Innovation Conference here in Boston. I'm Delma Caiati and I'm a research analyst here at Guggenheim. It's my pleasure to welcome Josh Mandel-Brehm, the Chief Executive Officer from CAMP4 Therapeutics. It's a pleasure to have you here, Josh. Maybe, it's an exciting moment for the company because you are moving into the clinic and you expect the first patients to be dosed by the end of the year. But before jumping into the Q&A session, why don't you give us an overview of the different programs you're running, where you stand, and the key milestones that we should expect over the next 12 months or so?
Yeah, absolutely. Thank you for inviting us here. We appreciate it. Good pronunciation of the name. Most people
Oh.
don't get it right. You got it right.
I was really afraid of that.
No, you did good. That was good. So maybe just to take a step back. CAMP4 is using antisense oligonucleotides to increase gene expression. So you can think of us as the inverse of the Ionis and the Alnylam of the world, which is really a greenfield and massive opportunity. The way our technology works is by increasing genes twofold. That's where we live. And that positions us in a really good sweet spot for diseases that have a haploinsufficient nature, meaning one of the two alleles is no longer functional, and so essentially you have one functioning gene that gives you 50% of what you otherwise need to be healthy. So, that's how we think about the types of diseases that we go after. For our own purposes, we are building a pipeline of CNS haploinsufficient diseases, and that starts with SYNGAP1.
But the platform itself is broadly applicable to any tissue or any disease where you want to increase a gene. So, for example, we put in place a relationship with GSK to go after larger indications. This next year is a year of building, I think, execution. So, we are the first company to bring a disease-modifying approach into SYNGAP1, which I know we'll talk about more. So we're going to be making a lot of progress over the next year as we start dosing patients, as you correctly pointed out, and we've got into data in the first half of 2028. We've also just recently announced some new programs with SHANK3 as well, Phelan-McDermid syndrome behind that. So that'll be another thing that we're working on.
Thank you for that great overview. So maybe stepping back to the platform, can you walk us through how does it work? So how is it different from other genetic approaches? How do you identify target regulatory RNAs, and do you ensure selectivity for them, which is a critical part of, especially for genetic programs?
Yeah, absolutely. So, to start with, every protein-coding gene in our body has its own unique RNAs that control the expression. These are called regulatory RNAs. Now, what makes them very unique and special is that regulatory RNAs are specific to the protein-coding gene that they're acting on. So, every protein-coding gene has its own RNA. That RNA is not acting on many different genes. So you have built-in specificity at the genetic transcriptional level. We've chosen to use antisense oligonucleotides to drug those regulatory RNAs to maintain that specificity, because ASOs are specific as well due to the nature of their chemistry, which is RNA binding. So, we preserve that specificity for the reason you're acting, because we agree specificity is important.
What makes us really unique is that we are acting at the transcriptional level, meaning we're essentially turning the faucet on more, right at the source of the problem. Other approaches are either packaging some type of RNA or protein and delivering it, like an AAV approach, or they're acting further downstream. They're trying to essentially change things at the RNA level, if you will. We can talk more about the advantages and disadvantages of that.
Yeah, maybe following up on that point. As you were mentioning at the beginning, a key feature of your program is the ability to regulate, to increase expression up to two-fold.
How do you ensure that is enough, first of all, and considering the type of disorders you are targeting? Also, how do you ensure that you don't overshoot expression, which is always a risk when you modulate gene expression?
Yep. We have learned, because we've been doing this for so long now, that we actually never get above a two-fold increase. There's some biological reason for that, but we think that's a feature of the system, right? Because you're certainly correct that there's many diseases where overexpression would be a problem. We don't believe we have that problem just based on the biology and what we've seen so far. To turn that around, then you would ask, "Well, where is that most relevant?" As I mentioned earlier, any disease that has a loss of protein in it, if you will, is a really good place for us to start. Now, we like single-gene diseases, because those are easy to understand, if you will. It's very clear what the culprit is that's causing the disease.
Interestingly, in many of these cases, human genetics can give us a clue as to how much upregulation you actually need. In the case of SYNGAP1, probably 95%-98% of the population is haploinsufficient, meaning they only have 50% protein expression. However, there are a very small subsegment of patients that are, say, 1%-2%, they have a milder mutation that gives them about 75% instead of 50%, okay? You are halfway to being fully normal. We know that these patients are milder. They can respond to some medications. They can go to certain types of schools. Mother Nature has essentially told us that if you start to put more SYNGAP1 back into the system, it is essentially a gradient, and you are going to create a healthier way to live for patients.
Makes sense. Maybe digging more into that indication. SYNGAP1, your first clinical program, that is a very severe disorder. It is characterized by both seizures, neurobehavioral delay, problems with cognition. Maybe, what is first of all, from an epidemiological point of view, what is the target population there, and how should we think about the difficulties in diagnosing, and how is the diagnostic rate changing over time?
Yep. This is one of those rare diseases that I believe will become very important moving forward. Every three to five years, a new rare disease shows up and people start with, "I have not heard of that," and then it becomes a household name, if you will, which is a good thing for the patient organizations. SYNGAP1, I believe, will be like that. This is a disease that was discovered about 15 years ago, right? It is a single gene disease, meaning one of your two alleles is no longer functional. It has an ICD-10 code. It has a natural history study. This is all thanks to a very well-organized and powerful patient advocacy group. Really, that is, I think, the most important thing about these rare diseases. It used to be in this type of disease that you went on an odyssey.
You would have a kid, a child that had it, they did not quite know what was going on. Now, thanks to, one, just awareness, but two, whole genome screening as well as genetic panels, typically what happens is these children miss their milestones or they have seizures by the age of two or three, and they are immediately referred to what I just said, and they get diagnosed. Diagnostics went from a 10-year odyssey down to one year, right? I think that is really great. It is still massively underdiagnosed. Why is that? Well, it is just the case in rare diseases. Before you really have an approved treatment, there is sort of a lag in diagnosis. But we are very confident that there are at least 10,000, if not more, patients in the U.S. I think that has been well validated by KOLs, by secondary research.
The more we learn about this disease, the more we talk about it, the more we start talking about treatments, the more patients are coming out of the woodwork as well.
Makes sense. We spoke before about the rationale, the scientific rationale for this indication, but what about the preclinical data that you have generated? What did you learn from the different approaches you have tried, and how did that inform the phase I trial?
We are fortunate, and to give credit again to the patient organization, they really did a nice job here. They had the foresight of creating a humanized mouse model. Models are models, but as far as preclinical models go, this is a pretty good one. The way we think about things at CAMP4 is we start in vitro, like many companies. We like to work with patient-derived cells to start with, and we did that, and we saw a twofold increase. Then we went into this humanized mouse model, right, where we showed we could have a dose-dependent increase in the SYNGAP1 protein.
We also showed that we could completely reverse the symptoms of the disease. Learning and memory, cognition, anxiety, which were replicated in the mice, were completely restored when we gave them our treatment. Also we were able to create a induced seizure state, if you will, by using a chemical, and we showed we could reverse that as well. That was, I think, a very important proof of concept that you can, in fact, at least from a model perspective, have a reversal of this disease. The next thing we wanted to do was to go into primates. Primates are really interesting when you're talking about antisense oligonucleotides because they have great homogeneity with the human sequence. It turns out that our human clinical drug is perfectly cross-reactive with primates.
When we deliver the drug intrathecally, which is exactly how we are going to do it in the clinic for patients, we showed that we could upregulate the gene in a statistically significant way at doses that would be projected to be relevant in the human setting. That was very powerful for us because if you look at the history of antisense oligonucleotides, things that tend to work in primates tend to translate to the clinic as well, if not even better. I think that was very compelling from an efficacy perspective and from a safety perspective, and essentially showing that we could actually model this out and have a shot of going into the clinic with it.
And do you get broad tissue distribution-
Yeah
in the image? How important is that?
It is very important in the sense that there are certain regions of the brain you want to make sure you get to. We are using Gen2 chemistry, which is, I would call it state-of-the-art. It is the same chemistry in approved products like SPINRAZA for spinal muscular atrophy. We are not reinventing the wheel there. We are doing intrathecal delivery, which is perfectly fine for this disease and gets you right into the brain. You asked a question about distribution. We get very good distribution into the hippocampal regions as well as the cortical regions, and these are the key areas where you want to get drive expression for SYNGAP1.
Got it. Okay. Now you are moving into phase I. Where do you stand with the site activation and with the regulatory clearances, both in the U.S. and outside of the U.S.? Maybe walk us through the key features of the trial design itself.
Yep. We took a very ambitious initiative here, and what I mean by that is we wanted to take a global effort for our phase I/II study. Maybe I will just start with the study itself. We are going directly into patients. It is a phase I/II. We are going directly into a multiple ascending dose study. Every patient will have the opportunity to get three doses over the course of three months, and then there will be a six-month follow-up.
We have also put a control arm into this study. We felt that was important, so it is 3-to-1 randomization. In addition, we do have natural history data that we can leverage. There is over 1,400 years of natural history data. Lastly, all patients will have a one-month baseline run-in, so every patient will be their own control as well. So that is three different control systems we have in place.
The reason for that is, if we see a signal we like, we want to have full optionality to talk to regulatory agencies, and for that reason, we believe a control is important. From a sort of approval perspective, we went and got regulatory clearance in Australia, in Argentina, in the U.K., and now the EMEA. So that is four distinct regulatory regions, which I think just speaks to the unmet need and speaks to the fact that the study we have designed has been consistently approved across the world.
We are approaching the FDA now for the same discussions, and it is just more just following people's processes. There is no real rhyme or reason for that as well. You asked about site activation. Yes, every jurisdiction, every hospital has their own sort of process, and we are in that process, and we are looking forward to dosing the first patients.
Got it. This is a signal-seeking study, right?
Yeah.
Is it powered or no? I guess not.
It is not because we do not know the optimal biological dose yet.
Makes sense.
As you point out, we have three cohorts to start with. I should have said at least eight patients per cohort as well.
Okay.
We are safety, finding the optimal biological dose, but in order to do that, you need to see efficacy as well.
Makes sense. From an efficacy perspective, you are measuring several clinical measurements there, ranging from seizures to, I guess, behavior. When we look at the data, I guess in the first half of 2028,
where should investors focus on in particular? What matters there? What is the bar for defining clinical success and for moving forward to, I guess, a pivotal program?
Yeah. So maybe just to start with, these patients that have this disease can have hundreds of seizures a day. They cannot speak many times, so they are cognitively impaired. They have motor problems. They cannot sleep. You name it, they have it.
If you were to meet the parents of these children, they have bite marks up and down their arms because the kids are so frustrated they cannot communicate. It is a devastating disease, and it is caused by one gene that is mutated that does not make enough protein. We are assessing all of these things in the clinic. For example, seizures, which of course is an approvable endpoint, we are using EEGs as well.
So there will be an overnight stay where you can look at the EEG signals, because we know from the natural history data that the EEG signals are different in healthies than they are in patients. We also know that we can look at things like GMFM, Bayley, and Vineland to look at cognition and other types of metrics where we see separation from natural history. We are doing actigraphy, which means you wear a band to measure sleep.
All these different things we are looking at, and why are we doing that? Because we believe if we see an effect in any one of these dimensions of the disease, that is a win for the patient community and something that we can move forward. We believe the drug acting at the transcriptional level will be disease-modifying. We believe it should have an impact across all these. Nobody has ever done this before.
You used the right term, we are signal-seeking, but we get to define success. I think we will work closely with the regulatory agencies to pull that forward as we see from the data.
And maybe pushing further on that point. As you said, there is no disease-modifying therapy approved for this indication.
Yeah.
There is no regulatory precedent on what should we expect from a potential pivotal program. What's the FDA standing so far in terms of what could be the potential path that you're going to follow? Are you thinking about accelerated approval
Yeah
for instance, or for the classical double-blind trial?
Yeah.
Which kind of endpoint would you be focusing on, or would you expect to be accepted in a pivotal trial?
Yeah. I mean, look, I'm really encouraged by what we're seeing at the FDA with regards to the discussions they're having around just rare diseases writ large. I think that's a really positive thing. We're doing a lot of work. I say we, I include the patient organization with the FDA already, for example, in educating them about SYNGAP1, right? Making sure they know what it is. I think that's really important, so you don't just come in with, "Here's my disease, here's my data." It's a little too early, I think, to weigh in on what the path forward would be, beyond saying that, of course, we're going to pull the thread on accelerated approval and ask questions and try and understand, given this unmet need of this disease and that there's absolutely nothing for these patients. That goes back to our trial design.
One of the reasons we have taken a global approach, one of the reasons we are putting a control arm in, is that depending on the types of results we see, we do want to be able to have those discussions. We know just from looking at precedents that if you don't have a control, I think it's very difficult to even open the door with the FDA for accelerated approval, for example. I think we've built in really nice flexibility to create that optionality based on the data that we get.
Makes sense. Okay. Your initial data will be in the first half of 2028, right?
Right.
Shall we expect any interim readout on safety or pharmacokinetics from between now and then?
No. I mean, we are in Well, we like to under-promise and over-deliver, and so we-
That's the right way to do it.
We've told people, "The cake will be baked and ready to be eaten in the first half of 2028, and if it comes out sooner, we'll let you know." We'll give some updates along the way in terms of just the progress we're making. We think credibility is important in doing what we said we're going to do. But we're really heads down here, and we want to maintain that blind as long as possible unless there's a reason to not have it.
Got it. When we think about the commercial opportunity here, which of course includes also the potential for premium pricing, I guess. If you can give any idea of potential peak sales in this indication or at least target population. How are you thinking about that?
Yeah. I would use the word massive. I think this is a big opportunity. I do not say that lightly. I will not weigh in on the revenue other than to say if you look at this unmet need, right, and you compare it to diseases like spinal muscular atrophy, cystic fibrosis, I would argue it is as bad, if not worse, okay? In terms of the amount of patients, I think that there is at least 10,000 in the U.S., many of which, some portion of that is already diagnosed. If you just comp it out to other rare diseases that look and feel like it, to your point, you put a reasonable price on it, you start to get to something very provocative very quickly, right?
I think that is what is really important here. I think that there is a massive opportunity there, but it starts with the patients and the unmet need and having that impact there.
Makes sense. Maybe can you give us an overview of the competitive landscape?
Yeah. It is pretty sparse. We are by far furthest along. More competition is coming, and that is a good thing. What gives us an advantage is this gene itself has six different isoforms, and because we act at the transcriptional level, it is a benefit of our mechanism of action, all six isoforms get produced. Nobody knows which isoform is most important, but we do not have to solve for that because we are just keeping the natural proportion of those isoforms.
Gene therapy cannot do that, and there are no real commercial efforts there yet. There are some academic efforts. There are some splice-switching approaches that act downstream, but those have not seemed to move the needle yet. They have been in discovery for quite some time, so we cannot weigh in there. I expect there will be competition at some point, and I think that is a good thing.
But I still believe our approach is the most rational for the reason I said, which is biologically, we're just asking the gene to do a little more of what it's already supposed to be doing.
Got it. Okay, and moving now to the pipeline. You recently announced SHANK3 as a second indication. Why that one in particular, and where do you stand with that program?
Yeah, Phelan-McDermid syndrome, a haploinsufficient CNS disease caused by a single gene mutation, SHANK3. Very similar in regards to the setup for SYNGAP. 45,000 patients in the U.S. with this disease, no approved treatments. These patients have massive learning disabilities, cognition problems, all types of other issues. Sounds familiar to SYNGAP1. What I think makes it really interesting as far as the setup is, if our SYNGAP program shows that it works, this should show that it's going to work because you're doing an intrathecal delivery with an antisense oligonucleotide to increase a gene that's in the cortical regions where you just want to shift it up modestly. It should be a rinse, wash, repeat.
Our own preclinical data, it starts to look and feel like SYNGAP, but the reason we chose that disease is the biology, the unmet need, and the overlap with SYNGAP. Many of the same patient provider treaters and whatnot, and there's a few other ideas that look and feel just like that we haven't disclosed yet, but we said we're working on as well.
Makes sense. There is actually a lot of excitement also from pharma on the DEEs.
Yeah
So these developmental and-
That is right.
Have you considered the possibility, I know it is early, but of a basket trial for like a pivotal program? Are you planning to go indication by indication?
Because these are genetically distinct diseases, I think we go indication by indication because we are acting at the genetic level, which means each oligo is designed for that specific disease.
I am not sure, were you asking basket about different diseases or different patient populations?
Well, yeah, different diseases.
Okay
Like Dravet or LGS, or.
No, we're not acting at the symptomatic level, and our mechanism is really at the genetic level. I think we have to stick to distinct-
You have to stick to each of them.
Yeah.
Makes sense. Okay. From a BD perspective, you have a partnership with GSK.
How is that going, and are you considering other possible partnership for, especially for programs outside of CNS?
Yep. It's going very well. Those are the types of deals we like to do. It was announced at the end of 2025. GSK came to us with two diseases they were interested in upregulating the gene underlying that disease. One is a large CNS disease, one is a large kidney disease, so that speaks to, I think, going beyond the CNS. The deal is that we identify the regulatory RNAs and create antisense oligonucleotides to increase the gene that they're interested in. Then at some point, we hand it over, and they take over from there, and we get milestones and royalties. What we like about that is what I tell investors is, "I don't want you to pay for my platform. I want you to pay for my assets." That's what you're buying for right now.
We're going to keep the engine running through business development, which makes a lot of sense because we unlock more value there. We like to do those types of deals. We're very selfish about our own assets right now, but discovery deals, we are working towards doing a few more of those as well.
Thank you for that. Maybe in these last few minutes, what's the cash runway? How should we think about the spending rate moving forward? Yeah.
Yeah, we like to keep it tight. We have $124.5 million, $124 million, let's call it, at the end of Q3. For us, that's a lot of money. It takes us to the end of 2028. We've got to do the first half of 2028 for our SYNGAP milestone, so with that money, we can do a few different things. One is we can flip the card over for CMP-002 for SYNGAP, which is, I think, a massive value driver. We can also advance our SHANK3 program, as well as the other undisclosed programs as well. So we're really heads down and focused on that for the moment.
Perfect. Maybe there is a question I like to ask all the times, what do you think is most underappreciated about your platform?
Yeah
About the company?
Yeah, I mean, I'd give a two-part answer to that. I mean, I think if you look at our stock and our market cap relative to what I just told you, I think we are deeply undervalued, if we're right? I think there's comparable companies. I think it's very clear where the value goes if we're correct for SYNGAP, based on SYNGAP alone. But as I just told you as well, the probability of success should go massively up if we are correct about SYNGAP because the next things we're doing are exactly like this, right? The thing about antisense oligonucleotides is it's mechanical, right? Once you get to DC, you know exactly what to do to get to the clinic, and you can move pretty efficiently.
I think it's sort of once we show that this works in the clinic, I think a lot of value gets unlocked pretty quickly.
Thank you so much for that. What should investors focus on over the next 12-18 months?
Well, I mean, starting with the data readout in the 12-18 months, of course, that's a main focal point. That's a value creation one, but we're moving very quickly. As a result of that, we'll be updating as much as we can, and a lot can happen, and sometimes things can happen faster than you think.
Thank you. That was great.
Great. Thank you.
I appreciate it.