Okay, let's get started. Welcome, everybody. For those of you who don't know me, I'm Mike DiFiore, one of the Senior Biotech Analysts at Evercore . With me now is Yuval Cohen, CEO of Corbus Pharmaceuticals. Yuval, welcome.
Thank you for having me.
Thank you for coming down to sunny Miami to tell us a story. Before we delve into Q&A, I would love for you to give an overview of the business and what we could look forward to maybe in the next six to 12 months.
Got it. We are a drug development company. We're based in beautiful Norwood, Massachusetts. Not exactly a biotech hub, but we really like it. We're a small company. There's about 40 of us. We really like being small. We have a very peculiar pipeline. It comprises of two indications: oncology and obesity that have absolutely nothing to do with each other, possibly on purpose. We'll talk primarily around our ADC program for Nectin-4 and, I guess, our CB1 program for obesity. If we chart the next pretty much year on the ADC front, Mike and audience, Q1 would be a regulatory update around our pivotal study, registrational study for the Nectin-4 ADC monotherapy second line head and neck. What we're aiming for is something that looks as close as possible to Petosemtamab, second line monotherapy.
It's a template that we think is a very sensible template for a study design. We have Fast Track already, so that helps that conversation. And then in terms of data for the ADC asset for CRB-701, middle of the year, monotherapy head and neck, more patients, longer swim lanes, and durability. Durability is really the last question that is left to ask. It's a very sensible question. It's an important question. Following that, in the second half of next year, are two more questions to be asked. Monotherapy second line cervical, what does that look like as it matures? And lastly, the one that is maybe a most intriguing one, because we just don't have data at the moment yet, is a study we started over the summer, which would be first line therapy 701 plus Keytruda in front line head and neck. That's a really interesting one.
All those three will be out in the second half of next year at different medical conferences. CB1, imminently, we will have our SAD/MAD data press release. We're looking forward to that. We probably will talk about that later this afternoon with you. Then the middle of next year, our 90-day or three-month dose range finding in obese non-diabetics. That's a really important one. That's sort of a really clarifying study for us.
Got it. Now, thank you for that, Yuval. So let's just start with CRB-701 first. You've just reported pretty compelling ESMO data for 701 and head and neck and cervical cancer. And you gained fast track in both indications and also extended your cash runway into 2028. So to set the stage, where do you see Corbus today and what are the key milestones investors should focus on over the next, I guess, 18 months across just pertaining to 701 right now?
Yeah. So yeah, starting from next year, mid-year to end of the year, three conferences, as I said, is monotherapy head and neck, combo therapy front line head and neck, and then monotherapy cervical. That's plenty for us. That's a lot. And for each one, we know what the benchmark is. Monotherapy head and neck second line, the benchmark we don't think is going to be the EGFR therapies. Those really are going to become kind of the default of the front line. Second line monotherapy is a pretty grim reality for patients. They basically get another round of chemo, maybe another round of pembro. And it's grim. It's really grim. It's very, very poorly effective. And the PFS is something in the range of two months and change. Moving on to cervical, it's equally grim. Cervical second line is either more chemo or Tivdak, Mike.
Tivdak is not an easy ADC to tolerate, but it's also not a particularly efficacious one. The ORR is only 17%. It's not the preferred standard of care. It's an A standard of care. But because of its difficulties, it's not a default one. And so that will be between that or chemo. Again, that's the standard to beat. And so far, the data is shaping very favorably in our favor. The big unknown is that front line combo with Keytruda. We don't know what our data would look like. And that is a very interesting, dynamic, chaotic, competitive landscape in the front line. It seems to be becoming more and more dominant by the EGFR therapies. There are three combos being explored: J&J, Bicara, and Merus Genmab. But we can already see that there are populations where that's not going to be appropriate for.
Whether, for example, they're HPV-positive and they inherent bias towards the HPV-negative of EGFR therapies, or whether there are populations, for whatever reason, the combos are inappropriate for. But we'll see. That one's a really interesting one. That one we just don't know how to benchmark yet. We need to see data.
Got it. So just recognize in the program, it's still very early. But even at this stage, your data shows activity across a broad range of Nectin-4 expression, HPV status, and even PD-L1 status. And even as you highlighted before, the Nectin-4 itself is highly expressed across many other tumor types. So as you map out the longer-term trajectory of CRB-701, can you clarify how you think about the broader platform potential here?
Yep. We're small and we're hyper-focused. So for example, we have data, and our Chinese partners have a lot more data around bladder. As a standalone company, we're not going to go after bladder. It's not because it's not likely to work. It's an immensely heavy lift for a company of our size. It would mean going head to head with Padcev plus Keytruda. And that is for a big pharma to do. There are other tumor types that are enriched in Nectin-4. Some of them, for us, are more intriguing than others. We like open swim lanes. We don't like spaces that are very competitive. But again, we have to temper that with our size and our resources and our focus. But I wouldn't say that we're only going to focus necessarily on these two.
There may be other tumor types that show up and that are sensitive to us.
I see. Okay. CRB-701's every 3-week single-day schedule, and it's got a highly stable linker. They keep free payload, which is MMAE, exposure very low, which kind of may help limit systemic exposure or systemic immune suppression and make it easier to combine with a PD-1 agent like Keytruda, which depends on a functioning immune system. So how do you think about that overall profile in terms of potential differentiated synergy with Keytruda as you move towards combination data?
I like it. But we'll see. We know that Padcev plays really nicely with Keytruda in bladder, right?
Yeah.
Our Chinese partners, as you know, have publicly declared that they are in late-stage studies in combination with 701, known as SYS6002, and their in-house anti-PD-1 and Enlonstobart. So they're probably not doing it. They're probably doing it because whatever they've seen excites them. I think that's a sensible assumption to the outside world. We'll see. We'll see what our data looks like. But on paper, it's a very logical hypothesis that the two should play nicely together.
Got it. Got it. Just putting ethics aside for a moment, when you think about the safety profile, CRB-701 is a very different real-world profile, or it's just safety profile compared to Padcev. Q3 week single-day dosing, much lower neuropathy and skin tox, but more ocular monitoring. So how do you think about the potential of that regimen and safety as a commercial advantage if 701 reaches the market?
Favorably. So the Q3 weekly thing is actually pretty significant for physicians. And the marketing people will like that too, especially if you think about combo. It's a real; it makes a real impact for the patient. But the most important thing is we have what seems to be a highly differentiated, best-in-class, low levels of peripheral neuropathy. They are not just us. Again, the Chinese data set independently. They are just markedly different than our peers, let alone from Padcev. And peripheral neuropathy is a showstopper for patients. It is irreversible. And once you have it, and it's typically just a question of time, once you have it, the clock has started in terms of you no longer being able to be on Padcev, for example. So that's a big differentiator. The ocular tox we see is what we're seeing with other stable ADCs.
It's because of the stability. It fluctuates as sort of a spectrum, Mike, right? On the sort of lower end of it is, believe it or not, Padcev. Padcev had 44% ocular tox. It's just that nobody cares. It just was meaningless in terms of patient discontinuations. Where we're coming up is we are somewhere between Tivdak and Elahere. We all use the same tactics. We don't allow patients with active eye disease. Remember, audience, this is all surface of the eye ocular tox, not the back of the eye. So it's keratitis and dry eye, which means it's reversible. None of us is anywhere near Blenrep. That just got approved. I think the reason for that is, for oncologists, ocular is just a very different risk profile than something like peripheral neuropathy or even skin, which can be life-threatening for Padcev.
Ocular is not viewed as such, especially if you're talking about mostly grade ones and twos. Grade one, remember, is asymptomatic.
Perfect. Now, a lot to look forward to there in terms of data flow. So I want to pivot now to obesity and your CB1. For folks not as familiar with the phase 1 designs, could you briefly just tell us how long it is and what the dosing is?
Classic SAD/MAD phase 1 study in the U.S. We're very sensitive about generating U.S. data, especially in obesity. We want the population to be highly reflective of the U.S. population for regulatory reasons. The SAD is a classic SAD. You climb a ladder. And in SAD, you give an enormous, and MAD, you give enormous amounts of drugs. To put it in perspective, Monlunabant is efficacious at 10 mg a day. Rimonabant was efficacious at 20 mg a day. SAD/MAD that we're dosing, which is classic, up to hundreds of milligrams a day. I mean, you'd never give that in an actual clinical study to a patient. That's the purpose of a SAD/MAD, is to really push the envelope and get the PK, of course. The MAD is seven days of dosing and an additional seven days of observation, all of it in the clinic.
So for two weeks, your volunteers are in a very controlled environment. And that's super helpful. I'll remind everybody that CB1 inverse agonists, these small molecules, both the old generation and the new generation, us and Monlunabant, have wonderfully long half-lives. And so that's something to think about in terms of momentum post-dosing termination. Most of the volunteers are non-obese. And so it's really about safety and PK. But yeah, it's always wonderful to hunt for PD signals. Everybody likes that. So we'll see what that looks like.
Got it. What's the half-life of Nano? Have you disclosed that before?
We've not, but it's long, and it's in line with the entire class, both initial, first generation, and second generation. The half-lives are in days. They are long half-lives. These are super stable molecules that are all Q-day, as is ours. They're all once-a-day molecules. That's very normal.
As you know, I cover one of the CB1 companies. But in terms of modality, whether it be IV peripherally administered or small molecule modalities such as yours, why do you think that the small molecule approach could be the more optimal route here to proceed?
There are two approaches that have emerged for CB1 targeting. CB1, a reminder, is a GPCR. It's a unique GPCR. It's only one of them in the body. The one approach is us and Novo in the second generation, and then Pfizer, BMS, Merck, Sanofi in the first generation. All of these are small molecules. They're oral. They're once a day. And what they do is they go into the active site of the GPCR, and they inverse agonize it. Now, a lot of people, some people may not be familiar with inverse agonism. So think of it as the gearbox of an expensive Italian sports car. Agonism is you put it in drive. Antagonism, you block it. You put it in neutral. Inverse agonism is a trick that some GPCRs do, and CB1 is one of them.
It actually goes in reverse, which is amazingly interesting and cool in terms of nature. What all of us did, all the NABs, because that's a nomenclature they all share, the suffix, is all of us are small molecules. You pop them once a day, and they put this GPCR in reverse. There is a second approach to this. It emerged from Bird Rock Bio with J&J that then became Sky, and independently from Takeda and Goldfinch. That was a very different approach, a very elegant approach, a very, very different approach, which is to take an antibody to the GPCR. Antibodies are enormous. It sits on top of the CB1 and interacts with it. I think the biggest difference is the CB1 inverse agonist small molecules to date have all led to weight loss in the clinic.
I'm not familiar with any one of them that hasn't. The first generation, Monlunabant, and there'll be questions around ours, but I think that's a pretty sensible hypothesis that we too should lead to weight loss. We certainly do preclinically. The mAbs are different. The mAbs have been tested far less. There've only been two companies that tried them. And it's still not entirely clear how they function, what the signals are, what the efficacy signals are, et cetera. So I'd say, Mike, those are the biggest differences.
Got it. When you think about brain penetrability, I think you guys had a nice slide that showed like 913 is like maybe 1/50th in terms of brain concentration compared to rimonabant. And just given the history of the entire class with this new generation of CB1s, I know that there's this effort to kind of thread the needle. I guess what I'm asking is, is a certain minimal level of brain exposure required, or can just peripheral exposure just do the trick?
I think that our data will be the first time monlunabant is only half as much in the brain as rimonabant, right? So that just doesn't give you a good enough feel. It is a lot more potent than rimonabant, which is super interesting. Monlunabant, folks, to put in perspective, to us at least, looks at least as potent as orforglipron, maybe more potent than orforglipron, which was completely lost in that unusual press release that Novo Nordisk put out. The question with our compound is, what happens when you have something that is highly, highly peripherally restricted on the one hand, and on the other hand, just blankets the periphery? We blanket the periphery even more than monlunabant. And I think that'll be really interesting because that will answer once and for all, is it the brain, or is it the periphery?
But remember, this is all through the medium of a CB1 inverse agonist. The mechanism is as important as the distribution of the drug.
One of the key things of Sky's data, the phase 2 we did that just read out, is that the combination arm with GLP-1s actually showed, I guess, 30% more efficacy than semaglutide alone. So just given that observation, how does that maybe shape your strategy, your view of 913 going forward? Will you just pursue monotherapy? Or given the Sky data, what will combination therapy be like the path here?
Regulatory path has to start with mono because it's a novel. Preclinically, we showed two years ago in DIO mice beautiful additivity with semaglutide to tirzepatide and liraglutide, as did Novo with monlunabant, by the way. There are three things you could do with a drug like ours. You could do monotherapy, and that depends on how potent it is. If it's as potent as rimonabant, probably less, though. If it looks like orforglipron, that's a very different story. You could combine it probably with a GLP agonist because it's an oral-oral, and then they play together. That could take the GLP agonist from the low teens maybe to the high teens. The last thing is you can do induction maintenance. Oral daily molecules tend to lend themselves very nicely to chronic lifelong therapy.
And so you can imagine a situation where we lose weight with an injectable pen. And at some stage, we switch to an oral daily drug that we feel nothing on other than we don't regain the weight.
Got it. Got it. In the final seconds we have left, you, Valerie, just more of a financial and strategy question. You've got just under $180 million in the bank.
Yep.
And a lot of important readouts, apparently, as we spoke about. So just if things all go your way next year, which I hope it does, by the way, how are you thinking about prioritizing investment in sequencing development of everything you have going on?
Top priority is second-line monotherapy head and neck, followed by cervical, with a wild card being front-line combo head and neck, just because we don't know what it looks like. Then nine months three, let's see what it does on the 90-day. If it does well, I think that's an easy answer, and if it doesn't do well, that's equally easy.
Got it. Excellent. Well, unfortunately, that's all we have time for. But, excellent discussion.
Thank you, Mike.
Thanks for coming down.
Really appreciate it.
All right.
All right.
Star.
Thank you.