Hi. Welcome to the 45th Annual GS Healthcare Conference. I'm Matt Hart from our Biotech Investment Banking Group, and it's a pleasure to introduce Corbus Pharmaceuticals. With me today, I have Yuval Cohen, who's the CEO of Corbus. Welcome.
Thank you, Matt. Thanks for having me.
Of course. Let's just jump in. You kind of have two distinct, exciting programs. We'll start off on the oncology side, and then we'll pivot over to two metabolic diseases. Starting with the Nectin-4 ADC program, can you talk a little bit? You recently had some data at ASCO. Can you talk a little bit about the construct there, the DAR of two, how that improves the safety profile and tolerability, and how that fits within the competitive landscape?
The CRB-701 is a Nectin-4 targeting ADC with MMAE as a payload, a DAR of precisely two, and a stable, cleavable linker. In many ways, it's a fairly typical next-generation ADC. What's unusual about it is it uses a platform that comes from CSPC. It's a proprietary linker. It's also a proprietary mAb. The idea behind this construct is to deliver a construct that would be more like Padcev with a longer half-life, and to reduce the amount of free MMAE that arises from the instability of Padcev. Those free MMAE levels drive, what we believe, a meaningful amount of the adverse events that are associated with Padcev.
Ultimately, what we want to have here is an ADC that's in many ways similar to Padcev, but that can be dosed higher than Padcev, longer than Padcev, more tolerable than Padcev, but still yielding the type of predictable clinical efficacy and activity that you would see with Padcev. Beyond that, that next question is, beyond bladder cancer, what else? Where else can we venture into with this concept?
Yep. That makes a lot of sense. And then you recently had some data at ASCO with your partner across multiple tumor types. Can you talk a little bit and give us a summary of what you saw in that latest cut of data that was presented at ASCO?
This was the next data cut. The first data cut we had was at ASCO GU, which was in late January. That was a January data cut. What we showed at ASCO, what our partners showed at ASCO, was a data cut that is three months later. It's not a lot more time, but one of the things that we were immensely impressed by is that in that time period of just basically 90 days or 100 days, they doubled the number of participants in the study already. What we showed was that there is a pattern that's emerging. That pattern is a longer half-life, the emergence of what seems to be a really differentiated clinical safety profile, especially focusing on peripheral neuropathy. We had just a single case of peripheral neuropathy.
It was grade one, and it was transient after a very short period of time. And then a lower rate, a markedly lower rate as well of skin rash. We had just one grade three skin rash, and that was reversible after just eight days. Moving to the PK, what we continue to show is even as we go into higher and higher doses, and just to put it in perspective, Padcev has sort of a very unforgiving ceiling at 1.25 mg/kg. We are already dosing the highest doses at 4.5 mg/kg. And even at that highest dose, we're seeing markedly less free MMAE than you'd see with Padcev at 1.25. And that leads sort of to this last thing, which is what happened in terms of efficacy.
The way to think that we think about it is we look at bladder cancer as our positive control. That's where Padcev has clinical validation and a very large body of clinical data, both for safety and efficacy. We see our bladder cancer patients responding, responding very nicely, in fact. Then we also turned the focus on another Nectin- 4-rich tumor, which was not explored with Padcev, which is cervical cancer. It's also a tumor. It's Nectin- 4-rich. We were the first to show patient-level data responses in cervical cancer that we're really delighted with. So while incremental, it just seems that there is, as I said, a pattern emerging, and we found that very reassuring.
That's great. Continue to see validation both in the early cut of data, but then reinforce that data cut at ASCO, and then you'll have data from the U.S. study early next year. Can you give us the setup and in terms of anticipated patient profile characteristics of patients, and then kind of how should we think about what constitutes a compelling response profile in the anticipated?
Not dissimilar to China, we in the U.S. are recruiting patients from a family that are of solid tumors that are known to be Nectin-4-enriched. I suspect we'll have quite a few bladder cancer patients. One of the things that's interesting is we're seeing in the U.S. some bladder cancer patients who are Padcev-naive. So that's really satisfying to see them being shifted to our clinical study. We're also quite keen on seeing the other types of tumors that we're focusing on. I think the purpose of the U.S. study, which should be done by Q4, is first and foremost to reassure us and all of you that there's nothing unusual about this ADC in terms of the shift from China to a Western population. I don't particularly think that's a risk, and it's certainly not being seen with other ADCs, but nevertheless, that's reassuring.
And so we're very keen to see what the PK looks like and what the safety profile looks like. And to the extent that we will have patients with tumors that we're seeing responses, it'll be interesting to see the response rates as well. We should have that wrapped up by Q4 and hoping to share that with you early in 2025.
How many patients did you update at that time?
It's four cohorts, and it's a 3 plus 3 BOIN design. So north of a dozen patients, I think, is very reasonable. I would say that the recruitment is progressing in a very satisfactory manner. So we look forward to having that number of patients perhaps even more.
Great. That'll be nice. That's it. All right. Shifting gears away from Nectin- 4 to obesity and the CB1 inverse agonist that's kind of reemerged as a target of interest. Can you introduce the mechanism here and discuss a little bit the differentiation of these second-generation programs versus the first-generation inverse agonists?
So it's kind of funny. So we're sitting here in 2024. And for some of us, this sounds like a novel mechanism, but if we build a time machine, it would be pretty awesome. But if we build a time machine and went back to 2006 and we spoke about exactly the same mechanism, we would have Sanofi, Pfizer, Merck, BMS, AstraZeneca all talking about this clinically validated, very exciting mechanism of action for anti-obesity medication, CB1. And so a couple of thoughts on this, just in terms of introduction. CB1 is a GPCR, just like the incretins are GPCRs. Some big differences, though. There's lots of incretins. Evolution duplicated those GPCRs. There's one CB1 in the animal kingdom. Anything north of a sea sponge has got one CB1. And what they do is also different.
The way I naively think of the incretin GPCRs, these are very gut-centric, very digestive-oriented GPCRs, which is why they work so well. They very, very dramatically reduce gastric motility, and that has really amazing ramifications for obesity. CB1 is very different. It has a relatively very modest role in digestion. It does two other things. Again, this is not a redundant mechanism. It's an orthogonal mechanism. The first is metabolism. You find it in the big organs of metabolism: your muscles, your liver, your adipocytes, your pancreas, and the second one are these hedonic circuits in the brain, circuits that crave food, that convince an animal to go out there and obsess about eating, and so they're orthogonal. They do different things, but we've shown pre-clinically that these two mechanisms play nicely together. As I said, in 2006, this was very exciting.
In fact, one of these made it across the finishing line in Europe. That was Sanofi's Rimonabant, but then suffered a really very, very spectacular setback with FDA that made the entire class fall out of favor. That's probably an understatement. Two companies continue to pursue this: Inversago and ourselves, and both really draw their inspiration from the same academic lab within NIH. The way that this was pursued, Matt, was kind of cartoonish, but it seems to work really nicely. The idea was just make these things perfectly restricted. Instead of having these CB1 inverse agonists flood the brain, be very brain-focused, do the opposite. Keep them as far as you can out of the brain and focus on those metabolic organs on the periphery. So far, it seems to be working again.
The big turn, sort of the big disruptive event was Novo Nordisk's acquisition of Inversago last year, and then since then, the data that is emerging out of that, we are certainly very keen to see in the second half of this year the phase, I guess it's phase 2A data out of Novo Nordisk. I'll remind the audience that these are related compounds, and what I mean by that is we share a backbone that is similar. This is Ibipinabant. Two different patent estates, different functional groups, but overall, these are distant cousins. So we think that there will be some meaningful read-through from the Novo data onto the data of our compound.
You mentioned that this second generation of CB1s coming into focus, particularly with the Inversago acquisition last year in August, and that these are two kind of cousin or distant cousin molecules. Can you talk about what has been demonstrated clinically with the Inversago now Novo molecule? Both, I think Novo shared some initial data at their R&D day, and then subsequently they've had some commentary at recent conferences. Can you just comment on what they've shared and kind of how that sets expectations and what you're thinking through for your program?
Inversago published now their phase 1b. Their phase 1b is a very, very classic phase 1b in obesity. It's a 28-day study in overweight individuals and looking at weight loss, waist circumference, the usual outcomes. They showed a very satisfactory weight loss. This is not surprising. Again, I keep emphasizing this. This is a highly clinically predictable mechanism of action. What was reassuring was they had a focus specifically on the type of issue that really led for the downfall of that first generation. It is a very specific measurement called C-SSRS, which measures suicidal ideation. The results were negative, completely negative. I predict that they'll continue to be negative. That certainly was very, very reassuring to see. Since then, what we've seen is certainly Novo gives us guidance towards what they're expecting to see from their study.
So the study that they're executing, just to put it in perspective, the Inversago study where 37 patients for 28 days, one dose versus placebo. What Novo have inherited from Inversago is a larger study. It is about 240 patients, if I remember, four months of double-blind, placebo-controlled, and then an open label up to a year. And now they're doing a dose response, which is the right thing to do. They have a low dose, a middle dose, which is similar to the phase 1B middle dose that was used, and then a high dose. And interesting enough, the commentary coming out of Novo, the guidance seems to be mid to high teens. And depending on when and where, they've guided even with more granularity, 16%-19% or 18% weight loss, presumably annualized.
That would be meaningfully more than what was seen with that first-generation drug from Sanofi Rimonabant. But I also want to remind everyone that their highest dose is at two and a half times of the Rimonabant dose. So it's at 15 versus 20. Pre-clinically, our drugs and their drugs look very similar to Rimonabant. So I think it's actually quite sensible that that would be the expectation in terms of efficacy.
And so they've kind of teased this high teens efficacy on the safety side, certainly encouraging that they're aiming to dose higher. So that's great. Can you talk a little bit about what you discussed a little bit what they're suggesting? How does what the Novo data look like later this year kind of inform your clinical strategy and how you guys are thinking about your?
It will inform it in its entirety. And so in obesity, I think that as an industry, we tend to not want to embrace originality. That's actually a good thing. And so certainly our plan is we will do a SAD followed by a MAD study. Everyone does that. That's the appropriate thing to do. We would be very interested in also doing a 28-day study. I think almost every single obesity program goes to a 28-day study. We would want to do the dose response monotherapy in 28 days. Inversago did not. I think maybe for financial constraints rather than technically having the finances to do so. So we would want to do the dose response at 28 days. It's beyond the 28 days that it becomes interesting, Matt, and that's where sort of there's been a very meaningful shift in our minds because of what Novo are signaling.
Up until fairly recently, the way we were thinking about this, and I suspect many others were, was pre-clinically this looks like a Rimonabant-like efficacy. And so we were looking at Rimonabant-like clinical efficacy. That's about eight, nine, 10% weight loss per annum. With a drug that does that, that is a small oral molecule, synthetic, you could in theory make metric tons of it if you wanted. What do you do with a drug like that? It doesn't require titration. It has fewer gastric AEs because it's not as gut-centric as an incretin. And you could do a bunch of things with it. You could target populations that are either incretin insensitive, that's about 10% of patients, or incretin hypersensitive, intolerant, or at risk of sarcopenia. CB1 does not cause sarcopenia. You could go after ultimately a combination specifically with an oral small molecule incretin agonist.
And lastly, probably the most interesting thing would be an induction maintenance model. You drop weight using an injectable, which is expensive but very potent. But then for chronic usage, you switch to a daily oral drug. And all that drug needs to do is just keep you where you are. And at eight, nine, 10%, that seems like a very sensible task for that drug. The reason all of that might be almost comically irrelevant is because of what Novo is signaling from their 50 milligram a day, I presume the 50 milligram a day dose.
So if they're going to see an annual weight loss of, say, mid to high teens or let's say 16%-19%, just to put it in perspective, you will have an oral synthetic drug that you take once a day that I would expect to be much milder GI side effects that does not require titration, that at a minimum will be more potent than semaglutide and potentially very close to tirzepatide efficacy. If that's what you have, then suddenly monotherapy is no longer a niche play, in my humble opinion. Suddenly monotherapy becomes perhaps the main play. For the vast majority of overweight people, that type of weight loss is absolutely appropriate. It's only when you get to really elevated BMIs that you need to start to lose weight meaningfully more than that. And I think that's what's changing our thinking around this.
Our thinking for the post-28-day study was, right, that's where we start to combine it with either an incretin analog or an incretin agonist. But we'll see what that Novo data looks like. And it's entirely possible that the future of CB1, in fact, is to dominate as monotherapy. It will not be boring.
And you touched on this a little bit, but can you elaborate a little bit more on kind of how the mechanism and the molecule fit into kind of the clinical and ultimately commercial landscape? I mean, you've touched a little bit on patients that are not sensitive to incretin therapies or hypersensitive. I think we're starting to see that there's more dropout rates and compliance rates are more challenging or higher than people anticipated given the therapeutic benefit of these programs. So can you touch a little bit about how you think that this molecule plays a role in kind of the evolving landscape from a commercial perspective? And then the studies that would need to be done to kind of complement the initial weight loss studies, get the full payer buy-in support, recognizing that this could potentially be achieved.
There's a bunch. Let's talk about just monotherapy, for example. We know that 10% of patients out there who try incretin analogs just don't respond to it. We don't know why, but they just don't. It's probably epigenetic. For those patients, system of action, incretin analog, there's something about them that just doesn't respond to the incretin pathway. In terms of dropout rates, I think it's really interesting, the real-world evolving data coming out of it, which is the following. Blue Cross Blue Shield had data on this, a bunch of other folks. Blue Cross Blue Shield, for example, recently showed that for semaglutide, they lose about a third of the patients in the first month. Within the first month, a third of patients just stop. Within the first four months, half the patients stop.
And we know not only from Blue Cross Blue Shield, we know it from Novo themselves that by the end of the year, they're down to about a third of patients. And there's a variety of reasons why, but I certainly strongly believe that AEs are the strongest reason for that. It's a feature. It's not a bug. Gastric motility is why they work, the slowdown in gastric motility. But it's that same slowdown in gastric motility that makes it challenging. And I'll remind everyone that it's one thing when we're talking to a KOL who's in a big academic center and he or she's surrounded by all these care units that can handle a very hands-on approach to and holistic approach to a patient. It's very different when it's a PCP.
And you have a patient that's trying this, or let alone without a PCP, a patient trying this and their reaction in terms of especially GI adverse event is challenging. It's immensely difficult to handle. And so that's probably a bigger portion of the market than we imagine. And for those people, if you could have something that is easier to tolerate, that would be immensely attractive. And then we have the patients at risk of sarcopenia. So typically geriatrics, perhaps patients who are especially morbidly obese or immobilized, etc. And there is just a fear of what happens if you put them on an incretin analog, what will happen to their muscle tone, especially if they cannot actually exercise. So that's the monotherapy, as I said.
Ultimately, there will probably be something called Orforglipron XL, which will be an incretin agonist in another API in that pill that will be a CB1 inverse agonist, and they're orthogonal. And we showed that in a paper last year that pre-clinically, these two orthogonal mechanisms work really nicely together. They're beautifully additive, and then the last one is the one I'm most excited about. And that's the induction maintenance, and that is, I think, essential for the future of these drugs in the short and medium term. We know it's difficult to manufacture these drugs. What we also need to remember, it's very difficult to reimburse these drugs, especially once CMS comes in.
And so I think there's going to be increasing pressure to go almost like a contract where payers will say, "Okay, I will give you six months of an injectable incretin and you will lose weight dramatically, hopefully." But beyond that, since I need chronic treatment and we know we need chronic treatment for these AOMs, it doesn't matter what the mechanism is. Beyond that, you have to switch to something that is sustainable. The advantage to the patient is that it can also be milder to tolerate. And I think that CB1 fits really nicely there. It doesn't have to have the same oomph, as it were, as an incretin analog. And then you're basically going to end up with something that looks like a prescription statin or prescription antihistamines back in the day or proton pump inhibitors.
It is a drug that you take once a day in the morning for the very long, hopefully for a very long life, and all it needs to do is just keep you out of trouble. It needs to keep the weight from coming back.
Perhaps you can, in the maintenance hypothesis, perhaps you can titrate down the doses, lower the doses and not need as much exposure.
Correct.
Kind of wrapping up here, you did a financing this year. The company is well capitalized to unlock multiple milestones to continue to execute across both programs. Can you kind of touch on, as we close here, the milestones for both programs, cash runway guidance, and then anything else you want to cover in closing?
Sure. So yeah, we are very fortunate to be very well capitalized. We last disclosed that we had about $120 million in the bank. That's more than three years' worth of cash for us. And this is what we get for it. So for the ADC, expect us to have the last cohort ready by the end of the year in the U.S. And so early next year, we look forward to sharing what that looks like. I think the next snapshot out of China would be next year. And that should actually be quite meaningful. Again, I gently turn everyone's attention to the fact that they doubled the number of patients in three months. China is remarkable at recruiting patients. And so I think that that is not going to be an incremental data. That could be quite a marked data cut.
On CB1, we should have our IND by the end of the year. There's no particular drama. It's a small molecule. The mechanism is very validated. We know what we need to do pre-clinically to do it. We will hopefully have some more pre-clinical data. We love working on DIO mice. If you look at our paper from last year, our mouse data was BID. That's because we really wanted to hit that receptor a lot. I'm very curious to see what happens when you give Q-Day. I also suspect I know exactly what's going to happen when we give Q-Day because the entire class is very, very amenable to Q-Day. We'll have some more pre-clinical data later this year. We'll have our IND.
But I think that kind of pales into insignificance compared to the Novo data, which will be sometime in the second half of this year. There are two very big obesity conferences in the second half, one in Europe in September, one in the US in November. Or it might be outside the scope of a conference. But I suspect that's going to be potentially quite impactful on us.
Great. Well, thank you very much for your time. Appreciate you coming down to Florida. Hopefully, you can make it back on your flight tomorrow given the weather. But it's been a pleasure to have you. Thanks again.
Matt, thank you so much, and thanks for the audience for coming over. Appreciate it.