All right, we are going to get started. Good afternoon, everyone, and thank you for joining us to Leerink Global Healthcare Conference 2025. This afternoon, I have the pleasure to have Josh Mandel-Brehm with me, CEO of CAMP4. Thank you so much for your time. Maybe, we have initiated coverage. My name is Lili Nso ngo, Analyst here at Leerink, part of the Genetic Medicines team. We have initiated coverage of CAMP4 a couple of months ago now. Maybe for the people in the room that are new to the story, can you provide us an overview of the company and its platform? Yep, absolutely. First, thank you for hosting us. It's a pleasure to be here. Thank you for getting my name right. Nobody ever gets that. I practiced. You got a gold star right off the bat. I practiced. Great. CAMP4 is using antisense oligonucleotides to very specifically increase the expression of genes. That is the purpose of our company. The way that we are able to do this is through a brand new area of biology called Regulatory RNAs. These are RNAs that arise out of and are transcribed out of enhancer and promoter regions. We now know that every protein-coding gene in our body relies on its own unique set of regulatory RNAs to control its expression. One of the more proprietary and novel aspects of our platform is being able to apply it to particular human cell types and catalog all the different RNAs and the protein-coding genes that they control. We have a database of tens of thousands of RNAs and all of the genes that they act on. The second step is that we can take any one of those RNAs and drug them very specifically with antisense oligonucleotides and have a very deliberate increase in a protein-coding gene. Now, why that matters is there are an entire category of diseases, both prevalent and rare, that have a genetic basis where you're missing just a little bit of healthy protein. The difference between being sick and much healthier could be just putting anywhere from 30%-70% of protein back in the system. To just give a little more color to that, less than 3% of these diseases have approved treatments. It is a very, very big area. As an industry, we're really good at getting rid of toxic stuff. We haven't been as good at putting things back in the system. That is the entire purpose of CAMP4. All right, thank you. Maybe diving into your initial program, for urea cycle disorder, can you provide an overview of the current treatment paradigm for UCD and where you see the greatest unmet need? Yeah, absolutely. I'll start by saying what we always hear from the doctors that treat this disease, which is it's a devastating genetic disease. These patients are living a life that is very difficult and in constant fear of life-threatening attacks that essentially, if they don't take their lives, can have permanent damage. The disease is caused by a mutation in any one of six enzymes that are necessary to take ammonia and convert it to urea. It's called urea cycle disorders. If you have one of these mutations, essentially, your only options are to be on a highly restrictive protein diet, which is effectively malnutrition. These patients are very, very ill, and it's hard for them to live a very normal life. Alternatively, they can take a drug called RAVICTI, which is essentially a nitrogen scavenger. Nitrogen is the precursor to ammonia. You try and soak up some of the nitrogen so that it cannot convert to ammonia. Because what happens for these patients is by not being able to convert ammonia to urea, they get a quick toxic buildup. It's called a hyperammonemic crisis. Ammonia is a very toxic molecule. It can go throughout your body, and it can cause coma. It can cause permanent neurological damage. It is not uncommon to find that these patients get into their teens or adulthood having low IQs and all types of issues. Another example of a disease that we want to treat early and often to avoid the progression of the disease. Can you talk a little bit on the mechanism of action of your program? Yeah. What we wanted to do was to apply our upregulation approach to this disease in a way that would allow us to go after the great majority of patients. If you recall, I said earlier there are six enzymes that work together to convert ammonia to urea. In this particular disease, urea cycle is more of an umbrella term. You could have a mutation in any one of those enzymes that would render you incapable of converting ammonia to urea. The most common subtype, which people are familiar with, is called OTC deficiency. This is an X-linked disease. It occupies about 60% of urea cycle disorder patients. There are companies that have tried and are trying to create drugs there. There are other mutations, ASS, ASL1, for example. Now, what we've chosen to do is to actually increase the expression of the first enzyme in the cycle. It's called CPS1. And it's a really interesting enzyme. It has two purposes. One is it immediately starts the conversion of ammonia to non-toxic byproducts. So by increasing it right off the bat, you could take any reservoir of ammonia and start to convert that to non-toxic molecules that can go throughout the system. The other thing that CPS1 can do is actually increase downstream enzymes. So when you increase CPS1, you can increase all of the other enzymes, including the partially active enzymes. In totality, you can get to the underlying mechanism of the disease. That is the ability to clear ammonia to urea in a mutation-agnostic way. We call it the pan-UCD approach. Speaking more specifically of the pan-UCD approach, obviously, there are other companies that are targeting specifically OTC, particularly. In your approach, in the preclinical data that you've shown, you've seen increase in protein that were downstream, so all those six enzymes. Are there proteins that you see the most increase in by targeting CPS1? What I'm getting to is, are there subgroups of mutations that you think this approach is better suited to, or is it truly a pan-UCD approach? Yep, that's a great question. Interestingly, we had, when we first started, two different approaches to this disease. One was CPS1. The other was actually directly increasing OTC. What we found was they were comparable. There is one model that exists for OTC preclinically. When we took both approaches into that model, we had comparable results. That was really encouraging for the CPS1 approach. As you pointed out, the idea of being able to go beyond OTC to the other subtypes was also very compelling to us because there's just nothing out there for them. The two other approaches that are in the clinic that you're referring to are OTC-specific. One is an AAV approach. It's only for OTC. It's a once and done. You couldn't redose. It's for patients 12 years or older. You can't get to them as early as you'd like. The other approach is an mRNA-LNP approach, which is an infusion. It's worth talking about those because actually, what's interesting about our approach is not just the mechanism of action, but also that because we're using GalNAc, it allows us to have a once-monthly dosing paradigm. Essentially, people come in, they inject themselves in the stomach, and that's it once a month. Why that's really interesting is it opens up the aperture for what we can potentially do with this drug. In an ideal world, we're treating all the subtypes. Interestingly, what we've learned since starting our study is that there's an entirely other population of patients that exists that haven't really been talked about as much. That is the female carriers. As I mentioned, OTC is X-linked. The females are essentially functional haploinsufficients. They get sick. They can have seizures. Excuse me. They can have seizures, but they can also go into these crises. They can have all types of neurological side effects. Now, it may not be as severe as the males, but that's a population in need of a drug. Actually, our profile would be very interesting to them as well, whereas they're not going to take a gene therapy or RAVICTI or other types of drugs. That is something that we've become very interested in. Expands the population also, creates an opportunity to help more patients. Thinking of the different approaches, of course, you've mentioned that there's a gene therapy approach. There is also a more kind of mRNA approach. Thinking of the data so far, have you seen any differentiating element within the preclinical data that's available? Yeah, it's hard to do a head-to-head comparison. However, there are things you can look at. For example, if you were to look at the gene therapy in primate data, they get a nice response immediately, but it tends to reduce and wane over time. That's not specific to this gene therapy. I think that's something we see with others. The other thing about a gene therapy approach, which, by the way, I do think it has a place for patients. We think it's more symbiotic to what we're doing than competitive. You have to give them steroids as well, and that could cause a hyperammonemic crisis. You have to be very thoughtful about that. On the mRNA approach, yeah, we haven't been able to see as much data around that. They're also taking a different mechanistic approach where both of them are replacing the OTC gene. It's going to have a different sort of the data sets are going to look different. In totality, I think we've seen very comparable data in terms of the output. That is, in primates, for example, we showed we could increase ureagenesis, ureagenesis being the conversion of ammonia to urea. In the preclinical OTC mouse model, we also saw that when we gave the mice our drug, they could clear ammonia as well as wild-type mice. That was particularly encouraging for us as well. I think where the differentiation really comes and will come, if we're successful, will be through the way you administer the drug and the ability to go beyond just OTC, where, as I mentioned, it's not just the other downstream enzymes. It's actually the female population of carriers that we think is really important for this. Yeah. I want to talk about the patient population. There is, obviously, heterogeneity in terms of when patients are starting to see symptoms. You have the infant, which is the more severe presentation, but then you have later in life, and as you mentioned, also the female population. Can you tell us a little bit more in terms of the population you're targeting first and what it would take to expand to potentially younger patients? Yeah. We chose to start in healthy volunteers. There were a few reasons for that, and that's adults. One is we felt that for this disease, we're going to use an assay called the ureagenesis rate test. It effectively allows you to study how your drug is working in a very safe way. That is something that's important because not all of these patients have high ammonia levels. There is an approvable endpoint that is reduction in ammonia. We'll absolutely leverage that. If you want to also show that your drug works in other ways, using this assay can be really important. We're creating a massive database in a patient population that will set a baseline. More so, we know that from prior precedents, if you see a bit of a result in a healthy volunteer, so if you see some activity there, that can have high translatability, if you will, into the patient population. There is some precedent there as well. Lastly, to your question, we know from prior precedents that because we're using GalNAc, if you create a good safety database in adults, there is a path forward to go down to a very young age as well and a very efficient path. We are going to take advantage of that. In terms of the differentiation, when we first started talking about this program and when we went public in October, one of the things we spoke about was the need for a drug in the severe population, that being those OTC patients as well as the downstream mutations. That continues to be true. Interestingly, as I alluded to, we were not as familiar with the female population, which is also symptomatic. That in and of itself is a really unique and comparable market. We think there are at least 1,200 patients in the U.S. that are known about today that have that. That has us thinking a lot about the path forward in different ways that we can develop this drug. What we do know from clinicians is two things. One is they've urged us to get into patients as quickly as possible. What we've heard is if we see any activity, that is just, it's a home run, is what one KOL had said. These are healthy volunteers, and they have fully intact urea cycles. Obviously, we're going to be looking closely at safety. We've already shared some of that data. Our intention is to go very rapidly into the patient population with this drug as well because we think that that's going to be really important. We've heard a lot of support to do that. As you mentioned, as the clinical program progresses, there are two kind of hurdles to kind of take from the healthy volunteer study into the patient study. The first one, again, is the health status, obviously. Then the second one being that the healthy study was in adults, and you ideally want to target younger patients. How do you see the healthy adult data translating into sicker younger patients? Yeah. The good thing about a healthy volunteer study is it should translate extremely well. There shouldn't be any differences between children and adults or patients and not for our mechanism of action. On one hand, again, we're using GalNAc, which has been used prolifically by Alnylam, by Ionis, by any company, quite frankly, that is using a nucleic acid to deliver it via GalNAc. There's tons of data on that, and we can leverage that as well. In addition, because we're using standard ASO chemistry, we know what to look at, and we can take advantage of all the great work that's been done and published on. For example, we look at liver transaminases. We look at complement. We look at all the classic things you want to know about that are essentially red flags if you have an issue from a safety perspective. There is a very tried-and-true path using these data sets to effectively go into that younger population. Said differently, you do not have to do like another healthy volunteer study in pediatrics before you get there. You can go seamlessly, we believe, based on all the precedents that have been set there and the conversations we have had, right into, thoughtfully, but a younger population. You've already had conversations with regulators in terms of the path there? On balance, we're having that sort of, I'd say, globally, right? Our study is going in Australia, and we've built some nice relationships there. We have a couple of other things that are ongoing. Yes, in 2025, we're engaged in a lot of different discussions and really making sure we understand what those different pathways look like. I do think, I'll go back to it, that we're probably going to have one of the largest, if not the largest data set on ureagenesis using this assay, which is becoming more and more useful. I think that creates a lot of optionality in terms of how you can work with regulators to set up clinical studies that essentially allow you to measure how your drug is working and make sure that you're making decisions for the best interest of patients because these patients are very fragile. Alleviating their diets is so meaningful for them, but it's a scary thing because it can trigger a crisis. Having a way to really do that thoughtfully is very important in how we do this. Absolutely. Now moving on to the next step of clinical development. Can you provide an overview of the design of the MAD portion? Yeah. Just to take a step back, there's two components to our study: a SAD and a MAD. The SAD study was four different dose levels ranging from 0.2 mg/kg all the way up to 4 mg/kg. That was based on our preclinical data, so we're well within the efficacious range. Every participant was given either drug or placebo. We had four cohorts, 10 participants in each cohort, randomized 3:1. We shared that data earlier in the year, and we were quite happy with it. We're now more than halfway through our MAD study. The MAD study is very similar to the SAD, but a few key differences. First of all, there's four cohorts. There's 12 participants in each cohort, 3: 1 randomization, except the participants get the drug once per month for three months. One other thing I'll say is the way that this works is a participant comes in, and they are given what's called labeled sodium acetate. This is a completely harmless way of measuring how your ureagenesis cycle works. Whether you get the drug or not, and it's blinded, you take the sodium acetate, and then 30 minutes later, we can measure and see the amount of labeled urea that comes out on the other side. If you're given our drug and our drug is doing what it's supposed to do, you should be able to clear more of that in that amount of time, so area under the curve. We're deploying that assay both it was done in the SAD. We haven't used that data yet. We're going to put it in with the MAD, and we're using it in the MAD. You can use that in the patient population as well. Ultragenyx is taking advantage of that for their gene therapy approach. I think it's a really good way to go. We're going to have 96 participants worth of that data, around 50 of which have gotten our drug. All right. We'll have an update from the MAD portion of the study later this year, right in the second half. What should we expect for this readout? Yeah, we get asked that a lot. A couple of things. Ideally, we will be able to show that we've had some activity with our drug in a healthy population, meaning we'll see some separation. The tricky thing about this is that we, as healthy humans and participants in this, all have fully intact, nothing is wrong with our urea cycles. It would be, I'd say, unrealistic to think that you're going to get big responses in these participants. In fact, we know from prior studies they can be very mild to moderate. For example, CARBAGLU was given to participants, single dose, and they saw a little bit of separation. They had a 5x reduction in ammonia in NAGS deficiency. That just goes to show you that there is high translatability here. However, it's very hard to quantify that. Ideally, we would see some activity there. That would be something we'd be extremely excited about. However, given all the preclinical data, the safety data we've been seeing, KOLs have really urged us to rapidly get this into patients because they do not have fully intact cycles. Their belief system is it's very likely that you may not pick up everything in a healthy volunteer, but you'll see it in a patient study. Ideally, we would like to see consistent safety. It would be great if we could show some results there. We've told people that even a small signal will be a big impact, and we'd be very excited about it. We have every intention of getting this to patients as well. In that lens of getting to patient fairly quickly, what should we see in phase one for you to move into potentially a combined phase two, three study? I think it's fair to say that our expectation is to move into patients, so regardless. I think, again, that's based on more recent discussions we've had with KOLs and reviewing the data with them and sort of their point of view of like, listen, the mechanism makes sense. Don't ask too much of a healthy volunteer study. I think the expectation should be that we're going to move forward and be able to put this into patients, but that we are going to review the data carefully and see. Ideally, that would also help us make some decisions on the doses. We're not going to take four doses into patients, right? We'll be, I think, able to be a bit smarter. In fairness, three of the four doses are efficacious. The first one is sub-efficacious just from a safety perspective. Thinking that into inpatient study, how should we think about potentially regulatory endpoints? So kind of. Yeah. There is already one existing regulatory endpoint. That is the reduction in ammonia. That is good. However, maybe a third of patients come in with high ammonia levels. OK, you can look at that, and you should be able to measure that. Two-thirds of the patients, their ammonia levels are in check. The problem is they get an infection. They get sick. They get stressed. They get pregnant. Something happens, and they get this hyperammonemic crisis. It is very hard to design a study with that, not knowing when those crises are going to happen. This is where I think the assay comes into play that we are using. What you are able to do, and I believe we are following really in the footsteps of Ultragenyx, is create a responder analysis. What you can do is say, OK, patients are going to come in. We're going to use this URT. If it shows us that our drug is having activity, we should be able to make decisions, for example, alleviating their diet or removing the nitrogen scavengers, which is a clinically meaningful event for them. You could start to score that as a responder. That's another way. Glutamine is another thing that we can study. It's sort of analogous to what you would do in diabetes. That's another thing that we can look at here. This is, again, a really, really tough disease, life-threatening. As such, I think that there's a very pragmatic approach. If there's something that's safe that can work, finding ways to do it in a short amount of time that can get it towards approval seems to be where the field is going with this. I think that that's a good thing. We have orphan drug, and we have rare pediatric voucher, hopefully, that continues to get renewed. I think these are the things that get put in place when you have these types of diseases. All right. We look forward to updates from the program later this year. Yep, absolutely. I also want to take some time to talk about your CNS pipeline. Obviously, there could potentially be a lot of application to your technology platform. I guess to start, how did you choose SYNGAP1 as the next target? Yeah. Look, I am really excited about actually the applications there. I will make an analogy and say, if you think about Alnylam building an enterprise in the liver to start, I think CAMP4 is going to be building an enterprise in the CNS. The reason that I say that is, first of all, there are many diseases that have a haploinsufficient basis, meaning they have one remaining good allele. We really like those types of indications because we know, based on the genetics, that a modest increase will have a big impact. It's squarely where our technology works exceptionally well. We know that we can deliver oligos into the regions of the brain that matter for a lot of these diseases through intrathecal delivery. We know, because of the devastating nature of these diseases, that it is amenable to them as well. That is also so haploinsufficient, we can deliver it there. There's a huge unmet need. Most of these have very minimal competition. There's just not a lot that's there because they're very hard to treat. It's really ideal for CAMP4. I can tell you, we spent a lot of time the way we built CAMP4, we can parallel process a lot on the front end, meaning we can test our technology very quickly. We've gotten good at this where we know if something's working and if it's not. Quite frankly, if something's not working the way we want, ideally, we just move on from it. We don't waste that much time on it. It's not worth problem-solving yet because we have enough confidence of how our technology is working. What I can tell you is we have no shortage of ideas in the CNS. Some of the ways we prioritize diseases beyond what you just asked is we look at the unmet need. We look at the biomarkers. We look at the amount of patients that are out there. We understand the patient advocacy groups if it's a rare disease. We look at the models that are there. SYNGAP really got us excited because, quite frankly, the disease was only cloned in 2012. A lot of people will say to me, I've never heard of it. I'm like, it is actually pretty interesting because our math tells us there's at least 10,000 patients in the U.S., but there may be as many as 30,000-40,000 if you believe that 1% of learning disabilities are SYNGAP. It's a cystic fibrosis-like opportunity in that category. There's nothing that's disease-modifying or proven. There's nothing yet in the clinic that's disease-modifying. We may be one of the first programs to get into the clinic, if not the first. The patient advocacy group is incredible. They just published a paper recently. They have a registry. They're doing natural history studies. They've been really great to work with. Lastly, the data. The data for that program continues to excite us. We think that that's a disease that's highly applicable. We base all our decisions on data. We've already shared that we have patient-derived neurons where we can essentially restore function. At JP Morgan, we showed that we could take mice with healthy genes, healthy human genes, and upregulate to levels that we know would be potentially corrective. We have more encouraging data, and we're continuing to get very excited about that. When should we expect the next data readout for the program? Yeah. What we've talked about is initiating GLP tox studies, and we still intend to do that. Ideally, given the unmet need and the opportunities there, we are working to get this into the clinic as quickly as possible. We'll have more updates, hopefully in the coming weeks, to share on that. That one is a big opportunity. I should say behind that, there are other genetic epilepsies that have a very similar line of logic behind them in terms of same genetics, haploinsufficient state, same idea for technology. The data looks pretty good for us in terms of moving those forward. All right. I guess kind of expanding beyond those two programs, what's cooking in the hood? What is next? You mentioned at the beginning of our discussion that there are indications where just a little bit of upregulation can have a large impact. Where do you take that next? Yeah. I kind of maybe I buried the lead on this, but we're going to be, I would say, we're going to be building a lot more in the CNS. We like the way that's looking. Behind SYNGAP, we announced a program for GBA1 for Parkinson's. That's also a haploinsufficient state. I can tell you there's at least five to seven other encephalopathies or genetic epilepsies that are haploinsufficient states. There's also some really, really interesting targets for other diseases that actually require upregulation approaches, Huntington's, ALS, and others. No shortage of ideas, stuff that we really like, and we think we can move forward very efficiently and quickly. On the other hand, the biology that we're going after works in every different cell type. Partnerships are going to be really important to us. We announced a partnership with BioMarin late last year. That's been going extremely well. High science company. I can talk more about that. We are quite interested in applying our technology to other tissues that perhaps have even bigger, more complex diseases but have a genetic NASH, fibrosis. Those are other examples of diseases where you can pull out genes. That would be interesting. I'd say we're going to be building in the CNS, but you're going to see us doing partnerships in other areas where we're going to be making the drug that gets handed off for them to go after those diseases. You touched upon the BioMarin collaboration a little bit. Maybe can you give us a little additional color on the two targets there? I wish I could. I can tell you. We won't tell anyone. I know. That's what they all say. What happened there was they came to us, and they had confidence and said, if we can upregulate these genes for these diseases in these tissues, it would be a home run from our perspective. We said, OK. The way we set up that relationship is really actually a good example of how we want to do things, which is they came, they gave us the gene targets. We apply our platform. We identify the RNA. We make the oligo leads. They're even bringing some of their own assays, which is great because they have expertise in this particular area. There's a handoff point preclinically. We get about $200 million in milestones and then high single-digit royalties. More so, one of the interesting parts we don't talk about is it's in a tissue where we've done some initial work, but now they're funding us to do a lot more work in it. We're getting a lot smarter there. They're benefiting by getting a drug. They've basically just funded our expansion into a new tissue, which we will eventually be able to talk about. For reasons I understand that are important for them, we're not able to talk about those genes yet. What I can tell you is it's not in the CNS. That is still owned by CAMP4, if you will. All right. Thinking about that expansion beyond CNS to this other area that will be disclosed at a future point, how should we think about bandwidth to support other potential collaborations? Yeah. The short answer is we have bandwidth. Interestingly, we built this company. This has always been a scrappy company. I think every year is another year we're running out of money. That causes you to prioritize things and be super efficient, actually. That's built into our DNA. We have about 60 people at the company. We have one program in the clinic, another moving towards it. We're prosecuting at least one collaboration. We're still building a pipeline. That's how we like to do things. Just to give a little more color to that, though, where we're really efficient is on the front end. We've really got that going well. I'd say we can process anywhere from five to seven genes at any given time. We can do that in three to six months, if you will. In steady state, we're doing that on our own for our own purposes. If we bring in a collaboration, we can either reprioritize and continue to do that, or we can add incrementally. We have bandwidth because of the way we built CAMP4 and because we already have the database of these RNAs and because we've built chemistry at CAMP4. It allows us to move super quickly and not necessarily rely on external vendors. That's all within our control. Where things become a little more time, resource, capital expensive is, of course, when you get into higher species, primates, tox, whatnot. Typically, by handing it off to a partner, they take that on. We don't feel the need to do that. We're happy to do our own programs on that. I'd say we could take on at least two more collaborations of the discovery nature. When you start getting into things where we're doing more heavy lifting and further along, you have to start to think about that a little bit differently. We're a little bit further away from having to make those determinations once the studies are into the clinic and more intensive in terms of. Those will come. Those will be important because we can't do it all on our own. What I can tell you now is a lot of companies that are talking to us are really interested in the application of upregulating. It is interesting because they all have their own pet targets. There's not as much overlap as you'd think. Some are very focused on big CNS diseases, some kidney, some liver. That's good, actually. That actually makes it a lot easier for us because they're not competing with one another. We look forward to see where you take the platform. We are just at time. Thank you so much for your time. Thank you. I appreciate it. All right. Thank you, everyone.