Okay, good afternoon, everybody. Thank you for sticking around for our last presenting company, at least in this track today, Camp4 Therapeutics. My name is Ted Tenthoff. I'm a Senior Biotech Analyst at Piper Sandler, and before I begin, I am required to point out certain disclosures regarding the relationship between Piper and Camp4 that are located at the back of the room and also at the registration desk, so Camp4 is developing regulatory RNAs, or regRNAs, as a novel therapeutic modality. Camp4 designs antisense oligonucleotides that target these regRNAs to upgrade gene expression to treat a range of haploinsufficiencies. Here with us from the company are my good friends, Josh Mandel-Brehm, President and CEO, and Kelly Gold, CFO. Thanks for being with us, and congrats on the recent IPO.
Thank you.
Thank you, Ted.
So Josh, maybe you can start off by describing these regRNAs. What are they, and what is their typical function?
Yep, and that's an important question because it's the heart and soul of the company. So regulatory RNAs are RNAs that are transcribed out of enhancer and promoter regions, so non-coding regions of the genome. They were discovered about 15 years ago, and like many other types of RNA, were considered junk. And over the last few years, what we've discovered through the labs of, for example, our founders, Rick Young out of the Whitehead Institute and his colleagues, is that these regulatory RNAs play a very important role in controlling the local expression of protein-coding genes. Now, the way that they're able to do this is they are three-dimensional structures because they're RNA, and they form landing pads for transcription factors and other activators and repressors that essentially come together and stick to these RNAs and form a kinetic trap that essentially holds the homeostasis for the protein-coding gene.
And so they can shift upward or downward the expression of genes in a very specific and local way.
That's really helpful. And now you guys are using your proprietary RNA-activating platform to map these regRNAs and also design antisense oligos to target them for therapeutic purposes. Maybe kind of break this into two pieces, sort of how you do this. Tell us about the proprietary nature of discovering and mapping these.
Yep.
Because it's pretty, it's not just a walk in the park here. These are pretty complex stuff.
Yeah.
And then why do ASOs make so much sense to target them?
Yep. As our scientists always remind us, it's not just rolling out a method to do. We've been working on it for many, many years, actually, and so the platform itself is a combination of next-generation sequencing technologies that generate billions of different data points when we apply them to human cell types, and that's very, very important because it turns out the regulatory genome is very different between cell lines and human cell types, so that's something where we've done a tremendous amount of work in, if you will, applying our technology both for cell lines and for the human condition to be able to ascertain the differences there. The other aspect is that we generate so much data that you really can't do it with the naked eye, and it's a nice example of where machine learning comes into play.
And so we have an entire data science team that's built algorithms that allow us to make sense of all of that data and effectively turn gene expression into an encyclopedic exercise. And so for any cell type, for example, hepatocyte in the liver, where we apply our technology, which takes three to six months, we've created, quote unquote, that map of the cell. We have catalogs of all the different regulatory RNAs mapped to all the different protein-coding genes that they control. And that takes a lot of little tricks and a lot of different types of technology to be able to go through and do that. The question you asked about the modality is really important. So when we first learned and discovered these regulatory RNAs, the thing that we liked most about them is that they acted very locally and specifically.
So that was one feature of them that got us excited. The other feature is that they had the ability to control gene expression in the upward direction, which is a magic trick that not that many people have figured out how to do with different technologies. So we wanted to preserve the ability to maintain specificity that was already built into these RNA targets. And so because these regulatory RNAs reside in the nucleus and because they are RNA, Watson-Crick base pairing, we felt like antisense oligonucleotide was the right modality to be able to take advantage of that. And it turns out that's true. What we discovered was when you take these RNAs and you put them at very specific locations, or the oligos on the RNAs, you can have a very deliberate increase in the protein-coding gene. And it turns out it is specific.
It's not throughout the genome. And that's pretty unique. And it's something where it essentially opens the aperture for that technology because now you can upregulate instead of just downregulate.
Yeah, that makes a lot of sense. And just to be really, really clear and make sure we hit on this, it's not like these are typically involved in disease process. You're actually taking advantage of their natural properties to really change expressions in diseases. So just to kind of understand.
That's important, actually. I'll deviate a little bit and offer another point of view on that, which is interesting. But firstly, all the diseases we're working on are places where you have a genetic mutation in a protein-coding gene because you have two copies of genes. Many times, for example, haploinsufficient states, you have one remaining healthy gene. So the actual system, the conservation of the gene expression is conserved, to your point. Whether you have a protein-coding mutation or not, it still involves the same RNA to control its expression, which is the point you were getting at. So that we could take advantage of. Interestingly, the detour I was going to tell you about is many of these non-coding GWAS hits, our suspicion is these are mutations in your enhancers, and they are disrupting transcription factor binding and RNAs as well.
So there's probably a whole new avenue you could explore here. We're not doing that today, but our technology allows us to look at that as well.
Yeah, that's really helpful background. So your lead program is CMP-CPS-001 for urea cycle disorders. Before we get into the compound, maybe you can tell us about these urea cycle disorders. What causes them? What do these poor children go through?
Right, so this is a rare genetic disease. We've actually known about it for many decades. There is, unfortunately, a very famous story about a gene therapy for OTC deficiency where a child had died back in the day, and so this has been a very prominent disease, if you will, so what ends up happening if you have a urea cycle disorder is you have a mutation in any one of six enzymes that effectively work together to take toxic ammonia and convert it to non-toxic byproducts like urea that can get excreted. Now, if you have a mutation in these enzymes, although you retain some enzymatic function, it's not enough to prevent the buildup of ammonia, and so you get what's called a hyperammonemic crisis, and this is a life-threatening event. You can go into a coma. It can lead to death.
Even if you do not succumb to the disease, it causes permanent neurological damage over time. So it's cumulative. So as you said, these poor children that have these diseases, it's not uncommon to see them in their late teens where they have low IQs and all types of other neurological problems because ammonia is such a toxic molecule. It just pervades your body. And so, unfortunately, the only real treatments out there for these patients, despite the fact we've known about this disease for such a long time, is a very, very strict protein diet that borders on malnutrition. I mean, this is not a good quality of life. And then secondly, there are nitrogen scavengers that are on the market. The most widely used one is a drug called Revicti, which had been part of Horizon and will now be part of Amgen.
That does not prevent these hyperammonemic crises, but it certainly does help soak up some levels of ammonia. It's an option for patients, but symptomatic mainly in nature.
Yeah, and so tell us about how CMP-CPS-001 works to increase clearance of the ammonia?
Yep. So I mentioned there are six enzymes that are working together to convert ammonia. It's a step-by-step process to break it apart and continue to deconvolute it down to urea. The first enzyme in this cycle is a very interesting enzyme and powerful one. It's called CPS-1, carbamoyl phosphate. And actually, what ends up happening is that if you increase carbamoyl phosphate, all of the other downstream enzymes also increase. So it has downstream transcriptional action, and that's very unique. It also happens to be the first step in converting the reservoir of ammonia to the first non-toxic byproduct. So simply by upregulating CPS-1, you get two really powerful features. The first is you start the conversion of that ammonia reservoir to non-toxic byproducts that can get taken up even by the partially mutated enzyme. The second is all the enzymes are increased by doing that.
Therefore, you get more capacity to convert more ammonia and its byproducts to urea, and so we like to call it the sort of pan-UCD approach because if we're able to increase all the different enzymes, we should be able to go after more than just OTC deficiency, which is, of course, the most common subtype, but there are other subtypes as well.
And then there are some that you wouldn't be able to treat, but these are very rare too.
Right.
The majority would be.
Mutations in, there's three things we wouldn't be able to do. One is there are about 1% of patients that have a mutation in CPS, so we wouldn't be able to help that. NAGS deficiency, where there actually is an approved drug, that's about 2% of the population. And then, unfortunately, there's a very small subset of the population that is very, very sick. They have very low enzymatic activity, less than 5%. It's called early onset, which is a funny way to call it because late onset means you live past one month of life. But early onset, you need a liver transplant immediately because you essentially have no enzyme and it's not compatible with life.
But this approach really is the best way to address the majority of these patients.
We think so. I mean, if it ends up working in the human condition the way we expect, we think it would be a huge improvement for patients, and it would get to the underlying issue, which is their ability to convert ammonia to urea, ureagenesis.
Yeah, that's a great point. So tell us about the ongoing phase I study in healthy volunteers. What's the current status and when can we get data?
Yep. So we've already told folks we expect Q1 safety data. And so they have completed the SAD dosing. We don't expect to see anything remarkable there, but we'll have that data coming. And then we are on track to finalize the MAD portion of that study in the second half of next year.
So let's dig into that a little bit because with the multiple ascending dose, even in healthy volunteers, you are looking at a biomarker or a test called ureagenesis test. Maybe start by explaining that and then what should we expect or what could we hope for from the healthies?
Yeah, this is a really important question. So let's take it into two steps, as you said. So there is a test called the ureagenesis rate test. And what this allows you to do, and we're not the first ones using this, for example, Ultragenyx is using this assay, and many researchers use this assay as well. So essentially, you can take a labeled, a harmless labeled carbon isotope, so sodium acetate, you can drink it, and it will be taken up by your actual body and your urea cycle. And because it's labeled, you can measure it. So you can measure the actual ability of the body to convert the sodium acetate into urea. That's the ureagenesis rate test.
It's been published on, so people have actually published to show that you can differentiate between patients with the actual disease of urea cycle and healthy volunteers using this assay, so there's really nice data to show that separation. And in fact, it's been used by other companies as part of their development plans. In fact, most recently, the FDA has bought into Ultragenyx's phase III plan in terms of using that assay to help score responders to their drug. And so although healthy volunteers have a fully functional urea cycle, we believe there may be an opportunity that if we give them our drug, we can still boost some of their cycle. And we may be able to see that difference using that ureagenesis rate test.
And the reason we make that claim is that through our own non-human primate studies, which are also completely normal healthy monkeys, we were able to actually use that same assay and differentiate between the monkeys that got our drug and didn't. Now, the really interesting subpoint I'll make is when we spoke with KOLs, and this is a rare disease, so let's call it 15-20 around the world really know this disease. We asked the question, you know, what do we need to see to get you really excited? And they said, well, obviously safety. But they said the other thing that's interesting is these are healthy volunteers. We said, yeah. They said, well, just because you don't see a big signal there does not mean that it's not going to be hugely impactful. They're fully healthy.
So we'd really like to see you put this into patients. And so that was really interesting to us because it tells us that, one, just how low the bar is, but two, just how these physicians think about this test and how to use it. So if we see any signal, what we've told people is we're going to be really excited about this because this is something where it shows our drug is working on top of a fully healthy, functional human, and we can measure it. But we're also very clear about we think it's important to get into patients as well. So we think there's a lot of ways to win and help these patients.
Let's talk about sort of those next steps. Again, a lot of what you're proving out here in the phase I is safety, PK, and just understanding the dynamics around that. What would be the plan to get into patients, and could that be registrational?
Right. So let's just say we are having lots of different discussions. We're learning a lot. We're trying to be very thoughtful about how to approach this. It's certainly going to be a global strategy in how we do it, not just in the U.S. And we are in Australia, by the way, just to remind people for our healthy volunteer study, which has been great because there's a couple of KOLs there as well. So there are patients there. So there are, for example, drugs that have been approved, as I mentioned, on ammonia lowering. So we know that's an important endpoint. Ultragenyx is doing some really nice work for their gene therapy approach and working with the FDA and some other endpoints.
And we believe that actually this study sets us up to have a very efficient path forward in terms of being able to rapidly go into what we think would be more creative phase II, three studies. So tying things together that allow us not to waste time, to be able to do what you typically do in phase III, but also be thoughtful about going right into a registration. So that's what we had talked about. That's the strategy we are working on. And as you can imagine, we are sitting with regulatory agencies and having those discussions and being very thoughtful. But it's very clear to us this is a disease that not just the patient community, but the regulatory agencies want to pull it forward. We have different drug designation, rare pediatric. So there's a high unmet need, and they want to get drugs to patients.
Yeah. And again, even with Revicti, it's something that could really change the mechanism here and change the disease, could be very impactful. So you guys are focused on some metabolic diseases in the liver. You also are targeting some programs in CNS. I think the most advanced and one that you guys have become increasingly excited about is CMP-SYNGAP. So let's start by talking about the disease. What is SYNGAP? And then maybe we can kind of get into the program itself.
Yep, so SYNGAP is a haploinsufficient disease, meaning you have one remaining healthy gene. The other one is not functional, so you're 50% down of what you'd otherwise need to be a healthy human being, and in SYNGAP, it's a transporter mutation, and so essentially what happens is you can't get the SYNGAP protein to the membrane, and then you end up getting hypertranslated, hyperexcitability, which is not actually a good thing, so in SYNGAP, these children and adults suffer from epilepsy and learning disabilities and all types of other issues, but it's very, very similar to Dravet syndrome, Ted. In fact, many times patients get misdiagnosed as having Dravet, which is also a haploinsufficient disease, but one of the key differences is there's actually no disease-modifying therapies approved for SYNGAP. There's not really much in the clinic.
And it's a disease that we've really started to understand, the community starting to understand just writ large for these epilepsies. We're starting to learn about the genetic basis. And I think Dravet is a really nice example of what Stoke has been able to do with upregulation. And we believe that has a lot of read-through to the concept of what we're trying to do in Syngap, which is why we're very excited about it. And we think it's just as big of a disease with no real treatments there.
So tell us how you target it with the reg RNAs and what are your plans to advance into the clinic?
Yep. So in this case, by the way, it turns out there's over 30 different haploinsufficiency diseases in the brain, most of which have no approved treatments. And they're not just rare. You can get oligos to the brain by intrathecal delivery by virtue of there being approved products on the market that do that. For example, Spinraza for spinal muscular atrophy and Qalsody for ALS, both examples of oligonucleotides delivered via intrathecal delivery. It turns out for diseases like SYNGAP, the regions of the brain, cortical regions and whatnot that we want to get the drug to are amenable to intrathecal delivery. So that works for us. We like to de-risk the platform as much as possible and leverage where other folks have already shown that you can use that technology. So that's one key aspect of it, if you will.
We've designed an oligo that essentially allows us to target the regulatory RNA that controls SYNGAP1. We have a lot of really nice preclinical data showing that we can upregulate that and have an effect in different models that we believe would translate to an effect in the clinic.
Great. And when do you think you guys might be able to get into the clinic? Not to put you on the spot there because I know this was, you know, the priorities really to advance CMP-CPS-001, but what's your thinking?
The priority is to do that, but the priority is to build the next version of Alnylam . We have to have products behind that. We are on track to put that into, I'll say, "IND-enabling studies," but I use that term in quotations because it doesn't necessarily mean we'd start the study in the U.S. I'm using that as a term of art to say the last round of GLP toxicology studies, if you will.
Yeah. Awesome. You could always say CTA enabling.
That's probably right. You're right.
So you guys did announce a partnership with BioMarin. What can you tell us about this deal and what are other partnering opportunities for Camp4?
Yeah, we announced the deal with BioMarin at the end of September. It is a two-target discovery deal in a therapeutic area that we're not disclosing at BioMarin's request, but I will say that it allows us to go beyond where our current therapeutic areas are with our current pipeline. So we're focused, as you said, Ted, in liver and the CNS. And the reason for that is that we are leveraging oligo delivery technology that is very well established from a regulatory and delivery perspective. And so our platform is applicable to any tissue. And so we would love to be able to move on the CNS or GalNAc-conjugated liver delivery. And so this particular partnership allows us to move into a completely novel cell type, which is really exciting. It's something that we wouldn't be able to do on our own.
I think it's a nice example of how we're planning to leverage partners to allow us to capitalize on the breadth of the platform. The mapping exercise Josh described is about a six-to-nine-month exercise, and it's a completely novel cell type. We've done it in a dozen cells right now. Once we've done that mapping work, the process of zeroing in on a regulatory RNA that controls any gene that's expressed in that cell type is actually very efficient. The process of identifying and pulling targets out of these maps, so to speak, is very, very fast and very efficient. We're sort of encumbered by the same limitations everyone else is in terms of drug development. We really do look to partners to help us capitalize on the breadth of what we can do.
And so we really like the multi-target deals, whether it's in a cell we've already worked in or something new as we're doing with BioMarin. And then as we progress our pipeline, I think we'll probably look for opportunistic partnership opportunities with our pipeline programs as well.
Josh, you talked about, for example, 30 haploinsufficiencies and CNS. You said you want to be the next Alnylam, which I love and totally support and believe this is a platform that could get you there. What are some of the next areas that you're considering? Where does it make sense to develop this technology longer term?
Right. So I think about it in two dimensions. One is where does it make sense for Camp4 to bring forward a pipeline? And not surprisingly, rare diseases are places where we think we can carry that torch. So there's actually quite a few genetic epilepsies that we're interested in. But there are larger diseases. And we haven't disclosed those yet, but there are examples. You could look up GBA1 for Parkinson's, for example. That's a haploinsufficiency. Progranulin is a haploinsufficiency for FTD. So there are bigger opportunities there, Ted, where I think it makes sense to potentially think about partnerships. Interestingly, back to the liver, there are some really great emerging targets that go well beyond rare diseases that go into metabolic space or go into obesity and things of that nature that we think are perfect targets for upregulation as well.
So I think it makes sense for us to revisit those in the context of partnerships. And then the last thing I'll say is there's really wonderful proof of concept happening with these conjugation of oligos, right? We've seen Dyne, Avidity and others that are now saying we're going to go to the heart. And we've seen a couple of companies come up that are targeting the kidney. And so I think same problem, same solution where they're all doing downregulation plays. And as Kelly said, our platform is applicable to every tissue because it's same biology. So if you unlock a tissue where you can deliver and you want to upregulate, we want Camp4 to be the shop to go there.
Yeah, I love it because that really gives a sense of the breadth of where you can go. So following the IPO, I think you guys have pro forma cash somewhere around $80 million. How long does this fund the company and what's it enable you guys to accomplish?
Yeah, it's an important quantum of capital for us because it gets us about two quarters past the receipt of the healthy volunteer data from the MAD study. So between the SAD and the MAD portions of those studies, that's going to be 96 patients' worth of safety and ureagenesis data. We think that's going to be pretty meaningful in terms of proof of mechanism and really will not only de-risk the program, but this is our first homegrown program to go through a clinical study. I think for us to be able to establish that upregulation works and the platform is able to achieve upregulation in a way that's clinically meaningful, I think will really not only be de-risking of the program itself, but of the platform as a whole. We really think there's quite a bit to come following the receipt of that data.
Okay, well, we're excited for the first clinical data coming out next year and continued pipeline expansion and progress, so Josh, Kelly, thanks for being with us.
Thank you, Ted. We appreciate it.
Thanks, Kelly.
Thanks, Ted. I appreciate it.