Right, let's get started with this next session. My name is Paul Jeng. I'm one of the biotech analysts at Guggenheim. And our next presenting company is Corbus Pharmaceuticals. And I'm very happy to welcome Yuval Cohen, CEO of Corbus. Yuval, welcome. Thank you for having us here, Paul. Yeah, good to see you again. So maybe we could just start by doing a quick introduction to the company and your key pipeline programs. Sure. Corbus is based in beautiful Norwood, Massachusetts. It's about 30 minutes away. Not exactly a hub of biotech, but we really like it and the rent is very affordable, so highly recommended. We are a small company. There's under 40 of us and we actually really like being that size. It's important for our culture. We have an unusual pipeline because it has three assets in it: two in oncology, and the third one's in obesity. The oncology one, the one that is top of mind, is our anti-Nectin-4 ADC. We just came back from ESMO with some updated data there and then on the obesity side, it could not be more different, is a small molecule, highly peripherally restricted CB1 inverse agonist and those two form the topics of 99% of our discussions with buy-side and sell-side. Fantastic. So let's start with the Nectin-4 ADC, CRB-701. Obviously, Padcev has validated the Nectin-4 target as an antitumor target, but has some well-known tolerability liabilities that narrow the therapeutic index. So how is your asset engineered to be differentiated from Padcev? The Seagen platform where Padcev emerged from is a relatively older platform. And one of its hallmarks is built-in instability. It has to do with a linker. It also uses a stochastic conjugation, which is something that's no longer used. Our ADC, which comes from CSPC in China, CSPC being the third largest Chinese pharma company, this is their fifth, I believe, ADC that came off the assembly line, is much more typical of the new generation of ADCs. What does that mean? It uses site-specific conjugation. So your DAR is very, very, very precise. It's no longer stochastic. So we have a DAR of precisely two. But like Padcev, we have MMAE as our payload. It uses, like many novel ADCs, a very stable linker rather than an unstable linker. In this case, the other difference with Padcev is the antibody itself at the one end of the ADC is different. It's not enfortumab. It is an anti-Nectin-4 antibody, but it binds to a different epitope. It's Fc-enabled. And equally importantly, it has twice the rate of internalization in vitro as enfortumab. And the whole idea here, Paul, is design a Nectin-4 ADC with MMAE as a payload that is much more stable. So less of it falls apart on the way to the tumor, which means there's less free MMAE. And that means there's less collateral damage, especially in terms of peripheral neuropathy and skin. And on the other side, deliver more intact ADC into the tumor so they can actually affect the tumor and destroy it. And what we've seen initially back in the day, three years ago in vivo, and now in the clinic itself, is precisely this very beautiful translation from the theory to the practice. So if we look at PK in patients, we see that we can deliver a lot more ADC. We see that it's a lot more stable. Our dosing is once every three weeks, not once every week like Padcev. A lot less free MMAE. And the clinical implications of that are important. We have what seems to be a best-in-class rate of low peripheral neuropathy. We have relatively low skin, lower than Padcev, low discontinuation rates. And on the flip side of that, our emerging clinical efficacy looks really very, very promising and already differentiated from Padcev. Perfect. So let's go into that recent update you had at ESMO, which was very comprehensive. So could you walk us through what you reported? First, I guess in late line, head and neck cancer, how that compares with the current standard of care, as well as the emerging landscape. Sure, so at ESMO, we had the dose escalation, the latest dose escalation data that was first shown at ASCO GU earlier this year, and then the dose optimization data, so combined, it's about 166 or 167 patients, of whom 60 were head and neck, and of whom about 40-something were evaluable. So what did we see for head and neck? I'll start with the safety. Like I said, a lot less peripheral neuropathy and skin than you'd expect with a Nectin-4 MMAE ADC. The price we pay, Paul, like so many of these novel stable ADCs, is ocular tox. So this is tox of the surface of the eye. We've now seen this over and over again with novel stable ADCs, and the way to deal with it is patient selection, eye drops, dosing holidays, very standard protocol that has now emerged across the industry. They're reversible. They tend to be sort of a hump. Once you get past it, they tend to not come back. Most importantly, they don't lead to discontinuations. That's really important. Unlike peripheral neuropathy, which is unfortunately a showstopper for the patient once that emerges. On the flip side, on the efficacy for head and neck, for two doses, we saw efficacy that was well above what was recorded with Padcev in similar lines, in fact, even less pretreated patients than we did. In perspective, monotherapy Padcev in head and neck is about 23% ORR. Our doses were 33% and 47%, respectively, depending on the dose. That feels a lot different than Padcev. That also opens the door to what is actually relevant in head and neck for us, because Padcev is no longer relevant. They're not moving forward. Pfizer is not moving forward for Padcev and head and neck, and in second-line monotherapy, there really isn't a lot. It's a pretty open swim lane. There is the peto monotherapy data, although a reminder that peto is really being positioned as front-line therapy in combination, but the peto monotherapy data in patients that were less pretreated than ours was 36% ORR, so that lines up in a promising manner. Our data set is young. It needs to mature. We haven't got PFS or DOR yet, but we'll get there, but overall, it's a very orthogonal mechanism of action in a very desirable tumor, in a very desirable swim lane for us, at least, and we're very, very encouraged by the data. Great. So I think the efficacy that you've shown is well appreciated for what it is. There may be some more nuances to the tolerability profile, as you alluded to. Can you sort of contextualize the clinical significance of avoiding some of the tox, like peripheral neuropathy or the skin tox, and how that might be balanced with how a docs will view the ocular tox and what the sort of burden of managing that is? Yeah, peripheral neuropathy is one of the worst things that could happen to a patient in their journey. It tends to be irreversible. It is often untreatable. And so, as I said, it sadly heralds the end of that therapy. It's the number one cause of Padcev discontinuation. The other sort of challenge of these Nectin-4 MMAE ADCs like Padcev are really potentially quite severe skin. So when we think about skin, we think cosmetic. This is not cosmetic. These are life-threatening skin toxicities. And our rates for both are low, especially for peripheral neuropathy. We have a best-in-class low rate. Ocular, as I mentioned, is very different. And what we've seen and heard from the oncologists in our study is the word that comes back over and over and over again is it's manageable. It's not a showstopper. They can maneuver the patient or guide the patient through the period of the ocular tox, and maybe, Paul, a quick segue. What is this ocular tox? I mentioned it's the front of the eye or it's the surface of the eye, so it's not within the eye. It's keratitis and dry eye. Grade 1, which is our most common grade, is completely asymptomatic. It can only be detected by an ophthalmologist. Grade 2, the best definition I heard of it is you're wearing contact lenses, and you forgot to take them out at night, and you woke up the next morning, so your eyes are red, and they're gritty, and they're uncomfortable. Grade 3, where we have under 10%, is where that discomfort leads to blurry vision. My vision is not as good as it was without them. I get that with contact lenses after about two hours. I'm a terrible example of that. Grade 4, which we don't have, would start to be changes to the surface of the eye. Thankfully, there are no Grade 5 is for ocular. That sort of puts it in perspective versus peripheral neuropathy, where when it gets bad, the patient falls out of bed or falls down the stairs or can't get dressed or can't drive. It really impairs his or her function. Of course, it can be very, very itchy, so they don't sleep, or very painful. Got it. OK. And the ocular tox that you saw. Appreciate the sort of additional color. How does that compare with some of the other ADCs that have shown this category? Yeah, because there's so many. So it's interesting. It's a spectrum. So Padcev, interestingly enough, had 44% ocular tox, mostly Grade 1 and 2. The reason we never think about it is it just wasn't a big deal. It wasn't a reason for patients to stop the study compared to, again, to peripheral neuropathy in the skin. Blenrep from GSK is on the extreme end of this. It wins the league, in other words. 95% ocular tox, 77% grade 3. You're basically guaranteed to get it. And it just got full approval, just to put it in perspective. Tivdak is similar to where we are. Tivdak is in cervical, has other issues. But the ocular tox is similar to where we are. And so it's a gradient of, and we see more and more of this. We will be continuing to see more and more of these as these novel stable ADCs come online. OK. And as you alluded to, most importantly, very few treatment discontinuations. AEs seem to be managed well with the interruptions. Anything you can say about the duration of these interruptions and sort of how you think about balancing the dose intensity overall with managing those adverse events? Yeah. The strategy is patient selection again. So if a patient has active eye disease, you're not going to enroll them. Eye drops, it sounds unsophisticated, but they actually work really well. And then these dosing holidays, so my colleague Dominic's team did an analysis on it. For the high dose, the average dosing holiday, in other words, the gap between a cycle and the next cycle was just six days. For the lower dose, the average was one day. And that was sufficient in order for the physicians to manage the ocular toxicity. OK, very clear. All right, so with these data in hand, what are your next steps and key focus for regulatory discussions before you kick off a potential registrational study? There's a number of things we need from regulatory authorities, FDA. We will update those on Q1. The most important thing is an agreement on the protocol for the pivotal study that will start in the middle of next year. It's very obvious what we would like. What we would like is the path that Merus, I guess these days, Genmab paved with petosemtamab second-line monotherapy, which is a controlled study against physicians' choice for late-line therapies. Those tend to have an efficacy at around 10%, sadly. So it's yet more chemo, for example, or yet more Keytruda. And then more recently, BioAtla on their subpopulation of head and neck patients negotiated a very similar study. And so that's what we would like to negotiate. It's one of those cases, Paul, we actually do not want to be creative when it comes to study design. That study will launch middle of next year, and part of that study, part of the advantages maybe of why we think that this is such a nice swim lane for us, to segue for a second, so in our data already, which is a small, young data set, but nevertheless really informative, we've already seen patients who, for example, were HPV negative and HPV positive respond, so that already starts to position it differently. We saw PD-L1 positive and negative patients respond, and that's also very helpful. We had a tiny number of patients who were EGFR experienced. We had two patients, for example, who were pre-experienced with peto, and we saw responses, so as we think about this study and the inclusion criteria, there are certain things that are really very attractive for us. And also, ultimately, as a positioning for the drug itself, our vision, and I don't think it's a particularly original one, is the future of head and neck for many, many patients will be one of now three potential EGFR therapies that are being investigated as the front line. But once they've chosen one of those three tickets, the other two choices are really taken away from them. It's unlikely that they'll revisit that mechanism after failing it. And that's where we're positioned with this really orthogonal mechanism of action. And that's what we find so attractive. And we think as we design the study and discuss it with the regulatory authorities, that's one of the things that's attractive. We're very grateful that FDA recently gave us fast track, and that's also going to be helpful. Great. And how are you thinking about the doses you'll advance to the pivotal study? So we have the bookends of those two. That's what we did for Project Optimus. We can't comment until we talk to FDA. But it's going to be somewhere between those, one or the other or between. That's simple. Makes sense. Is this purely a second-line plus focus for you at this point, or would you also consider front line at some point? In this summer, so a few months ago, we started combo study in head and neck with Keytruda. The first few patients have to be second-line plus for safety. You just want to see how the two agents play with each other. But very quickly, we're moving to front line. We're very curious to see what that looks like. We think there is an opportunity in front line in two ways. One is the combo to see what it looks like. Again, it's completely orthogonal to the three EGFR combos that will dominate that part of front line. But there are other advantages that we have, as I mentioned. 15% of patients are PD-L1 negative. The three EGFR, two of the EGFR therapies are entirely HPV negative biased. The last one, the jury is still a little bit out on that. We seem to be HPV agnostic, and that could be interesting for the front line as well. And so we'll have that data set maturing in the second part of next year. Along with earlier next year, we'll have the monotherapy maturing with PFS and DOR. OK. For the combo data that we might see, can you set some expectations for sort of the scope of what we might see in that data set? In terms of what? How many patients? Oh, yeah. It started this summer, several dozen. It's about our sweet spot. Okay, excellent. All right, so as you mentioned, you do have an additional pipeline. So I wanted to touch a bit on the CRB-913 asset and obesity. So yeah, where are you with this asset? Can you sort of explain the mechanism as it is and what's the next sort of inflection point for the program? I'll start with the mechanism. It's a CB1 inverse agonist. And anybody who was around in the early 2000s will remember that was at the time an immensely exciting drug class for weight loss. Many, many, many big pharma had very expensive programs in that mechanism. So these are all small molecule drugs, oral small molecules that bind to the cannabinoid type- 1 GPCR. And what they do, Paul, is super cool. They don't block it. This is not an antagonist. They inverse agonize it. Think of this GPCR as a gearbox of an incredibly expensive Italian sports car. They put it in reverse, but not in neutral. And what's so fascinating about it is that every single one of them led to weight loss. There were a whole weird and wonderful slew of them. Every CB1 inverse agonist ever tested in the clinic that we are aware of has always led to weight loss. It's one of those classes where you're not wondering if it's going to work or not. What you're wondering about is, have we managed to get rid of what ultimately doomed that first class, which was a perception of a risk of neuropsychiatric adverse events, and that is because those drugs were highly, highly, highly brain penetrant on purpose, and so what we did and what Novo ended up buying from a company called Inversago is we are one of two peripherally restricted CB1 inverse agonists. It sounds almost cartoonish, but it's that simple. They basically don't go in the brain. They're cousins of each other. The big difference is our peripheral restriction is over a log more than theirs. So we really don't like going in the brain. Preclinically, they all work. In mice, they all work. That's easy. Monlunabant's data was published earlier this year or a few months ago. It's good news, bad news. The good news is it is whoppingly effective. It's actually astonishingly effective. To put it in perspective, for those of you who follow obesity, monlunabant looks shockingly like orforglipron. 8% in four months. That's pretty remarkable, especially for a CB1 inverse agonist. The bad news is too much of it still goes in the brain. It also has an enormous amount of GI adverse events. Very surprising for the class. The class is not usually associated with it. What we're about to show before the end of the year is our first clinical data. Now, it's SAD/MAD data. So it's mostly healthy volunteers, single ascending, multiple ascending doses. It's really about safety for a short period of time. The MAD is only seven days of dosing. PK, which is exciting for us, but not for many others, et cetera. But that opens the door, and that's in a U.S. site. All our studies are only in U.S. sites. That will open the door, Paul, to a much more exciting study, which is a 90-day study that will start before the end of the year in obese non-diabetics, dose range finding. In that one, safety, of course. In 90 days, we'll see the safety. That's more than enough time to be differentiated. But equally, 90 days are going to lose weight. And so it is highly likely that they will lead to weight loss. What we don't know is how much weight loss. It's highly likely because every CB1 inverse agonist has always led to weight loss. So SAD/MAD before the end of the year. And then the launch of the next study. And then the middle of next year or so, that 90-day study. And that should be really informative. OK, excellent. Then very quickly, I want to touch on the third program, CRB-601, which is a solid tumor program. What's the next inflection point for this asset? So it's still in dose escalation. We had a study in progress poster at SITC. This is an unusual asset because this is the one where we don't know if it's going to work or not. It's so different. The other two, we're following the footsteps of others. Here, we're following the footsteps of Pfizer. They have a nearly identical drug. We just don't know what data they got. And they're ahead of us by two years. So we'll see what we get. We're very curious to see what they got. But it's an IO play. We're first looking at monotherapy. It's a TGF-beta play. So it's a high risk. But if it works, it's high reward. We'll see. We'll see how we get. Would you expect monotherapy activity, or is it mostly a combo? We would hope for it, but it's IO. We're setting a high bar for this. If it shows nothing in monotherapy, that will give us some pause, and I think it's actually, Paul, it doesn't matter what we think. It's what buy side and sell side think. I think we've seen so many IOs without monotherapy that then fail that it would really give us some pause to move forward. Super. All right, so three very interesting assets and a lot of upcoming inflection points. Not boring. Can you wrap up maybe then just reminding us what you expect in terms of your cash runway, as well as what the most near-term focus is for? Yeah, we just raised some more money. So we're immensely grateful for that. We have a hundred and I should know this, just under $180 million in the bank. So that's good. That puts us into late to end 2028. Plenty of milestones. The priority is the CRB-701, the ADC monotherapy second-line plus pivotal study that will read out the ORR. That's super important because that will be the trigger for accelerated approval traditionally. And so that's the number one priority. For the CB1, we're funded for the 90-day study. That asset will either, if it fails, there's no point funding it forward. If it succeeds, we're not particularly worried about funding it. I think that'll be absolutely straightforward. Super. All right, so with that, I think we'll wrap there. So, you've all, thanks so much for joining us today. Thank you so much. Really enjoyed the conference. And it's looking forward to the end of the year with this SAD/MAD coming up. And then 2026 is just going to be very, very milestone rich. So really looking forward to having this conversation with you next year. Perfect. Thank you. A pleasure. Thank you, Paul. Appreciate it.