GUGGENHEIM 3RD ANNUAL HEALTHCARE INNOVATION CONFERENCE - CORBUS PHARMACEUTICALS HOLDINGS INC

Good morning, everyone, and welcome to this first session of the third annual Guggenheim Healthcare Innovation Conference. My name is Paul Jang. I'm a biotech analyst with Guggeheim, and I'm very excited to be welcoming our first company of the day, which is Corbus Pharmaceuticals, and with me I have Yuval Cohen, CEO. Yuval, welcome. Morning, Paul. Thanks for having us here. Yeah, good to see you. So, you know, Corbus obviously has a very unique pipeline with assets in very different disease areas. I think it'd be very helpful for those that are new to the store, if you could start by providing a brief overview of the company and your two core assets. With pleasure. So Corbis is based in the Boston area. We're a small company. There's about 40 of us or so. We are a drug development company, and we have a pipeline that, as you said, is out of the ordinary because we have two assets that are just completely unrelated to each other. The one asset is an oncology asset. It is a Nectin-4 targeting ADC armed with MMAE, so conceptually the same logic as Patsiv or Enfortimavidodin. It's quite late stage in terms of its development. We have just launched its phase three registrational study in second line oral pharyngeal. And like so many of the ADCs these days, this one too is a partnership between a U.S. company and a Chinese innovative company. So this one comes from CSPC in China. The second asset we have could not be more different. It, first of all, is a small oral molecule, once-a-day pill. It's not at all in oncology. It's actually in obesity. and it is a mechanism of action that is, in a sense, a comeback story. The mechanism of Action is an inverse agonist of the GPCR known as CB1. This was 20 years ago a highly, highly sought-after high-visibility mechanism of losing weight. It had some major obstacles thrown in its way, And now it's having a comeback with us being sort of at the forefront of that. And that two-pole is in the clinic, as you know, and just completed a, technically it's a phase 1B, but it's a pretty large one. It was a four-month in total, three months of dosing, once a day, double-blind placebo-controlled with about 250 patients. Great. So maybe starting with the oncology acid, the Nectin-4-ADC, and as you mentioned, you're developing this for patients with oropharyngeal squamous cell carcinoma. So can you maybe walk us through the rationale and the data supporting the strategy to focus specifically on an anatomically defined subset of head and neck cancer? With pleasure. I'll start by, first of all, maybe a little bit on why this is different than Patsiv. The idea is not to come up with a biosimilar to Patsriv, but rather with something that improves upon the design of PADSEV. And so conceptually, it's quite simple. It's take a Nectin-4 targeting ADC armed with MMAE-like PADSAV, but make it considerably more stable. And so the ability to hold on to the warhead for much longer, meaningfully longer, translates into a very different safety and tolerability profile, where what has been engineered out or down to a minimum are peripheral neuropathy and skin which are the sort of the issues the friction points more than friction points or be the drawbacks of using passive once that's been established then the question poll is what do you do with something like that and the way we approached it was at least as a starting point in clinical development and commercialization is not to try and compete with pets and that would be very ambitious for a company such as ourselves and so the swim lanes that we found were other types of solid tumors in metastatic settings that are known to be highly enriched in nectin form and the two that we are um exploring the first one as you mentioned is oral pharyngeal it is the third most nect and foreign rich tumor type um passive has shown very promising data there as well, but again, always hindered by their safety and tolerability profile. And we are moving forward and have started, as I said, a phase three study. The second tumor type we focused on is cervical cancer. Again, very, very enriched in nectin-4. I believe it's the second most enriched necten-4 tumor. And that's where we have maturing phase one day great so yeah obviously the lead indication generated some pretty interesting data there most recently at ASCO so can you sort of contextualize how the data you generated compares with the current benchmarks and second line patients as well as investigational options to the degree that they're relevant here sure so let's start with the second line because that's where in phase three as you mentioned second line head and neck in general is a really acute, unmet medical need for patients at the moment. There really is very, very little available to them. Our own data analysis has shown that probably close to half the patients elect not to have anything done to them in the second life because the options are just so, so modest in terms of efficacy. And so there, what we have shown is in the oropharyngeal subset of head and neck, which is usually associated with HPV positivity, right? That's a type of head-and-neck tumor type that is driven by HPV rather than the other forms of head, and neck which are typically driven by smoking and drinking. In that tumor type, what we've shown is monotherapy second line plus in a maturing data set of phase one was an objective response rate of about 43%, durability, and again, just a very, very satisfactory minimal levels of peripheral neuropathy and skin. So that one is in phase three. That is our TEMPO-1 study that has started. What you've alluded to, Paul, is the possibility of going beyond just the second line plus setting in oral pharyngeal in our case, and there the most sensible one would be what happens one step before that in front line. In that sense, it's merely emulating what, back in the day, Maris did with Pitot, starting in second line and then moving to front line. And for that matter, what back in a day was done with Patsev in bladder, second line first and then, moving into front line, the front line being, of course, in combination with Pembroke, which would be standard. That data set, which is an exploratory data set should mature enough for us to look at in the first quarter of next year. And that will be very, very interesting because if that is the case, then that obviously opens an even larger market opportunity. Great. So maybe before talking about that study and the readout, obviously two weeks ago, GenMap had a very meaningful update. positive top line results from the Lager HN1 study in frontline head and neck cancer, which did allude to benefit for both, been the primary important for both HPV positive and negative patients. So, you know, obviously very big milestone for the field. Would love to get your thoughts on what are the ramifications for 701 as you think about moving perhaps into the early line. So super exciting data, and I'd say really highly disruptive. Primarily disruptive for the other quote-unquote players in the front line, right? So we're thinking of companies such as with other EGFR bispecifics or other mechanisms that are already well underway in front line and they certainly reacted to that news sometimes quite dramatically. For our drug in the second line setting, the effect of the frontline changes are not zero, but they're relatively minimal. At some stage, sadly, patients will fail the frontline and then will need something else in the second line. And if anything, the opportunity that opens up here is it really seems highly unlikely that PETO will be a second-line therapy option for patients. even timing-wise, by the time that data reads out, it's almost, again, colloquially, what is the point? You would want to have Pito in the front line with Pembro, and so when they reach the second line, what do you do with those patients? A very, very interesting point you've raised is what about the HPV positivity, the oral pharyngeal? We sort of use that interchangeably. If we look at the way, for example, that GenMab uses, has previously used the nomenclature, it was oral pharyngeal HPV positive. And that's where they're very different than the other EGFR bispecifics, because both by Kara and Johnson & Johnson specifically exclude oral pharyngial HPV1 patients, HPV-positive patients. And I think that's why the GenMAB, even in the context of the front line, is what's kind of intriguing and maybe thought-provoking, the way in which what we know about EGFR bispecifics is that they don't work as well in HPV-positive patients as they do in HPV negatives. And we've had data in second line from back in the day Marist with an ORR that was very modest, about 13% in oral pharyngeal HPV positive. We have data from the early studies of Johnson & Johnson, Vicaera, and Maris in the front line in those patients. Vicaea and Johnson & Johnston, very, very modest effects combined with PEMBRO in oral pharynageal HP positive, around about 27%, 29%, which is pretty much PEMBROS. GITMAB the sort of the odd man out at about 50%. It is interesting how they chose to disclose the data. We do not know what they saw in HPV positive versus HPV negative. They've declined to give that breakdown. And so that will be very, very interesting to see. I think the assumption is the HP-positive did not do as well as the HPB-negative, which is sensible. The question is, is it enough to get them over the line or not? What is intriguing is take a step back away from GENMAP for a second and go, okay, what do we know about a Nectin-4 ADC armed with MMAE in the frontline setting with PEMBRO? We don't have our data yet, but we have PADSEV data. And PADSeV in that setting in the oral pharyngeal HP- positive, had a really striking efficacy, right, about 82%, if I remember correctly. Small number of patients, of course, but really highly, highly differentiated than what EGFR bispecifics given that. And so I think for us, what would be interesting in our front data would be front-line data is, do we look more similar to the EGfr bispecifics or do we looks more similar the PATSF example? And that delta will tell us, is there a path forward there or not? Patsy is, while the efficacy was really remarkable in that setting, again, that peripheral neuropathy and that skin probably makes it a very tough fit for frontline therapy. But if you could conceptualize something that works like that without those, that could be incredibly attractive. Got it. So then, yeah, looking ahead to the data you'll have in combination with PEMBRO, can you set some expectations for sort of the scope and perhaps the venue for the data update next year? We like to talk in medical conferences. The EGFR biospecific frontline data sets with Pembro has always been very consistently about dozen patients, sometimes fewer. We'd like to have about one or two dozen patients. That feels right. And it will be really response rates. We're not going to have something like durability yet. Okay. And then progress is being made on the second line plus setting, as you mentioned, the 10 for one study began enrollments already. How do you think about the pace of enrollment and sort of line of sight into an interim OR readout? But yeah, I think we've worked hard on building a track record of being on time in terms of our clinical development. I'm delighted to say that so far it's going very well. And so we look forward to the plan being that we are hoping to have enough to file for accelerated approval and really following in the footsteps of, for example, what GENMAB are doing in the frontline, right? They change their order in the second line, but in the frontline it's just very sensible. We try and have as frictionless a development program as possible. There is an advantage that we have in the sense that there's not a lot happening in second line, and our patients are ones that are particularly overlooked, right? These oral pharyngeal or HPV-positive patients are the ones where, for example, the EGFR revolution is really not that applicable to. Okay. Okay. All right. Then maybe that's a good time to switch to the other program, which is equally exciting, CRB913, CB1 reverse agonist, as you mentioned, a mechanism that has a history. And it would be great to get your thoughts on how 913 is engineered to specifically overcome the history of its class and maybe what the headline takeaways were from your update recently. Yeah. So there is an analogy here to our ADC in the sense that there's something that clinically worked, had a problem, and you try and engineer it out. So what clinically worked 20 years ago was every CB1 inverse agonist tested in the clinic led to weight loss. There were no exceptions to that. It's a highly, highly predictable mechanism of action for weight loss. The problem was, the first one to cross the finish line was Sanofi's Rimanobant. And in a sort of a very controversial interaction with the FDA, what came out of it was a highlighting of a potential risk for psychiatric adverse events that led to the drug being rejected in the U.S. and then withdrawn later on from the rest of the world. And you can imagine that left a pretty meaningful trauma on the class. The class was completely abandoned. No other drug filed for submission. Twenty years ago, even, you can find publications that said, wait, we can fix this, quote-unquote. Let's just not get these drugs into the brain. And it's a little bit easier said than done. It took a while to actually engineer drugs like that. There were two attempts, one from Novo Nordisk ahead of us, and the second one is us. And the bottom line poll is that the difference between our drug and Monlunabam, which is Novo Nordisk, boils down to the degree of exclusion from the brain. So to give you an idea, they're at about half the amount in the brain of the old generation. If you look at our brain to plasma ratio, we're at about one-fiftieth of the amount of the older generation. So it's not a subtle difference we are highly highly highly brain um excluded as a cb1 inverse agonist and we did a study that was very similar to the monolute amount study roughly three months for us four months for them 250 patients for each one of us obese non-diabetics and you're looking at safety and you looking at weight loss um i'll start with what looked very uh strikingly similar which is both of our drugs lead to weight loss. And what's interesting, Paul, and somewhat unexpected, I think, by some audiences, was they work a lot better than the old generation. So the concept, 20 years' worth of concept, was, right, you need to go in the brain to lose weight. There was a tiny minority of academics who said the opposite, who said, no, no. The weight loss actually is derived from the peripheral action of CB1. And it turns out they were right. We have two examples of two drugs that are excluded from the brain to different degrees that are markedly more potent than the first generation because they flood the periphery. That's really important. So to put that in context, the weight loss that we saw, the old generation, you're looking at 6% weight loss in a year. We saw 5% weight lost in three months, double-blind, placebo-adjusted. To put that in the context of what is relevant to today, that looks very similar to Orfaglipron. Monlunabat at one year was almost 13% weight loss from baseline. That's better than Orfoglipon. That approaches Oral Wegovy. We'll see where we end up, but we look to be very, very similar. The first takeaway lesson here is by excluding CB1 from the brain, you actually markedly enhance the efficacy, and you're getting to something that looks early days, but it feels pretty tangible. It looks like an oral GLP-1 in terms of efficacy, despite the fact that it is entirely orthogonal. It has nothing to do with that mechanism. This is a completely different GPCR to the incretin family. The second thing was, of course, safety and tolerability, right? That's really the elephant in the room with this mechanism of action and so conceptually i think it was always easy to imagine right just keep it out of the brain and you'll have a better safety and tolerability tolerability profile but it's one of those hypotheses that it remains a hypothesis until you actually see it and that's where the data is is i think even more striking so to put it in context um we had no suicidality that's not exactly surprising um but our depression and anxiety look indistinguishable from a GLP-1. Like a GLL-1, they are mild. Like GLP1, if they happen, they happen early and they're transient and they go away. And there's no difference between us and the active arm in a placebo. There's no dose response, which is super, super reassuring. Again, this is something where the theory said it should work, but it's quite striking to see it in action. The other Another thing that was really satisfactory to see but less surprising is even the old CB1 inverse agonists were much milder on the GI. CB1 doesn't really affect gastric motility that much. It's not like an incretin. It doesn't slow down. That slows down gastric mutility. And what we saw was a dramatically reduced rate of vomiting, a markedly reduced rate of nausea, dramatically reduced rate of constipation. And we're down to diarrhea that looks anywhere from like a GLP-1 to an oral GLP1 to injectable GLP. And that's important, Paul, because the other thing to think about is not just this as a monotherapy for those patients who have tried and cannot tolerate or don't respond to an old GLP one. That is where you go, right, I'm going to give you something that has the same, in the same potency as an oral GLP-1, but a very different mechanism. So you're likely to be able to respond to it. But equally importantly, for those who can't tolerate it, if they can't tolerate an oral GLP1, it's almost always because of GI. Being able to give them a completely different orthogonal mechanism of action with a milder GI profile could actually be very impactful for those patients. So that's one way to think about it. The other way to think about is combining them. And the ability to combine these two mechanisms of action and enhance each other has been shown preclinically both by us and by Novo. That's something that in the clinic would be super, super interesting to see because if we could enhance the efficacy of an oral GLP-1 without without compromising or further deteriorating the GI adverse event profile, that again could be very attractive to a large number of patients. Great. So, yeah, obviously a very interesting profile and possible, you know, sort of different development lanes approaching. I guess on the psychiatric adverse events, that's obviously a huge focus. And, you know, you have the data you have. And I guess the question is, what gives you confidence that these events will not be cumulative or perhaps worsen with longer exposure? You know, what can it tell you about the long-term profile? So what's interesting about obesity is we know a lot about psychiatric adverse events of anti-obesity drugs and the psychiatry of weight loss. And what we see, for example, with the injectable GLP-1s is there is this murmured background of depression and anxiety and at times irritability, or the irritability is harder to pick up. And even suicidality, it tends to be very, very, concentrated early in the exposure to a drug. If you're going to have it on a GLP-1, you're gonna have it at the beginning. And so what is so interesting about these studies is the longer they are, the risk actually doesn't go up. It happens at the beginning if it's going to happen. And the analogy is to the GI as well. It's exactly the same thing with GLP-1s in general and GI. If you're going to have a really bad response from a GI perspective, you have it at the begin. There is a process of adaptation that happens in humans to these types of mechanisms. And that's what we saw. So for example, the majority of these murmurs of mild anxiety and mild irritability happen right at the beginning. And they tend to not to repeat themselves. And they happen both on placebo and on the drug, which is actually, again, very, very similar to what we see with GLP-1s. Okay, great. So maybe with our last few seconds, can you talk about the additional details we could learn at obesity when the full presentation is presented later this week yeah it will be our first time presenting at a scientific conference so that's really important it's a different audience obviously we have a bunch of other obvious endpoints to that we had in the study like waist circumference bmi etc we're also working on a publication that will have a few more things in it um but basically it's looking at that data that was in our corporate deck in a more comprehensive manner, presenting it to a more scientific audience, and being able to interact with those KOLs. I think that's really, really key. It's the first time that we'll present that data to an audience that remembers very, very well the mechanism of action and that I think is actually kind of excited about it. Okay. Fantastic. Well, so we'll look forward to that data as well as the 701 update next year. But I'm up on our time right now, so I wanted to thank you all for joining us and thank everybody for tuning in. Thank you, Paul. Thank you audience. I appreciate it.