a, you know, a budget, like 30,000-foot job of trying to describe what you're actually doing. But tell us in a little bit more detail, you know, what are these doing? What are regRNAs doing? Their typical function.
Got it. Yep, I'll take this one. So first principles that we all know, every gene uses a promoter and either one or a set of enhancers to control its expression. As it turns out, typically there's one or two enhancers that dominate expression. What we've since followed up on is that those same promoters and enhancers make RNAs. Those are called regulatory RNAs. And based on the work of our founder, Rick Young, out of the Whitehead Institute, we have since learned that those RNAs form a very important role in controlling the expression of a gene that is housed in the same loci as those enhancers and promoters. We know that every gene relies on its own unique set of regulatory RNAs to control the expression.
The big contribution from CAMP4 has been that when you drug these regulatory RNAs in very specific locations on their three-dimensional structure, you can essentially have an increase in a nearby protein-coding gene that is very specific. Now, it's not tenfold. It's around twofold, which is perfect for haploinsufficient diseases where you're essentially down twofold from what you would otherwise need to be to be normal. So that's the CAMP4 platform is any cell type where you wish to know regulatory RNAs and the genes that control. We map out those cell types, and essentially we turn gene regulation into an analytical exercise. We have it all on our computer. We can pull it out. We can show you everything you want to know about the gene.
That allows us to move very efficiently with antisense oligonucleotides, which are, I think, very, very good in terms of when you want to design something and when you want to make it to essentially run a screen and get very quickly to a development candidate that can increase gene expression and go into a particular disease to essentially restore a missing protein.
Yep, that's really helpful. Now, I'm going to start with CMP-002. This is sort of more of where you guys are focused going forward. I know you're really excited about this. Maybe you can start by describing what SYNGAP1-related disorders are and how you're able to target regRNAs to treat this disease.
Come up again. Okay. So I would say, actually, SYNGAP1-related disorders is a bit of a misnomer. They call it that because the SynGAP Research Fund initially wanted to make sure it touched all different types of patients that have a SYNGAP1 disorder. But in reality, it is a very homogeneous population. So SYNGAP1 itself is a protein that is critical to synaptic function. It essentially controls trafficking. And essentially, if you do not have enough SYNGAP1 protein, you have too many AMPA receptors in your synapse, meaning you get too much synaptic firing. Your synapses get very tight. As a consequence of having too much synaptic firing, you get seizures, you get learning disabilities, you get an inability to sleep, motor problems, all types of other issues that arise from the fact that your synapses are not firing properly.
That in and of itself is the biology behind SYNGAP1. The actual population of patients, about 80% of SYNGAP1 patients have a missense mutation, which means they are truly haploinsufficient. They only make 50% of what would otherwise be normal amounts of protein, and you get the consequences I just told you about. Another 18%-19% have truncated mutations. They, too, are pretty similar, have a slightly different phenotype, but are also pretty sick. They are haploinsufficient. And then there's about 1% of the population which they have an intermediate mutation called 75% level or 1.5-fold increase if you wanted to kind of direct that towards what's the threshold. These patients are still very sick, although they are more responsive to medications. They have some verbal acuity, and they can essentially go to some schools and not be institutionalized later in life.
So therefore, it's really SYNGAP1, but it's called SYNGAP1-related disorders for those reasons.
Josh, how many of these patients are there? I know the epidemiology is a little bit quirky. You guys are probably doing some of the first real work to try to understand this. What's the patient path? How are they diagnosed?
You want to tackle that?
Sure. So it's really in one main path to diagnosis today. I will say this is a relatively newly characterized disease. So, you know, the path to diagnosis today would vary materially to someone getting diagnosed even a decade ago. But right now, what starts to happen is these children within the first couple of years of life, they start to miss milestones, they start having seizures, and then eventually they'll be referred for a genetic epilepsy panel, and SYNGAP is on that panel. So that's the path to diagnosis today. We have spoken with families of older patients who had a far less linear path, if you will, and actually went through a couple of misdiagnoses of other genetic epilepsies before they were appropriately identified as SYNGAP patients. But I would say that there's now very good work being done by Cure SYNGAP1.
The SynGAP Research Fund has very recently rebranded to Cure SYNGAP1. They're doing a lot of good work in support of a patient registry, natural history diseases, and so I think they've done quite a bit to raise awareness of the disease, and so the path to diagnosis now is much relative to what it was, much more linear.
Can I talk about patient numbers?
Yeah, how many are diagnosed?
Sure. So there are a few different sources we can look at. You know, there's quite a range. We've sort of triangulated and actually very recently verified this through some work with a third-party consultant. But we believe there are more than 10,000 patients in the U.S. and about the same amount globally. So if we were to contextualize that with other genetic CNS disorders, that's very similar to the size of the SMA population, just to sort of give a reference there. There's still more work being done. There are some publications that suggest that SYNGAP1-related disorders are responsible for up to 1% of intellectual disabilities, which would actually put the patient numbers at a very high number. But right now, we're very comfortable at the 10,000-patient level.
I've been really impressed and have, as a result, been understanding your excitement about this program through the preclinical data that you're generating. Walk us through some of this because I think it really stands out.
Sure, I can start and let Kelly add on. So simply said, we have shown that we could increase the SYNGAP gene starting in patient iPSC-derived cells, SYNGAP cells, through a humanized mouse model through primates. So in the haploinsufficient setting, you know, starting with patients, we've shown we can fully recover the protein levels in an iPSC-derived patient cell. In a humanized mouse, meaning we took a mouse, we inserted the human SYNGAP gene, we made a haploinsufficient version of that. It has the regulatory RNA that we are, in fact, targeting. Therefore, we can use the human drug in that setting. We showed that we could reverse all symptoms of the disease that were non-seizure cognitive issues. So Y-maze, Porsolt, Rotarod, all fully recovered versus placebo, which I think was quite profound. Those are typically very hard things to do.
I think that's the first time anybody's ever done that in that disease. Then very importantly, through the route of administration, we showed, one, we could safely increase levels of SYNGAP, but we could also do it in a statistically significant dose-responsive manner in critical regions of the brain that we believe matter for SYNGAP, and at doses that corresponded to the efficacy we saw in mice. What I'll say as a really important point is when you look at siRNAs or oligos that are used against monogenic targets in primates, those tend to always translate to success in the clinic.
So I think the combination of the data sets that we put out at ASGCT, but the fact that we're seeing the same trends that other predecessors have seen in these models in other diseases that have translated to success has gotten us very excited, has gotten the foundation excited, and has gotten investors excited.
Very cool. And when do you think you could enter the clinic with CMP-002?
We initiated GLP-tox studies in the third quarter of this year. So those are three-month studies. We believe that we can be in the clinic as early as the second half of next year. So while those studies are ongoing, we are starting to form our regulatory strategy and initiate conversations in a few different jurisdictions and are doing all the things we need to do to be prepared to mobilize as quickly as we can.
That's great. I mean, really fast from concept to the clinic and probably proof of concept data as well. Now, we talked about this a little bit in the RNA panel just downstairs a few minutes ago or half an hour ago, whatever. You guys are developing regRNA medicines for other central nervous system disorders. Why is CNS so good of a target for regRNAs?
How well were you paying attention? Go ahead.
I think what's important for every platform company is to sort of figure out the sweet spot of their technology. And I think for us, because we upregulate gene expression in an allele-agnostic way, haploinsufficiencies are the best place for us to be playing. So in that sense, as Josh said, SYNGAP1-related disorders is a haploinsufficiency. There are a number of haploinsufficiencies in the brain that are DEEs, so developmental and epileptic encephalopathies. We really do see a lot of opportunity there. A lot of the diseases that we would think of as coming behind SYNGAP, which we haven't named publicly yet, look phenotypically a lot like SYNGAP. And so it's going to be the same treating population of physicians. It's going to be very similar endpoints that you'd be thinking about for studies. And so we really look at SYNGAP1-related disorders as the cornerstone of a broader DEE franchise.
There are a lot of great opportunities there. Even going outside of developmental epilepsies, there is a lot of opportunity even in non-rare diseases, we think, in the CNS. That's a very, I would say, a very rich pool of targets for us.
You guys have been in the clinic and really generated initial safety data proving that ASOs were safe to target regRNAs with CMP-001 for urea cycle disorders. Maybe you can kind of describe this first-in-man experience, what you saw, and what your plans are for that program.
Yeah, I'll start and please jump in. You know, that was a healthy volunteer study that we've been conducting in Australia for urea cycle disorders. The underlying mechanism that we were drugging was a little bit less direct, if you will, than going after a true haploinsufficient disease. We designed that study primarily to assess safety and PK. And we did also look at PD markers. The ureagenesis rate was the primary biomarker that we were looking at there. I think, first of all, as you said, it was our first clinical study. It was well executed. And I think we sort of established ourselves as a clinical stage company through the prosecution of that program. The data that we ultimately saw, we knew that there would be heterogeneity in it because within one healthy individual to the next, the rate of ureagenesis can vary quite a bit.
And so we knew it could be difficult to glean a signal from the data. I think what we saw certainly gave us enough conviction that there is still good work to be done. We had actually put the steps in place to initiate a phase 1b study in OTC heterozygotes in the Netherlands. So we have an open CTA there right now. So we have announced that we are pausing investment in that program and are seeking a partner for the program. So we'll be jumping into that process in earnest in the early part of next year.
And I think the benefit of having that open CTA in the Netherlands, very close to a treating center of excellence for urea cycle disorders, is that we're really nicely set up for a partner to come in and do a relatively quick, inexpensive proof of concept study in a patient-like population. So as I said, we'll be focusing on that quite a bit in the new year.
You guys have partnered with BioMarin. I think there weren't a lot of disclosure around it. What can you tell us about that deal? How do you guys look to partnerships going forward to kind of expand out this pipeline and this modality?
It's true, the BioMarin relationship. They had asked that we not disclose the therapeutic area. We can say it is outside of the liver and the CNS. It's a two-target discovery deal. They nominated two genetic targets, and we did cell mapping work. We basically applied the entire platform. We did cell mapping work to characterize the regulatory RNAs of all genes expressed in the relevant cell type. Then we identified a sequence of regulatory RNA and created an oligo for them. They have two targets that we can prosecute under that collaboration. The reason I note that it is outside of the liver and the CNS is because we are solely focused on the CNS at this point.
So when we can have collaborations with partners who are going to bring targets from other areas of the body and other therapeutic areas that we would not otherwise be doing on our own, I think that's a really nice example of how partners can help us create additional value from the platform in a way that CAMP4 on its own would not be doing. And so as we think about platform-based partnerships going forward, we are thinking about similar collaborations, multi-target early discovery deals. That's really the secret sauce, if you will, of the CAMP4 platform. And so as a small company that's heavily focused on prosecuting its own genetic epilepsy pipeline, we really do look to partners to help us capitalize on additional value.
I kind of asked you this question, Josh, in the last panel, but I'll bring in the cash side of it too. I think you guys had $75 million in the third quarter, but investors have agreed to purchase an additional $50 million upon acceptance of the CTA or IND for CMP-002. How long does this fund you guys? I guess more forward-looking, what's it enable you to accomplish, and where do you see the company going over the next several years?
I'll take the first half of that. I'll let you take the second. So yes, we had $75 million at the end of Q3. That is going to comfortably fund us into 2027, but more importantly, past this milestone you just described, on which we'll trigger a second $50 million under the PIPE financing that we announced in September. The totality of the funds from that PIPE will fund us to the point of where we believe we could see some clinical POC in a phase 1/ 2 study in SYNGAP patients. So we're really excited about that next inflection point and feel that we are well capitalized to prosecute that program in the way that we believe that it should be.
Josh, and really to both of you, as you think longer term out, what do you hope CAMP4 grows up to be?
Yeah, I mean, look, I think we want to be the next on that one, and why I think that can be taken seriously is in order to have that kind of trajectory, you need a technology that can essentially show that it can work in more than one place. Ideally, the things that come behind the first indication where it works are sort of related enough that the probability of success, it should be a high probability of success. And they too should be diseases that can command a relatively large market size, and so when you really hit that hockey stick moment, if you believe all that, is when you show something de-risked in the clinic, and we are going directly into patients in a phase 1/2. We're going to have a data-rich 2027 going into 2028.
That may seem far away, but it'll come sooner than you think, and we'll have other things happening in the meantime. But when that happens, that one unlocks, if it should work, and we believe it should, it unlocks an ability to go after diseases that you should put in the likes of DMD, CF, SMA, Dravet, TTR. A lot of patients, high unmet need, nothing there before. So in and of itself, extremely valuable multi-billion dollar opportunity. But then there are multiple other opportunities that follow suit right behind it where it should be a rinse-wash-repeat. And we've shown how quickly we can move with this technology. So if you believe what I said, you believe there's three, four, five indications along the lines of like SYNGAP, that's what it takes to start to create that type of value creation.
You're not that far away from it, even though we're sitting at around $150-$200 million today. I think it's a bargain relative to where we're going to be, and we have the capital to deploy to unlock that value.
Excellent. Well, thank you both for being with us. I'm excited to see what unfolds in 2026 and beyond. Thanks so much for joining us.
Thanks, Ted.
Thanks, Josh.