So we hired a couple of new folks on the team, Jinyu and Oscar, and their project was.
You won.
I love it.
Do you remember your project?
Thank you guys again for being here. Excited to have Corbus management with us. Do you have data coming now? So now we can actually talk about real data, but I'll let you kick things off.
Sure. Thank you for having us. It's not been a boring year, in a wonderful way. And, I think, 2025 is probably not going to be boring either, hopefully in a good way. On our Nectin-4 ADC, we have completed the dose-escalating study in the West, which is primarily U.S. sites with a handful of U.K. sites. That data we're aiming to present in Q1 at a medical conference, so we're excited about that. And then hopefully later in 2025, CSPC in China will showcase their dose expansion data, which is a meaningful increase in patient numbers versus their last update. So 2025 for our ADC is going to be a year where I think some of the sort of core seminal questions are answered. A couple of thoughts just to guide you on this data in Q1.
It is the top four cohorts from the dose escalation in China. We're mirroring them in the West, in the U.S. It's first and foremost a bridging study, which has become now so popular as people become more and more, drugs are coming out of China. We want to bridge it, as it were, to U.S. data, contextualize it with Western data. Seminal questions are: Does the safety look similar? Does the PK look similar? Is the drug clinically active? These are obviously fundamental questions. There's some interesting differences, though, in our Western study compared to the Chinese dose escalation study that we showcased earlier this year. The two big differences are in China, they started enriching for bladder and cervical very, very early on as they saw responses.
But that meant that there are a number of tumor types that were not explored, tumor types that are known to be Nectin-4 enriched that were just not explored. Our U.S.-U.K. study allowed us the opportunity to sort of stretch our arms a little bit wider and explore some other Nectin-4 tumors that we've not seen in China. So that will be interesting to juxtapose and see what are we seeing for the first time in tumors that are neither bladder nor cervical. We have those as well, but we have more than just bladder and cervical. The other difference is in China, you're allowed to, in a dose escalation, to set an arbitrary threshold for your H-score below which you don't have to, you can refuse a patient to enroll. You can't do that in the West.
For us, the difference is our patients are selected from a handful of tumor types that are known to be Nectin-4, but we don't exclude them based on the H-score. What will be interesting to see there is, what does that look like? In bladder, for example, we know that it doesn't really matter. That's why we don't have a commercial CDx for Nectin-4, is because pretty much all comers respond. That may not necessarily be the case for all tumor types. That's on our Nectin-4. Those are two pretty important data reveals in 2025. Then we have CB1. Omar, I'm guessing you have a whole bunch of questions there as well, but.
Yeah. No, no. So remind us on the timeline again.
Q1 for our Western data?
No, no, sorry, for the CB1.
Oh, for CB1?
Yeah, yeah. We're going right to the.
No, right to the non-boring stuff. First half of the year, we will crank out the SAD followed by the MAD. They are.
So you should have the data by May, June timeframe?
Summer. Yep. All in the U.S., all under an IND. We want no drama. We don't want sites in Canada or Australia or on the other side of the moon. It's irrelevant. We want U.S. sites under an IND. That's really important. It is a classic SAD /MAD.
To be clear, why? I remember some of the data for Inversago was generated in Canada. Why was that?
All of the data for Inversago was generated in Canada because they were a Canadian company.
But was there an IND filing issue in the U.S.?
I don't believe there was an issue filing IND because they filed an IND towards the end. I think it was just a constraint in terms of resources.
Okay. Got it.
The phase I-B we saw from Novo was started by Inversago and was exclusively Canadian sites.
Okay. What about dosing? Are you using daily dosing or, for MAD, is it single once daily, twice daily?
Once daily, and so we will climb a ladder with SAD that will guide us to the ladder to climb with MAD, and that will guide us to a phase I.
What are the doses or expectations for the range?
We do, so we don't know where this ladder ends, right? We have expectations for the range, which we haven't disclosed. We start with a low dose and we go up. And what will guide us, Omar, is peripheral levels of the drug. We can model those from the animals. And as we climb the ladder, when we hit those levels in the serum, that's when we know where we need to be.
Want to get to certain thresholds.
Correct.
And, okay, got it. And as it relates to sort of, I remember some of the very earliest stuff you guys showed from mouse models.
Mm-hmm.
We would see rimonabant, the Sanofi molecule, 10 mg daily compared versus Corbus molecule, but dosed on a BID basis. And I was always curious why you were showing BID versus QD.
That was our earliest data, right, that we showed last year. And that's because we really didn't know what to expect. We wanted to hit that receptor. What we showcased in Obesity Week this year, so that was last month, was what QD looks like. So really head to head QD versus rimonabant. We also showed a very wide dose ranging from, I think, 2.5 mg a day to 80 mg a day, if I remember, per kg per day in a mouse. And that's really to address what was very weird phrasing in the Novo press release where they intimated that there was no dose response, although they seem to have changed that a little bit in their earnings call recently. We're certainly seeing a preclinical dose response, and all CB1 inverse agonists that I've ever seen had a clinical dose response curve.
We seem to be behaving according to the class.
Got it. Maybe just one more quick one on this as well. On the, when we see your dose ranging work, I think 2.5 mg/kg all the way up to 80 mg/kg in animals is what we've seen.
Yep.
When we look at the brain concentration comparison versus rimonabant, it's shown 10 mg/kg versus 10 mg/kg, so you kept the dose the same. I think you previously also showed 2.5 mg/kg versus 2.5 mg/kg. What about doses above 10 mg/kg on brain concentration?
The ratio is really wonderfully constant.
You do have data above 10 mg/kg.
Not for all of those doses, no, but the ratio seems to be constant, which is nice, because you want it to be a constant ratio, and it's the same. We also see we've done it, so we've done it as an acute dose in lean mice. We've done it as chronic dosing in lean mice. We've done it in obese mice because the blood-brain barrier is different, so we looked at the ratios the same, and we've even done it in combination with an incretin analog just to make sure that when you co-administer, nothing odd happens to the brain penetration, and it doesn't.
Okay, got it.
So we try and cover all the bases, at least in a mouse.
How many patients in total in the phase I study?
It depends, but it will be a standard SAD, followed by a standard MAD. It's a seven-day MAD. We do not want to do in clinic, for example, for a month because people don't behave normally when you lock them up for a month.
You would have some safety endpoints in the phase I.
Oh, it's all about safety. Now the I-B is where it starts to get more interesting, right? That's, that's your dose response.
Right.
I-B, the primary endpoint is still safety, and that's appropriate. But what you're really curious about is, are you seeing PD and are you seeing clinical changes? And you should start to see those.
Got it. Okay. Makes sense. So as I look at some of the, I just sort of think through how this profile plays out in humans, any early sense on what the oral bioavailability should look like? And could the animal models be predictive on that?
In NHPs, and I think it's in our paper, it was over 50%.
Okay, so that shouldn't be a challenge at all.
It's not a challenge for the class. It's a very well-understood class.
What's your half-life versus Sanofi molecule?
They're both long. Rimonabant in humans, believe it or not, was 16 days half-life. That's just because their rimonabant is super stable. Most of the class are very stable. It's nice long half-lives.
Are you guys in over a week as well?
I'm trying to remember. We don't know in humans, right? In NHPs.
16 days was humans for rimonabant.
Humans, yeah. And so, but it's a daily drug, remember, reaches steady state very quickly.
Right.
So we will be, I think we're similar. I mean, again, we don't know the human. We'll find out, but we expect to be similar. Daily dosing, QD dosing.
Got it.
As is monlunabant.
Okay. Excellent. And, I guess, the idea here is that peripherally acting should still drive weight loss.
Mm-hmm.
Let's just go down that thesis. One of the data points we get now, or sooner than your data, would be Skye Bioscience. It's using an antibody approach. Presumably, how informative is that data set to the extent it shows a certain weight loss?
I don't know. It, so it's the same target, so that's really exciting. What I don't have a feel for is CB1 inverse agonism with small molecules has been explored extensively 20 years ago and now has a resurgence, as it were, with Novo and ourselves. That mechanism is highly, highly predictable and highly clinically validated. We don't have the same wealth of evidence in obesity for the mAbs, and so we'll see. Skye is the Bird Rock Bio. So that was a really interesting mAb. Takeda had the Goldfinch, what became Goldfinch, and I think Gilead had a mAb as well that never made it to the clinic.
But my point is, if you're engaging CB1, presumably, and if you're engaging CB1 and engaging CB1 peripherally should drive weight loss, we should see that in the Skye Bioscience program, or there should be a lot of translation from that over to oral, or would you not think of it like that?
I don't know because the one are small molecules that penetrate the receptor and inverse agonize them. So that was the first, that was rimonabant, otenabant, ibipinabant, taranabant, and now with monlunabant and CRB-913. So that's one group that's highly, highly predictable. The other one are mAbs that engage with the GPCR, and that is just different. And so I think.
Orals are inverse agonists. I see, I see.
It's just completely different. It does, it's exciting. It just, I don't know how to put a, I don't know what that would look like.
Got it. Neuropsych AEs, is there any way in non-human primates, et c., to get any early read on that?
No.
Or not at all?
No.
You would have to wait till phase I.
Correct.
When you start dosing on an open label basis, will you have visibility on neuropsych AEs as January, February, March, April goes on?
It's always a placebo group, and we will use this.
So on a blinded basis, would you know neuropsych AEs?
The way you capture it, the two most important endpoints are C-SSRS for suicidality. That's prospectively measuring suicidality. And PHQ-9 for depression, anxiety, et c. By the way, those are used by every anti-obesity drug. It's not a CB1 special. Every single one, semaglutide, tirzepatide, liraglutide .
So, C-SSRS and what was the second one?
PHQ-9.
Okay.
They are the standard neuropsych evaluation, and they're used by all anti-obesity drugs.
Okay.
That's how you capture those neuropsychs.
Okay. And that's incorporated in your trials?
Absolutely. It's mandated for any anti-obesity experimental.
For you guys, for the thesis on low brain penetration to play out in the phase I trial, I guess, should we be expecting no neuropsych, no psychiatric, no psych events at all, or how should we be thinking about that?
I think that a win would be no imbalance, right? Because that's what we care about is an imbalance. If you have in a placebo three patients who are anxious and in your drug group three patients who are anxious, you're not worried about it. If you have an imbalance, that's a problem.
Got it. Got it. And, I'm just trying to see in terms of brain penetration, can you just remind us what the ratios look like and what preclinical findings are suggesting so far?
Sure. So we only know for mice because that's really all we can do. If you think about it proportionate to rimonabant, and so, monlunabant is about half the brain amount as rimonabant, so it's peripherally restricted. We are 15x lower than monlunabant. So we are highly peripherally restricted. And if you think about it in terms of brain to plasma ratio, we are 1/15 of rimonabant.
Got it. Excellent. And for rimonabant, can you remind me, for the Novo molecule, monlunabant, how soon were some of their neuropsych AEs observed? Presumably, were they seen in SAD? I think there were definitely some in the phase I MAD, but I forget if they were in SAD as well.
So they never released a SAD and MAD studies. We don't know what those are like. The earliest data we have for monlunabant was the Inversago phase I- B, which was a single dose study, 25 mg a day for 28 days. It was negative for C-SSRS. And then it had three patients who had depression slash anxiety slash insomnia, depending on the patients. And upon further analysis, it looked like all three of them brought it with them into the study, all the history of it.
But then this replicated in phase II, these exact things, so somnolence, anxiety, so.
Minus the depression, which is interesting. The depression seemed to have gone away. And so it's anxiety, irritability, and insomnia that showed up in the phase II study. We just have no idea what they actually saw other than it's described as mild to moderate.
Wouldn't somnolence be the type of thing you can actually observe in non-human primates?
It was insomnia. It wasn't fatigue.
Oh, it's insomnia. Okay.
Yeah.
Okay, okay, okay. Yeah, they just said sleep disturbance. I didn't, okay, so it was insomnia in particular.
The word they use in the press release is insomnia. And the challenge Omar in everyone is.
But anxiety, irritability, that should be the type of thing you could see in non-human primates now. They're irritable and, like, behaviorally different.
These behavioral models do not translate into humans, so behavioral models, for example, are things like the forced swim test or the elevated plus maze model. The problem with what we just described, right, irritability, insomnia, and anxiety, is you often see them with weight loss in general, and because we don't have numbers from Novo, we don't know if what they're seeing is within the norm or different. We have no numbers for anything pretty much from Novo other than the weight loss for the lowest dose.
Got it. I guess for their phase II-A data, always puzzles me why they don't see those response for efficacy, but they saw those dose-dependent side effects.
So we don't even know that. What they, the language they use, because this press release, guys, is like the Rosetta Stone. The language they used is that they did not, that they saw limited additional benefit in higher doses. Although they seem to sort of backtrack it a little bit. Martin seems to have backtracked it a little bit in the latest earnings call, and so we just don't know. It's, it's.
What if they run an additional trial? I'm just going into a hypothetical now. They run an additional trial at two and a half and five mcg dose, and they're able to see, because from 10 mg to 25 mg to 50 mg, no additional weight loss. So they pull the dose down to, let's say, 2.5 mg , and they see close enough on weight loss, and neuropsych AEs kind of go away. I guess, how does that change? In some ways, it validates what you guys are saying. In other ways, it just creates more of a competitive risk. How do you think about those dynamics?
I'm less, if they've engineered out the bad stuff, I'm less worried about competitive risk.
But if it's 15 x lower, I guess I'm just going down this logic.
Oh, if it's 15 x lower.
Yours is 15 x lower, right? So if they can just cut the dose down at least 4x , so you're already starting to address some of that, and 10 mg is low enough to begin with. So how do you think that?
So that would naively mean that we could see us dosing higher and safer. So I love that.
Okay. Anything in the audience or any point we missed or didn't touch up on? Your base case, are you going above 100 mg dose?
For the SAD, it is.
Or you have to, I guess, for FDA reasons, right?
Well, it's part of the ladder. We'll see if we get there. Again, what will determine it is what does it translate to in the serum, but we have some pretty high doses in that SAD.
Got it. And is your base case that there's probably going to be a limited dose response beyond a certain threshold?
Not at all. I mean, beyond a certain threshold, there's limited dose response for every mechanism of action in AOM, right?
Sure.
Tirzepatide, for example, or semaglutide. The question is there, there is a dose response for every CB1 inverse agonist ever tested. There's got to be one for monlunabant as well, but we suspect there'll be one for 913. That's why in the mice, we just tested such a wide range to demonstrate that, and even at the highest dose, it wasn't plateauing yet. Now in humans, at some stage, you have to plateau, but we'll see.
Okay. Anything from the audience? Otherwise, we'll be respectful of your time. Thank you again for being.