Hey, everyone. I'm Matthew, and I'm pleased to be joined here today by CEO of CAMP4 Therapeutics, Josh Mandel-Brehm. Thank you so much for coming. Really excited to hear more about CAMP4. Maybe you can start with an introduction, and we can get to questions.
Great. Yep. Thank you for having us. I think it's our first time here, so we appreciate it. CAMP4 uses antisense oligonucleotides to increase gene expression. The way that we are able to do that is by targeting a new class of RNAs called regulatory RNAs. Every protein-coding gene in our body relies on its own unique and specific set of RNAs, called regulatory RNAs, to control its expression. We've built a platform that allows us to do two very important things. The first is for any protein-coding gene in which we're interested in increasing, we can use our platform to pinpoint the regulatory RNA that's controlling it, and then we can take advantage of state-of-the-art Gen 2 antisense oligonucleotide chemistry to very specifically drug that regulatory RNA and have about a two-fold increase in the associated protein-coding gene's expression.
Okay. Maybe we can start with your lead program, which is on SYNGAP. I guess, what was the biological rationale with starting with that?
Yeah. We've been working on this for a bit over six years, and I think the trick with every platform company is finding your sweet spot. Some of the metrics we used for that were, we said, first and foremost, where are antisense oligonucleotides delivered safely and effectively, right? Because we want to buy down as much risk as possible. As I mentioned, we're using chemistry that is already in approved products like SPINRAZA, but in hundreds of clinical trials. Lastly, what we've learned, and I alluded to this, is that we really live in two-fold increases, and that's actually perfectly suited for an entire category of diseases called haploinsufficiencies, where you have one of your two alleles is mutated and no longer functional, so you're only making 50% of what you'd otherwise need to be healthy.
And as it turns out, the CNS in particular has 30-40 haploinsufficiency diseases in regions of the brain that you can absolutely get to via intrathecal delivery of ASOs. Actually, the great majority of them have no approved treatments, and they are massive unmet needs. SYNGAP was a clear choice once we really started to understand it and then when we stacked the data behind it.
Mm-hmm. Okay. Maybe can you walk us through what sort of preclinical data, what sort of improvements did you see with the SYNGAP?
Yeah. We like to start at first with patient cells.
The first thing we do is we looked at iPSC-derived patient cells that replicate, obviously, a haploinsufficient state. What we saw very quickly is that we could restore the remaining allele in those iPSC-derived cells back to a two-fold increase. Essentially, you're bringing the patient theoretically back to a normal state. We're fortunate in that for SYNGAP, there's a very well-organized and strong patient advocacy group which is critical for any rare disease.
As a consequence of that, they have actually invested in things like natural history studies, which we will talk about, but also a humanized mouse model. The humanized mouse model's great because it actually has SYNGAP1 patient-derived cells. It's a haploinsufficient mouse, and it actually replicates the disease pretty well in terms of anxiety, learning, and you can actually induce seizures in these mice chemically. We took our human drug candidate, and we tested it at therapeutic level, at levels that would be therapeutic in the clinic. What we saw, which was very encouraging and nobody has done before, is that we could actually reverse all the symptoms of the disease.
I think that was very powerful. Then lastly, what I'd point out is we went into primates. Primates don't replicate the disease. They have two functional alleles, but it allows us to actually deliver the drug intrathecally, which is how we'll do it in the clinic, and it is 100% cross-reactive with primates. What I'll point out is we saw a statistically significant increase in the SYNGAP gene, and it turns out when you use antisense oligonucleotides against single gene diseases and you see a pharmacodynamic effect like that in monkeys, that tends to translate as well, if not better, in the clinic. That was extremely encouraging for us.
Okay. That's good to know. I guess maybe we can go to the clinical study, the design, and what you might expect to see.
Mm-hmm. We took a lot of time to balance, I think, a lot of learnings from previous companies that have used CNS oligos or worked in the DEE space, developmental epileptic encephalopathy space, which is what SYNGAP1 is. What we came up with was a study that, first and foremost, allows us to go directly into patients, so where it's a phase I/II study. We are skipping the SAD phase and going directly into the multiple ascending dose phase. We are starting with the majority of patients who are truly haploinsufficient, so 80% of patients have a mutation that renders them completely haploinsufficient, so those are the patients we are enrolling. Some of the criteria are daily seizures, inability to speak. Effectively, these patients are very sick, ages 2-18 years old, and we are taking a global approach.
We have approval in four distinct jurisdictions: Argentina, Australia, the U.K., and the EMA. Lastly, I'll point out, we have multiple different controls here. It's a three-to-one randomization. Three patients that get a drug, one gets a control. Every patient has their own baseline period, so they're controlled against themselves, and we can also leverage natural history data.
Okay. In terms of the endpoints, you mentioned seizure and other types of endpoints. What would you expect to see change in this length of study?
Yeah. Maybe it's important to take a step back very quickly and say that when you have a mutation in SYNGAP1, you have too many receptors in your synapse. As a result of that, you get too much synaptic firing. I think about it as the patient's brain is constantly short-circuiting throughout the day. As a result of that, patients can have hundreds of seizures a day. They barely sleep. They cannot communicate. They're not verbal. They have anger issues. They have motor problems. There's no part of the patient's life or a caregiver's life that's not affected by this disease. We believe because we're acting at essentially the genetic level by allowing the gene to make more SYNGAP, essentially trying to restore patients back to a normal state, that it's possible to have a disease-modifying effect across all of these different domains of the disease.
Nobody's ever done this before.
So, it's hard for us to predict the timing of things. We can look at other diseases. We are giving every patient three doses across three months, and oligos have a long half-life, so there's a six-month follow-up as well. So, we think that is enough time to be able to essentially see movement across at least a few of these domains, but maybe more. Then we will have an open-label extension once we identify the optimal biological dose.
Okay. How many doses are being tested, and how did you kind of come up, or how did you decide on those doses?
Yeah. To answer your first question, every multiple ascending dosing cohort, and there are three, all the patients will get three doses.
Okay.
So, we think that's enough to start to see an effect. As I mentioned earlier, we're working with chemistry that's well understood, so that allows us to take advantage of modeling, right? You can understand the PK and PD of these types of chemistries. So, we use that mouse data as well as the primate data to essentially predict doses that we felt would be therapeutic for the multiple ascending dose study.
Are you expecting the first dose to already be in kind of the therapeutic level?
We don't believe in giving patients a dose that won't help them, but we are very eager to get to the later cohorts as well.
Okay. When might we expect the data from? Are you going to give data from each dose separately or just wait till all of them are together?
Yeah. At this point, we're waiting till they're all together. What we've told people is the cake will be baked and ready in the first half of 2028, and if we see something sooner, we may decide to talk about that. But reflecting back on what other companies have done, we actually think it's important to keep the blind and just execute, so we've guided to the first half of 2028.
Okay. With intrathecal ASOs, there's been some, I guess, history with maybe potential tox. How would you describe your chemistry? How is it different from those programs?
So, I guess the way I'd talk about it is a few different things. This is a 20-nucleotide-long ASO, so nothing exotic about it. It's using the same chemistry that's in SPINRAZA, which is a very safe drug, or tofersen, or what Stoke is doing with their drug. It is steric, which is important. They tend to have better tolerability and characteristics than gapmers, so we're not degrading regulatory RNAs. What I'll point out is, interestingly, we haven't totally solved this as an industry, but the good thing about CNS oligos is that the monkeys are quite predictive of toxicity, at least at the levels in which you start seeing it. Now, why some oligos have better, if you will, features than others that go into the CNS is a little bit idiosyncratic.
But what I can tell you is what we saw with our oligo and the ones we brought forward is that it's quite clean, and we have a large therapeutic index on it. So, that allows us to have a lot of headroom and comfort going into the clinic. So, we feel really good about that. Again, we were able to leverage decades of antisense oligonucleotide chemistry and work that had been done by others that helped inform that.
Mm-hmm. Is the plan to continue advancing this in the intrathecal route, or is there any plans to change that?
I think that you start intrathecal, right? It is more than okay for this patient population. I say that for a few different reasons. One, it is a devastating disease. Patients and parents badly need anything. Two, thanks to other companies, intrathecal delivery has become more state-of-the-art, right? It's not a big thing for hospitals and physicians to do this. And three, the drug gets directly into the brain, which is a good thing. I think what you're alluding to is blood-brain barrier shuttles and whatnot. That is important, and it is of course something we are keeping an eye on, but I don't think that is ready for prime time yet. We are really focused on developing this as the first foray into SYNGAP and hopefully having an impact there.
Okay. Maybe talk about the commercial opportunity, epidemiology of SYNGAP.
Yeah, absolutely. Maybe I'll just start simply by saying we believe and we think, we've done a lot of work here and others have looked at this, that there are at least 10,000 patients in the U.S., if not more. Having worked in rare diseases my entire career, I can tell you sometimes you see rare diseases where you may never meet a patient with this disease. That is absolutely not the case for SYNGAP. We are seeing these patients pop up everywhere. People may have noted at the beginning of this year, the CNBC co-host Becky Quick came out and said, "I have a daughter with SYNGAP1." These patients are out there, and they are very proactive and well-organized. We are going to have 8-10 sites around the world. Everywhere we go, patients show up with their families.
I think this is one of those rare diseases which starts to become very big in a sense, right? People forget, back in 2013 or whatnot, people hadn't even heard of spinal muscular atrophy. That does still happen, and I think this is very much the case for this type of disease. We have shared a lot of information on that, and what I can tell you is if you just look at what these patients are going through and their families, and you line it up with other types of diseases, cystic fibrosis and SMA and whatnot, I would argue it's as bad, if not worse.
You can look at the patient numbers, and you can look at the approach we are taking. I think you could start to do math and understand why I think people are quite excited about the possibilities here and the potential opportunity if we have a drug that in fact changes their lives.
Okay. These patients today, are they refractory to anti-epileptic medication?
Yeah. SYNGAP is an intracellular protein. As I mentioned, if you don't have enough of it, you have too many AMPA receptors. It is not overly complicated, but as a consequence of that, the Fintepla or other types of drugs do not really seem to have too much of an effect here. Many times, these patients, I call it Band-Aid solutions, they're on valproic acid or they are taking cannabinoids, but the reality is it's not having a very big effect on these patients. More so, when you take those for a long period of time, they actually bring on their own side effects, brittle bones, GI problems, and other issues. Calling it an imperfect solution is almost not doing justice to the fact that there's really nothing for them.
Mm-hmm. I guess other companies out there, they are developing drugs not really SYNGAP-specific, but studying them in basket studies—
Yeah.
—with SYNGAP. Do you think that it's just harder to treat SYNGAP than those other DEEs?
Yeah. I think it is. I think that, yes. I think, one thing I'd point out is that even though those drugs can work for other diseases, say, for example, Dravet, I think it's very clear when you start to talk to these families and physicians and whatnot, they want disease-modifying therapies, right? The seizures are the tip of the iceberg, but there's so much more that these families and these patients want, and those drugs are not going to get to that. They're not going to modify the disease that way, and I think ultimately, at the end of the day, that's very, very important.
Mm-hmm. Okay. In terms of the regulatory pathway, I know it's premature, but what could potential endpoints look like? Is it going to be seizure endpoints, seizure plus other?
Yeah. We get asked this question a lot. I guess, the things I would say is nobody's ever done this before. We deliberately use the term signal seeking. We're going to let the data guide us. Where the drug takes us is theoretically where we should be talking about endpoints that are relevant for us. That said, if you look at what we are assessing in the clinic, so you pointed out seizures, and we're using EEGs as well. That's an approvable endpoint. You have the Bayley and the Vineland, GMFM, and these are measures that are being used in other relevant diseases, say Angelman or Rett syndrome, and the FDA's already said, "Hey, if you show an impact in one or two of these domains, we'll pull you forward." Stoke Therapeutics, right? They've got a sub-domain agreement with the FDA.
I think actually the answer is there's lots of possibilities here, but you first have to look at what the data tells you, then you go and you have the conversations about how you line that up. I will point out that one of the reasons we put a control in our phase I/II is we believe that that allows for a more robust set of discussions if we get the type of data we want with regulatory agencies, because the data is just more believable because you have a control.
That was something we did on purpose.
You mentioned earlier there's this rich natural history data set.
I guess from that, what would your expectation control untreated patients? How would they fare on these things? On the endpoints?
Yeah. No, no, good question. There's 1,300 years of patient data. That's a lot. Given a disease that was only discovered 15 years ago, it's pretty incredible, actually. We really use that natural history data to inform our phase I/II, both in terms of inclusion and exclusion, but also the assessment. As an example, if you look at certain domains of Bayley or Vineland or GMFM in the natural history, and then you look at healthy, you can start to see separation. That tells you, okay, these are things that effectively are going to show differentiation and could be things that we could assess and measure, because you know they start to drift away from what the normal healthy population looks like. I would say anything we're assessing is essentially something that we believe could potentially move with the drug and is assessable.
Now, the timing, right, is something we can't predict on these things. Some things move faster than others at times, but given the mechanism of action, we're hoping things happen more quickly.
Okay. Any questions from the audience on the SYNGAP program? If not, maybe we can talk about your second program.
Sure.
The SHANK3. Maybe just give an overview of that and what the rationale for that was.
Yep. The name of the disease is Phelan-McDermid Syndrome, and it too is caused by a single gene mutation. It's a haploinsufficiency. It is a learning disability, but again, it's genetically driven. It's driven by a mutation in what's called SHANK3. What we like about it for our platform is, again, because it's a haploinsufficiency, because there's a massive unmet need, because it's in a region of the brain, the cortical region, same place as SYNGAP1, and because we deliver intrathecally, if our CMP-002 drug for SYNGAP shows that it works, this should be a rinse, wash, repeat for the next thing and the next thing and the next thing, because it's the same regions and it is the same idea. The disease just checks so many obvious boxes when you start to look at it.
What I'll point out, interestingly, is there are 45,000 patients in the U.S. with this disease. This is a bigger disease, but still just as big of an unmet need, an extremely well-organized and powerful patient organization, which, by the way, is in very good collaboration with CURE SYNGAP1. We love that. The word synergy is great for it, but honestly, it's all about collaboration and relationships there, because ultimately, these patients need something. It just becomes an obvious choice for us and one that I think we get very excited about in terms of how we start to build a pipeline of these types of CNS haploinsufficiency upregulation opportunities.
Mm-hmm. I guess the 45,000 number is quite large, honestly. I guess, are these mostly undiagnosed or mostly diagnosed at this point?
I may not have answered this. For SYNGAP, we say there are about 10,000 or more patients, probably 1/4 of them are diagnosed.
I'll point out that diagnostics today have gotten much better because whole genome screening is much cheaper, sequencing, genetic panels, et cetera. That happens pretty quickly when patients miss milestones and whatnot. I think Phelan-McDermid Syndrome has a better diagnostic rate, right? But still, there's a lot of underdiagnosis there. But I think that number is quite robust and been cited by others. I will point out, there's more competition in that space, which is not a bad thing, actually.
It's a bigger opportunity. That actually creates a slightly different opportunity than SYNGAP because a few companies ahead of us will probably work out the endpoints a bit. But that's okay. We don't mind that at all.
Mm-hmm. And there's a lot of, I guess, overlap with autism—
Yes.
—spectrum. I guess, are they distinct or is this kind of like a subset of autism?
That's a good question. Interestingly, if you read about SYNGAP1, some people believe and have cited that 1% of autism or learning disabilities is driven by SYNGAP. By the way, that means you have like 60,000 patients in the U.S. That's a big number. I think it's overlapping, right? I think what you're finding is, it used to be 10 years ago, it was epilepsy, but now it's genetically defined epilepsies, right? We're starting to figure out that not all epilepsies are created equal, right? Many of them have their own distinct single gene mutation that's driving it, but it's still under an umbrella. I think to your point, SHANK3 overlaps with this, but it's own genetically distinct disease, which makes it, I think, therapeutically relevant for companies like ours.
Okay. Maybe you talked previously about the SYNGAP preclinical data.
Yeah.
Do you think you're able to show the same level of, I guess, disease modification with the SHANK3?
Yeah. In a broader sense, we've used our platform on over 40 genes. We know pretty well how this upregulation thing works, and we know what's real and what's not. You have to think about it differently than downregulation. It's a different beast. But we know that we live in twofold increase world. That's where we live. When we say we're going to pull things forward, it's because we have a belief that we can get to the relevant increases that are going to be therapeutically meaningful. So yes is the answer. We've said we'll have a DC for that program. That's our goal next year. Look, not all diseases are created equal in terms of preclinical models. We were fortunate in that SYNGAP had a beautiful model that we could work on.
SHANK3 doesn't necessarily have that. We have to. And this is true of all rare diseases. You have to bob and weave a little bit. We do know the path we follow based on SYNGAP, and we know what we're looking for. We do believe that we can restore it to twofold in that as well.
Mm-hmm. I guess looking at it beyond the expression, in terms of the reversibility of the symptoms of the disease, I think symptoms start manifesting around age two for Phelan-McDermid?
Yeah.
Do you think that changing the SHANK3 expression at that point can lead to still clinical change?
I think so. I'll lump them both together. These are not neurodegenerative diseases. These are neuro-arrest diseases.
Your brain is just kind of stuck at a stage. Do I think you'll get full reversal over time? I don't know the answer to that. I think that, for example, in SYNGAP, there's been groups that have studied models of the disease in mice and shown reversal at older ages. There's a very interesting academic paper that showed, hey, in Fragile X, if we restore Fragile X, can we restore plasticity? No, you can't. In SYNGAP, you can.
That's quite interesting. I do not know about Phelan-McDermid Syndrome, but I think that there is reason to believe that. With all that said, it's sort of obvious that you would like to get in there and get levels to normal as soon as possible so that you don't miss those development milestones and that you actually maintain the normal curve of development. Ultimately, that's where you should get to.
We're seeing Stoke go earlier in Dravet. We saw that gene there. That makes sense, right? Because the earlier you get there, the more damage you can prevent. I do think in these diseases, you can probably do more than just halt. That's my suspicion, but that'll have to be proven out in the older populations.
Mm-hmm. Okay. Anything else that you would like to discuss that we haven't so far?
No. I think what I would say about CAMP4 is, our goal is to be the upregulation company in the CNS. With that said, there are many genes and many diseases in our body beyond just the brain where upregulation makes sense. For example, the heart has a lot of congenital diseases, the kidney. To that end, we put in place a relationship with GSK last year where they chose two diseases, one large one in the CNS and one large one in the kidney, where there's a distinct specific gene target they want to upregulate about twofold, and that collaboration's going very well.
That 's another way that we like to unlock value. The way I think about it is we want our shareholders to buy into the assets, and we want to keep the engine running through business development and unlock other value for diseases that maybe are too complex, too big, or off-strategy for what we would do on our own. So that's another pillar that we are building at CAMP4 and focused on.
Next year will be an exciting year. We're going to execute on SYNGAP. We're going to continue to pull forward SHANK3. We have other programs we haven't disclosed yet, and we'll be looking to do more collaborations as well.
All right. Thank you so much.
Thank you.
It was a pleasure.
Thank you.