We good? Okay, terrific. All right. Welcome everyone back from lunch, and thanks to everyone on the webcast for joining us. I am Steve Seedhouse with Cantor, and it is my pleasure to open our next session and welcome Camp4 Therapeutics. I am joined, of course, by CEO Josh Mandel-Brehm. Looking forward to a great conversation about a really important topic and some exciting progress that Camp4 has made recently, and that we are anticipating that you will continue to make here in the coming weeks and months. Thanks, Josh, for being here. First, just to start, tell us about SYNGAP. This is one of these things where as we have gotten to know the company and the indication as you have been prosecuting this program, those who know it, I think, have gotten to know it quite well and are pretty excited about it. I feel like we still need to keep getting the word out about the unmet need at every opportunity, and this is one of those opportunities. Make the case for just the importance of novel therapeutics for this really critical unmet need, I would say. Yeah, absolutely. Thanks for inviting us as always, Steve. Appreciate being here. Maybe I will do a little bit of storytelling, but I will- Quickly. Sure. It is good, yep. A little bit of storytelling, but I'll start with some background. SYNGAP1 is a genetically defined rare disease. It is caused by what's called haploinsufficiency, which means you have one remaining healthy gene, and essentially you're missing 50% of what you'd otherwise need to be healthy. The genetics are very elegant. What we know about this disease is that SYNGAP is a very important protein that regulates the AMPA receptors. Meaning, if you do not have enough SYNGAP, you have too many receptors in your synapses, and you get too much synaptic firing, which leads to many different downstream sequelae, learning disabilities, cognition problems, seizures, anger. Anything that essentially you think could affect these children and adults, because there's no early death here, is plagued by this disease, all caused by this missing protein. The storytelling part of this is what's really interesting, having spent 25 years in rare diseases, is every 3- 5 years, you learn about a new rare disease that causes you to say, "I've never heard of that," and then it becomes a very important rare disease. Examples would be SMA, Dravet syndrome, TTR, on, and on. Last year, when we began talking about SYNGAP, I think everybody we spoke with started with, "What's SYNGAP?" What I can tell you now is, we never get that question anymore, which I think is important and speaks to the importance of this disease. A lot of credit given to the patient society and the patient organization, who's really done a wonderful job of getting the word out there. The other thing I can tell you is these patients keep popping up everywhere, and in the public setting as well, and more recently, Becky Quick on CNBC said, "I have a daughter with SYNGAP," and others. We keep hearing about this. I think this is going to be one of those rare diseases that's not so rare. It's a really important approach we're taking because there's nothing out there. There's nothing but unmet need. Nobody's ever developed anything. We're the first ones to do that, which I think creates an opportunity we'll talk more about. But to start with, we got to do something for these patients. Yeah. It's gratifying to hear, because it was really probably a little over a year ago maybe when we were talking, I think it was maybe during one of your fundraisers, and really the biggest lift it felt like at the time was just creating awareness about SYNGAP, and you had the preclinical data. Yeah You had this regRNA approach that seemed to be working. You could restore protein expression, but it was almost like a, "I just need to educate people on this condition. Yeah. It sounds like you've certainly made a ton of progress on that in the last year. So credit to Camp4, also, you mentioned the patient advocacy organization stuff, but credit to you all at Camp4 for doing that as well. Then congrats also on the recent authorizations to proceed with your clinical trial, which is going to start in Australia. This is exciting. You mentioned Argentina as well, I think you're approved. So maybe open-ended question, any additional updates on the phase I preparation, or just outlook for adding new geographies or anything logistical here in the coming weeks and months? Yep. So one quick update, we are now approved to start in the U.K. As well. Okay. Congratulations. We'll send a press release for that tomorrow, and we're working on the rest of Europe. I know one of the questions you had was about the FDA, and that is in the works as well to go. We believe it's really important that we're able to start this study, and we've guided to initiate the study in Q4. Just a little background, we chose all of our sites based on a few features. One is thought partnership. For example, in Australia, one of the leading experts, clinicians, one of the first people to clinically diagnose SYNGAP, Dr. Ingrid Scheffer, is there. Two, making sure there are patients there, cohorts of patients, and that's usually surrounded by patient advocacy. Three, making sure these sites were set up to be able to do intrathecal delivery as well as all the measurements we want to do for this disease. We're going to have 10 to 12 sites. Just to plug, I know we're going to ask about this, we'll have an analyst day on September 28th, where we'll talk in much more detail about this. We're ahead of schedule. We've made great progress. We're heads down, and we're really looking forward to being able to start treating and dosing these patients. Do you find that when you're interacting with sites in Australia versus Argentina versus U.K., et cetera, that the sort of priorities of each of these places in terms of endpoints that they care about or their patient experience that they're used to, is it similar, or are there some differences there that are going to be important when it comes to randomizing or just prioritizing certain sites? No, I think they all have the same intentions in mind. Actually, they've been very good about talking to us about the types of patients they have and asking if they'll qualify for the study. Interestingly, we have many in the U.S. reaching out to us asking if they fly to Australia or other places, can they get in this study, which I think just speaks to the need for this. Can they, or is that not- No, that is not something that we are doing. But again, this is why we are aiming to open up sites in multiple different places because the demand is there because people need help for this disease. Okay. When do you anticipate starting dosing? We have guided to Q4 initiation. When people sometimes think, "Oh, you have got an approval," so we immediately start dosing. Many times what ends up happening is you get approval, then the hospital is then allowing the drug to be shipped in, and you can start working with them to get everything set up. So we are in that process right now. Okay. I am going to walk through. You shared some of the details publicly about this study, so I am just going to ask you about what you have shared to the extent that you can elaborate. That would be great. If not, you can just sort of clarify and confirm maybe some of these details. A lot of this is from an interview that you did, in fact, with CNBC Cures, so I am extracting some of it from there, particularly for folks that were not able to catch that or who want maybe some incremental color. I think you talked about 30-ish or 30-ish plus subjects in the study. I guess, is that the case? Are you thinking less or more, and sort of how confident are you that you can find that many patients and enroll them, and on what timeline, I guess, is realistic? Yep. Well, maybe going backwards first. Timelines, I think we will really start tightening up guidance once we get going and have a better understanding of enrollment. We want to always try and be as accurate as possible, not overpromise. We do not anticipate enrollment challenges for the reasons I said, both choosing sites, but also just how proactive the patient community has been, and CURE SYNGAP1 has been fantastic in helping get the word out. So I think that is important. As far as patient numbers, yeah, give or take, that is about where we will be. We have built into the protocol the ability to be adaptable based on what we see and what we need to do. So, just at a high level, we will start with three cohorts of patients going directly into patients, and Three dose cohorts? Yes. Okay. Yep. We'll give more detail at that on the Analyst Day that's upcoming in a few weeks. You've said many times, I think, this is right into a multiple ascent. It is. We've taken advantage of what a lot of other companies have done before us in the CNS oligo space, both in terms of learning from places where they maybe had made some mistakes, but also taking advantage of places where they've done really good things. One of the things that we think is getting to a dose that matters for patients quickly is the ethical thing to do. Going directly to a MAD study makes a lot of sense, and I think the regulators saw it that way as well. Yep. I know obviously there's a humanized mouse model that you've leveraged, but also you have primate data. How confident are you that with this gene and with this oligo, that the primate data is going to be pretty useful to project those first in human doses? Are you confident in translation? Yeah, maybe I'll answer that in two ways. First, I love the question. It's interesting if you go and you look at siRNA and oligos used in monkeys against single gene diseases, monogenic diseases, that tend to show a good pharmacodynamic effect, that tends to always translate to clinical success. That's not a guarantee of anything, but we like that probability, and we like the target. Likewise, you asked an important question of how valuable are the monkeys to think about dosing. What I can tell you is, by triangulating the efficacy we saw in the humanized mouse, which replicates the disease, through the pharmacodynamic and safety markers we saw in monkeys, which doesn't replicate the disease because they're healthy, we're able to use that to directionally have a nice starting dose that we think is going to be meaningful in terms of where we're going to be able to get to. But as with all ASOs that go in the CNS, it's directional, and you really have to do some dose finding in the clinical setting, but it gives you a good starting point. Okay. Obviously, this is a disease that you mentioned affects all age groups, including adults, because it's not a fatal disease. What age are you intending to enroll in your initial study, and why? Yeah. Like many rare diseases, we want to get as early as possible, right? This is not a neurodegenerative disease, which I think is important to call out. It's a neuroarrest. There's reasons to believe that you can have an effect later in life based on academic work, as well as some other analogs. Nonetheless, we'd like to get there as soon as possible. The two things we have to balance are safety, right, and then also being just thoughtful about how young to go. But ideally, we will start with the sentinel. That is a first patient, maybe around 8- 10 years old, and then we'll drop down as quickly as possible to get to 2- 3 years old. How do you think about dosing across age groups, because I think, you know SPINRAZA well. Yeah. There's various different dose regimens that are required depending on adult versus pediatric. Yeah And with varying degrees of effectiveness. Yeah. How do you solve for that as you move this? Yeah into the clinic? Well, I guess the two answers, one is kind of embedded in the question you asked, which is there's a lot of data out there that we can take advantage of to make those decisions. A lot of it's based on our own PK/PD data. For example, we studied our drug in younger monkeys that translate more to pediatrics as well. I'd say between our own data that we generated as well as what's in the field, we have a pretty good starting point in how to approach this with younger patients. Okay. The dose interval. I guess I'm going to ask this two ways. One, what are you intending or- Yeah thinking is viable here in your initial study? For regRNA therapeutics in general, it is a bit of a novel approach, right? It's not a typical ASO, in terms of knockdown. Yeah. It's not splice switching. You can use precedents, but I don't know. Is there a novelty here worth noting for regRNA, and how are you thinking- Yeah about dose interval? I think you're saying it's just really cool. yeah. I guess although we are pioneering a new way of using antisense oligonucleotides to upregulate, we have found that the PK/PD properties seem to match that of other oligos. as a reminder, the chemistry is the same state-of-the-art chemistry that's in approved drugs like SPINRAZA. we did that deliberately to not only lower risk, but also to be able to take advantage of those properties. based on all our primate data, our mouse data, everything that we've looked at in terms of distribution as well as efficacy It seems to match up with the same characteristics as other oligos. we fully expect that it shouldn't be different in that regard. Okay, great. One comment that you've made that I just find interesting and kind of funny is you alluded to measuring everything- that you could in this study from an activity or from an efficacy standpoint. Presumably seizures is included in that, but what is the scope that we're talking about here? Because- Yeah there is a lot of symptoms and manifestations of- Yeah SYNGAP disorder, as you know. How onerous is this going to be to collect all the data? I got nervous when you started asking that. Just to remind everybody, this disease impacts so many domains of a patient's life and the caregivers. Right. Lucky for us, all of these domains are already measurable for the most part. Okay. There's already either existing technologies or measurement systems, and many of them are actually approvable endpoints, too. Great opportunity for us. For example, we will use Bayley, we use Vineland, GMFM. There's a scoring system for sleep that we'll take advantage of. We'll use video EEG and EEGs, right? We will use patient-reported outcomes, of course, with caregivers and diaries. It is a heck of a lot to do, going back to how we chose sites and whatnot, but we actually worked with the patient organization and shared our designs with them to get their input as well. Is this too much? Is this doable? It did cause us to actually think about, okay, what's realistic in terms of how many patient visits to the hospital can these patients handle, whatnot. I'd like to say it's a good balance between what we know the sites can handle, what we think the patients can handle, but also the types of data that we think we need to measure to create the best opportunity here of showing that our drug could work, and working to develop endpoints that we can pull forward. I should also say, interestingly, the majority of what I just mentioned, too, is already being done in the natural history study. We know that it's doable as well, and it creates a comparator set for us. Yeah. You have that comparator set. Are you going to have a placebo arm in this study that you'll implement- Yeah as well? That'll be- We think it's important to have- Okay a control. Namely because if we see great results, we want to have as much optionality as possible to have robust discussions about how to quickly advance this. I see. Yep. Okay, then those patients, presumably they'll be able to cross over to drug- Right at some point, that's the Okay. Yep. Once we have the full data package you'd expect for safety and whatnot, we think all the brave patients deserve an opportunity to receive drug if they're entering into the trial, we'll do that. Okay. Maybe a curtain raiser on the Analyst Day in September. Just remind us what you're planning to cover there and where you think there's maybe education gaps that you'd look to address at that event and- Yeah is this an opportunity Yeah to sort of announce that you're imminently ready to start the study, which is in Yep fourth quarter. Yeah. We're really excited about this event. Our team has worked incredibly hard. There's been a ton of thought put into it by our CFO and CMO and others. We're really excited to be able to talk to the world about this and for a couple of reasons. One is, I've spent a lot of time talking about this disease, as has my team. Most people haven't met these patients. It's one thing to see a picture of them and to read about them. It's a whole another thing to experience them. I know you have, Steve, so you know what I'm talking about, having gone to the CURE SYNGAP1 Conference, which is a wonderful thing. We are going to invite in a family with a SYNGAP daughter to speak about their situation and actually share some videos of the daughter. Very cool. I think that's going to be really important for people. We've invited in a KOL to come talk, and this is virtual as well, so people can register, and it's on our website. Very importantly, our Chief Medical Officer, Yuri Maricich, is going to take time to go through the design of the critical study, all the detailed questions folks are asking. At this point, we would have enough buy-in from different regulatory agencies that we feel confident in what we're sharing, that this is the design. Interestingly, it's been very consistent, which is really good. The last teaser I'll put out is we'll spend a few minutes talking about what's next, which we get a lot. Our technology's applicable to more than just Syngap, and we've been quietly working on the next Syngap-like diseases, so we'll be talking about that as well, which I think will be exciting. Yeah, just within DEEs alone, I guess there would be some opportunities, I would imagine, to apply regRNA technology. Beyond that, I guess the- Yeah I think you've identified probably thousands of regRNAs- Yeah at this point, right? you guys have published on that, so there's a lot of optionality. You name the gene, we can upregulate it with the regRNAs. The technology, at least pre-clinically, is working quite well for us. We're lucky in a sense Well, I shouldn't say it that way because it's about patients. there are many examples of diseases that are haploinsufficient, CNS, unmet need on par with SYNGAP, no approved treatments, same regions of the brain, totally applicable to our technology. I think there's a massive franchise opportunity for us, and our strategy is, look, when we show that SYNGAP works, we want the next program ready to go into the clinic, and I want folks like yourself to say, "Well, if that worked, this should work." It should be a rinse, wash, repeat. It's the same idea. that's what we're setting up for. I think with SYNGAP, and maybe I'll ask the question with SYNGAP as the sort of case study, but with the regRNA approach, you really are, in this case, you have a haploinsufficiency condition, and in some cases, depending on where the mutation is and in which exon, you don't necessarily lose 50% expression, right? There's a gradient of sort of- Yeah severity of mutation. Yeah. there could be risks of overexpressing SYNGAP. You could disrupt these neurons- Yeah as a result of hyperexpression. Yeah. you really are just trying to restore from that 50% or 60%- Yeah 70% back to 1. that wouldn't be true necessarily of a gene therapy or- Right maybe a splice-switching therapy or something. There are different considerations. I guess therein lies the sweet spot for indication selection, right? You'd be looking- Yeah for other scenarios where it's precisely that, where you're not just trying to maximize potency and overwhelm some- Right system with protein. I guess what you're saying, to paraphrase, is that you think there's a lot of these types of indications where this is the perfect sort of well-tuned approach. Right. Yeah. maybe a couple quick comments on that. The bug is a feature I like to say. Our bug is that we can only twofold. That's where the system taps out. I can't tell you exactly why, but I can tell you we've done it enough to know that cells will allow for about a twofold increase. we turned that around and said, "Well, where is that applicable?" as you just alluded to, in haploinsufficient diseases, twofold is exactly what you need. when we get the question of what about overexpression? My answer, or CSO's answer, we don't really worry about that because we've never seen that happen. I don't think that's a major concern. You're exactly right. In these types of diseases where you're replacing such important proteins or ion channels with a gene therapy, I think there's risk in that. It's being pursued, too. we'll see. Yeah. I would imagine this space is going to attract competition as- Absolutely you proceed. Competition is good, and I can tell you there are a lot of different companies thinking about this right now, as they should. It's a great target, and it's a patient population in need, and it's a big opportunity. Just to give an example, these things are never as simple as they seem. SYNGAP protein comes in six different isoforms. How do you choose which one? The elegance of our approach is because we're acting at the transcriptional level, we are boosting production of all six isoforms. proportionally, they're increasing- That's correct. Yeah. Nobody argues that that's a prudent way to go. If you're going downstream, you have to likely choose one of the isoforms, as with the gene therapy as well, because you can't fit the gene in the gene therapy. I think there are unique challenges in these things. To bring it back to the higher level, which you put out there, yeah, I think that there's a whole sweet spot of diseases here of these haploinsufficiencies that look and feel just like SYNGAP, that we hope we can build around with our technology. just on that isoform point, my understanding is from following the literature, and just sort of seeing the new studies and announcements that come out is we kind of understand how the splice isoforms can be disrupted, and there may be some correlation with severity, but you don't really know what each individual one. Yeah what's the most important one. Yeah to restore, what's going to happen if you only restore one, or if you, at the expense of one, you're repopulating the other isoform, maybe then you lose some importance of. Right the other. Is that all fair? We don't really have a whole answer. That is fair. I'm kind of smiling because I'm like, it's the analogy of, well, I guess one kid's going to college and the other one isn't. Yeah. You're exactly right. There's no perfect way to do this. Yeah. You essentially are taking from one to give to another, and we don't know, right? Yeah. I think there's some risk there. Nonetheless, it's good that lots of companies are thinking about this and trying to help these patients. Yeah, I think it's great. Going back to your preclinical work, so I thought you had an important update a few months back where you were able to measure the seizure phenotype in mice as a model where you're inducing seizures, and you could treat. I think that had been challenging for some time to recapitulate the seizure phenotype of SYNGAP in even these humanized mice. Maybe can you talk about that experiment and the importance of that finding- Yep the confidence it gives you as you translate to human studies? Yeah. This was one area when we were out talking to investors before we did our pipe that this was the one thing that we heard a lot about. Because rightly or wrongly, I think people tend to look at seizures as an endpoint that should move quickly and is approvable, and that may or may not be the case here. It turns out, though, that in SYNGAP, the types of seizures are different than your classic drop seizures. They're absence seizures, right? what does that mean? It means that they're very hard to see in humans. They're certainly hard to see in mice. They're not overt. there's two things you can do there. One is you can measure EEGs. That is very technically complicated. We have an ongoing collaboration to do that. It's not easy. The other thing you can do, though, is you can use a chemical to induce seizures, and that's exactly what we did. at least to us, not surprisingly, when we did that, what was really reassuring is that we showed you could not only reduce the frequency of seizures, but also the severity of seizures in the humanized mice that we studied. Which we think it was the last missing piece that folks were asking about in terms of things we're going to study in the clinic, had they been recapitulated by our preclinical data. I think it helps, too, if or when you see that improvement in the clinic and seizures, it reduces the likelihood that it's sort of a spurious result, right? Right. You can sort of also demonstrate it in the mouse model. I thought that was I agree. I thought that was pretty cool. We were happy. Yeah, indeed. What is your current understanding of. I think you were alluding to the fact, basically, we're going to have a placebo-controlled study, multiple ascending dose. Yeah. It's going to be a pediatric patient, so we want optionality for what to do with that study. There could be an accelerated pathway towards a conversation to approval, maybe even accelerated approval or conditional approval, or maybe not, maybe just outright full approval on a single study, given the natural history data. How advanced are your conversations globally with regulators, and what's our understanding of what it would take to get to market? Yeah. My answer might not be as satisfying as I hope it will be in the future. One of the answers we've given people, because we get that a lot, given the unmet need and that there's nothing out there, is we want to signal seek with this study and let the data do the talking for us. Back to your original question, you're measuring lots of things. Our strategy is a parallel processing strategy. For one, we think we are going to be able to have robust discussions based on the study design, and we're going to let the data tell us what to do. If people recall, for SMA, Biogen and Ionis created CHOP INTEND. They created a novel endpoint to pull it forward. Yep. We think that opportunity may be here, and we're setting up for that. We are starting to engage and think about with regulators, "Hey, could we talk about what the future could look like here?" We have not done that yet. Our first priority was getting agreement on the current design and getting started. More to come there. I do think that there's a lot of opportunity, but I think what we're doing, I think rightly so, is at least setting the study up in a way to be robust enough to allow for those possibilities. For example, we know if you do not have a control or placebo in this setting, it's very hard to have those discussions. So we built that in. We're going to, I think, try to have those discussions as data are being generated, but I'd also say we're going to let the data do the talking for us in terms of what happens. Obviously, if you get an extremely robust result, it makes those discussions all that more compelling. Yep, indeed. One thing that I think would help those discussions, of course, is the natural history work that you've talked about. How close are you to that data as it's accruing, and how is it informing your trial design as you contemplate that? Yep. What are we learning from the natural history study? Extremely important. Hats off to CURE SYNGAP1 again. Did it exactly right. There's so many rare diseases where, unfortunately, they didn't have the means to do this. SYNGAP1 has really done a nice job with this, where you have close to 1,500 patient years of data. That's a lot. Very robust data. We have access to it. We are actually helping form it now moving forward. We're very collaborative on it. We are going to talk about it at the Analyst Day, so we'll be sharing some of it, and it has absolutely helped inform our clinical trial design in terms of thinking about what to measure and which ones we think can actually move. Example, Bayley, Vineland, GMFM, these are all things that have been measured in this study that we can bring to bear to help inform our study, but I think also help discussions with regulators in the future. Okay. Is that study enrolling globally, the natural history study? Or is it just- No, it's in pockets. There's one in the U.S. as the PROMISE study that's run by a few different sites, and there's also one in Europe as well. They're separate studies, interestingly, but they're still very valuable. The one we're working with right now is the U.S. study. Okay. Beyond SYNGAP and then maybe even some of the other programs that you'd be in a position to announce in the coming months or years, with the technology, you've had some sort of collaboration- agreements in the past. This is a platform technology that you're validating. Yeah. How do you think about, strategically, how to partner up with folks, and maybe any updates or anything to talk about with some of your historic collaborations- Yeah that are noteworthy for folks? Sure. We have a collaboration that's in place right now with GSK. That's the type of deal we enjoy doing, which is a discovery deal. They came to us with two targets in mind, two genes in mind, one for a large CNS disease, one for a large kidney disease. Both are opportunities that Camp4, left to its own devices, would not pursue. Right? We're really focused on the DEEs right now. However, our platform is quite robust and very efficient. So what we were able to do in that deal is map out the cells, identify the regRNA, create the ASO leads to hand off to GSK so that they can bring forward those against those two different targets and develop them, and we get paid milestones and royalties along the way. What I tell the investors is, "That's a great deal because that keeps my engine running. I don't want you paying for my engine. I want you paying for the assets that come out of it, like Syngap." So we love those deals. We're getting a lot of attention right now, because I think the upregulation field writ large is becoming more interesting to bigger companies. There's, for example, lots of great targets in the heart, lot of congenital diseases, kidney, muscle, also in the brain. So, we're looking to do more of those. There's a whole another category of companies which is interesting, which not surprisingly come and talk to us about Syngap and the DEEs, and are quite interested in that as well. Obviously, Syngap, we think we're the best ones to develop that right now, and we have our own aspirations, so we're very focused. The DEEs as well, but we have been having discussions, and it's all about how quickly can you move things forward and create value together. But I'd say in the nearer term, the types of opportunities we're looking at are more GSK-like for the types of diseases we wouldn't necessarily go after on our own. Okay. From a technical standpoint, is the ASOs, the regRNA targeting ASOs, are they comparable with some of these novel LNP delivery technologies that- Yep as you're thinking about hard targets and things like this, obviously delivery, it's harder for a gene therapy- Yeah now all of a sudden we can deliver to skeletal muscle and to heart muscle- Yeah stuff like this. It's neat stuff. It's on our radar. We get asked about it a lot. We ourselves are not doing delivery, yet at least. We're really focused on what we can do. We're a 60-person company. absolutely, a lot of the companies that come to us are like, "We don't know how to upregulate. Could you guys do that part? We'll do this part. Yep. I think it's on our radar, but also it's on other people's radars. Makes sense. we're looking forward to the Analyst Day here at the end of the month, obviously, and learning more about the progress as you head towards that clinical study, which is going to start, as you mentioned, in the fourth quarter. Really exciting stuff. Gratifying to see all the hard work that Camp4 and you, with your leadership, has been paying off to get you to this point. We're excited to see the data- Yeah emerging from that study. Thanks so much, obviously, for walking us through everything and for the update and, as always, enjoyed the conversation and looking forward to the next time we speak. Thanks, Steve. All right, and thanks everyone in the room and on the webcast for joining.