Okay, I think we'll go ahead and get started with our next fireside chat. My name is Ben Burnett, one of the biotech analysts here at Wells Fargo, filling in for Eva Privitera, who is out temporarily on maternity leave. I can report mother and baby are fine, and she will be back soon. But I'm pleased to be here with Ryan Cohlhepp, President and COO of Bicara.
Great.
Thanks for doing this.
Thanks for having us.
I think maybe just to kick us off, kind of frame for us kind of what sort of the next couple events are that we should be focused on.
Sure, so maybe to back up a little bit in terms of, so Bicara is. We took the company public almost a year ago, next week. We have developed and our lead asset is an EGFR TGF-beta bifunctional, which we had developed and, you know, entered the clinic in 2020, and have been developing that asset across a range of different tumor types, but, you know, really, the key concept in the development of that molecule was, you know, bringing EGFR and TGF-beta together. Historically, there's been a lot of work that has been done with TGF-beta. I think it's a mechanism that has had a lot of promise, but, you know, frankly, hasn't delivered much on the clinical side for oncology in particular.
As we were designing the molecule, we did so in such a way. We felt that what we needed to overcome was the ability to bring TGF-beta and TGF-beta inhibition to the tumor microenvironment, and could do so by, you know, using EGFR as a homing mechanism to bring the TGF-beta into the tumor and to penetrate the tumor. Again, as I mentioned, it went into the clinic initially both as a monotherapy in dose escalation, but also additionally had done work in head and neck cancer, where, you know, head and neck cancer patients probably 90%-95% of them had overexpressed EGFR.
Felt really comfortable empirically treating with our molecule to probe, you know, what kind of activity we were getting both from the EGFR component, where Erbitux is a precedent molecule, it has an approval in head and neck cancer, but what kind of additive activity could we get from the TGF-beta. Most recently, we presented our data in head and neck cancer, the recurrent metastatic setting at ASCO this last year. In that data set, we had two years of follow-up, and for the first time, presented publicly overall survival data. At ASCO this year, again, what we were able to demonstrate is a meaningful improvement over the current standard of care, which is pembro monotherapy.
You know, pembro monotherapy and a CPS of greater than one population, you're seeing about a 12.3-month overall survival, and what we showed in that data set at ASCO this year was 21.3. So, a real increase in that. You know, the data that has been maturing over the last couple of years, you know, gave us the confidence to move into a registrational trial, which we initiated in January of this year. Currently are enrolling that trial actively, anticipate some key readouts over the next couple of years for that trial. It's the FORTIFY-HN01 trial.
And near term, you know, beyond, you know, as part of that design of the FORTIFY trial, we are also doing a dose run-in for the FDA as part of Project Optimus, where we are evaluating both two doses: a 750 mg dose and a 1,500 mg dose. Again, the 1,500 mg dose is where the predominant data has been presented. That cohort that we presented at ASCO this year was 1,500 mg. You know, either later this year or early next year, we'll be presenting the 750 mg data, again, which is the alternative dose that is in that pivotal trial.
So I think that's a key catalyst for a couple reasons, one of which is, again, it's the other dose that's in the trial. But it also will double the total number of patients that we have in, you know, prospectively evaluated in a, you know, frontline head and neck population, where we're, again, able to see additional demonstration and a larger data set with our molecule. So it's, in our mind, de-risking of the pivotal trial. We also have been exploring alternative administration schedules. So we have a cohort at a higher dose every other week, and expect to be able to present that data in the first half of next year.
Outside of the data that we presented at ASCO last year, we've got cohorts, both with an alternative schedule as well as an alternative dose, that we'll be presenting in the near term.
Okay. Excellent. I think a lot to kind of unpack there, but, maybe first question, just sort of bigger picture. You know, you kind of mentioned a little bit about the mechanism of action and some of the validation with these targets. I guess now that you've seen some of these clinical data, sort of unfold, what is the relative contribution of the two different targets in that mechanism? How does that interplay with pembro?
Yeah. So, you know, part of, again, why we paired EGFR with TGF-beta is the known, you know, synergy that you get with PD-1 and pembro, knowing that that was a kind of a core element of head and neck treatment. Additionally, what we know is that TGF-beta is a key mechanism for acquired resistance pathways for EGFR monoclonal antibodies. So by pairing it with TGF-beta, we're seeing both the ability and combination with the EGFR component to mitigate acquired resistance, and at the same time, using TGF-beta synergistically with the PD-1. So we're really, in a lot of ways, that becomes kind of the core element that is, you're seeing benefits on both sides of that combination, both in the EGFR as well as the PD-1.
In terms of the contribution, you know, there have been a couple of investigator-initiated studies that explored cetuximab in combination with PD-1. One trial, you know, again, with cetuximab, pembro, which was done and conducted by Dr. Tina Sacco at UCSD. There, it really established for us a benchmark for... We knew what EGFR and pembro could deliver. What could the addition of TGF-beta give? And at that data set that we presented at ASCO, I think it was the first real clinical demonstration of the benefit that you get from TGF-beta. There, what we saw was a meaningful increase in not only PFS, but also duration of response. You know, as a point of reference, pembro monotherapy in the population that we're studying gives a 19% overall response.
And those patients who respond with pembro monotherapy, they actually do really well. I mean, you get 23.7-month, almost 24-month duration of response, but only one in five patients are responding. What we were able to show, we now have a confirmed response rate of 54%, so almost a tripling of the responder population. But we were able to demonstrate a 21.7-month duration of response. So as we came into the trial, you know, we knew that, you know, pembro monotherapy population were still gonna exist, you know, and they were gonna do as good if not better with the addition of our agent. But one of the key questions was, as you expand the responder population, what's your duration response gonna be there?
You know, we were really encouraged when we saw the data, and, you know, even with a dramatic increase in the responder population, we were able, in that group of patients that wouldn't have otherwise responded to pembro monotherapy, to see very comparable durations of response in a much larger population. Which ultimately, you know, we believe was a key contributor to the outsized effect that we've seen for overall survival. Again, where we've demonstrated a median overall survival of over 21 months.
That's great. And then on the safety side, what are you seeing on the safety side? You know, are you seeing kind of skin and bleeding events, or skin adverse events and bleeding events from the two different targets?
Yeah.
I guess, how are physicians sort of managing that?
Yep. Yeah, so, you know, if you break it, you know, the molecule down, you know, we're seeing the anticipated, kind of on target, EGFR-related acneiform events, predominantly acneiform rash. You know, I think very, very similar to what has historically been seen with cetuximab, with, I think, similar kind of management protocols than what the market has been using for a long time. On the TGF-beta side, the most common event that we're seeing related to TGF-beta is anemia. Again, the presumed mechanism around that with TGF-beta is around red blood cell maturation. And in most cases, physicians are able to treat that with oral iron. We've seen no discontinuations-
Mm
... from the anemia, and we also, in terms of dose intensity, we haven't needed to, you know, either go have patients take a dose holiday or a dose reduction, so it's been very manageable. We are seeing some transient, you know, low-grade bleeding events. Predominantly, you know, you're seeing some gingival bleeding. You see, some patients will get nosebleeds, but again, those tend to be transient, not require discontinuations or breaks in treatment, and you tend to just see them, you know, maybe one cycle, and then they go away and, you know, again, patients are able to maintain on the regimen.
Okay. Okay. And then maybe you mentioned a little bit about the phase II/ III pivotal study. Talk about the design of that study, and I think you talked about there being a dose optimization-
Yeah
... portion. What, what, what's behind that?
Yeah. So, FDA-
Okay
... with Project Optimus. So, you know, one of the things that we in our dialogue with the agency, in order to be able to initiate the pivotal trial as rapidly as possible, the agency was open to, you know, doing a run-in with two different doses. So the trial initiates as a three-arm where you have a 750 mg dose in combination with pembro, 1500 mg dose in combination with pembro, and then the pembro control arm. What we have agreed with the agency is that once we've enrolled anywhere from 10 to 20 patients per group, that we will look at that data....
and ultimately make a decision between the two doses, which dose we wanna move forward with, and then the dose, one of the arms will ultimately get dropped, and we'll continue at that point in a 2:1 randomization of, you know, ficerafusp to pembro monotherapy. Again, you know, what the agency was looking for there is to satisfy what they're looking for around being able to optimize dose and make sure that you're, you are seeing a meaningful increase in efficacy as you're essentially taking on, you know, more toxicity. So again, the agency was amenable, seeing the data that they saw. They also were developing this head and neck under the Project FrontRunner construct.
And so again, what the agency is looking to work with sponsors there to move drugs into earlier lines of therapy as early as possible. And so they also were accommodating in that design so that we could initiate the trial as rapidly as possible.
Great. And how should we think about the patient population? Like, is the patient population that's being targeted here, is it... Would you expect any kind of differences as you've moved on from a phase I to this?
Well, so early on in phase I, we looked at an all-comers population as it relates to HPV status. And what we saw in that data set, where we looked at both the HPV positive and the HPV negative, is that our drug behaved in those two different groups very similar to what historical EGFR monoclonal antibodies have. You know, there's data with cetuximab and also panitumumab, where historically, what we've seen across multiple studies and large groups of patients is that EGFR mAbs just don't do as well in HPV-positive patients. We saw that in our own data. There's activity there, but the activity isn't as good. In our own data, we had 11 patients that were HPV positive. We had three out of 11 patients responded.
And in fact, you know, two of those three responders were complete responses. So there's—it's active in HPV positive. We have a hypothesis, based upon our data, you know, as we've dug into that to try to understand, are there predictors of response in the HPV-positive patients? And in our own data set, what we saw is those patients who responded also had a history of smoking. And what we know, for example, in the HPV negative, the key driver of the biology in HPV negative is either alcohol use or smoking. What we have found, again, is, you know, I think, you know, you can have a similar situation where just because you're HPV positive, if you're HPV positive and you're a smoker, what we believe is the, the...
You have probably dual things that are driving that biology. And what we are seeing is, if you have any kind of smoking biology driving the etiology of the tumor, we are seeing activity there. So we've actually opened up a cohort of HPV-positive smokers. You know, and we're looking for patients who have a 20-pack year history of smoking. And we do believe that there is a subset within the HPV positive where that could benefit from ficerafusp. In terms of our decision in the pivotal study, we chose to select for HPV-negative patients only. There again, we think that there's a much greater benefit that patients will receive from a drug like ficerafusp, and we chose to select for again that population where we think that there's they're gonna have a greater benefit.
Okay. Awesome. And for the HPV negative, for the phase two/three, what have you said around kind of the powering and the stats?
We've not disclosed the powering there. The overall study is designed as 650 patients. Again, it's got two primary endpoints. It's got an endpoint of overall response rate, which could facilitate an accelerated approval. And then also the confirmatory endpoint is overall survival. You know, we will do the initial look at overall response rate, where you basically have ORR with six months follow-up to check the durability of those responses. And we'll do that, you know, somewhere between 350 to 400 events.
Okay. And then, you know, you mentioned your this is under Project FrontRunner. I guess, with this study, do you expect to be sufficient to go to the FDA and, you know, assume the study's positive, to seek approval?
We do. Again, in the dialogue that we've had with the FDA, you know, one of the things that at that initial approval, they have, you know, stated that they will also do their own analyses around overall survival to make sure that the trend is holding up. I think one of the things, you know, particularly if you look at some recent data from the lenvatinib program, LEAP-010, which was lenvatinib pembro versus pembro monotherapy, one of the things that the agency wants to avoid is what you saw in that study, where around the 12-month mark, actually, the curves crossed in favor of pembro monotherapy. Ultimately, the lenvatinib arm was inferior in overall survival.
So at minimum, what the agency will wanna look for is that you have some level of maturity around your survival curves, that those curves continue to separate, and they're not beginning to come back together like what was seen in the lenvatinib trial. So, you know, I think in the event that, you know, obviously we have, you know, meaningful differences in response rates and the Kaplan-Meier's continue to go directionally, you know, we do believe that it will facilitate accelerated approval on that study.
Yep. Actually, let's go back. That's a really interesting point. So with regards to overall survival, in, you know, from the data that you've seen in head and neck, how well do, like, the 12-month and 24- month overall survival sort of compare with the median?
Yeah, you know, I think it's, it's all over the place.
Okay
... frankly. You know, a perfect example is ALX Oncology. You know, they had in head and neck, in the exact same setting, I think, you know, an 85% 12-month OS. Ultimately, that trial failed. If you look historically at pembro monotherapy's 12-month landmark, and then you compare it to what lenvatinib was able to demonstrate with their twelve-month landmark, what you saw there was the lenvatinib pembro had was better at the landmark, but ultimately inferior on the median. And so I think our view is that, you know, that you have to be careful looking at the 12-month landmark. I think particularly you need to make sure that you're looking at it and thinking about it in the context of what your control arm's gonna be.
And again, that's one area where our design has differentiated from other experimental therapies in the head and neck space: again, by only having the HPV-negative. We do firmly believe that the control arm in our trial will behave differently than what it does in other trials. Because, you know, HPV-negative patients tend not to do as well, so we think that pembro monotherapy in our control arm as an HPV-negative only will deliver lower overall survival than what it will in a mixed population of HPV-positive and negative. And ultimately, you know, even if you look to that, the lenvatinib trial again, where you see the curves cross at 12 and the pembro mono do better from 12 to 24 months, you know, we think it's important to have longer follow-up.
And at minimum, it's important that you contextualize 12-month landmark relative to where, how you're designing your control. So I think there are a lot of considerations when you look at just the 12-month landmark.
Right. Okay. Well, maybe speaking, you know, of the, you know, the longer duration, you have phase Ib expansion cohorts, 750 mg to, I mean, 2,000 mg, is that right?
The 2,000 is every two weeks.
Every two weeks. So, and a couple updates coming. I guess, what are the importance of those updates? What should we be focused on? And I guess, how important is that to the overall kind of package you want to eventually put in front of the FDA?
Yeah, I think, you know, again, given that we are our run-in is both the 750 and the 1,500, you know, having being able to take a look at the 750 data for investors is gonna be important. So, and, you know, at the point in time when we select a dose, what we will be able to communicate is a dose has been selected and what that dose is. I think it will be important, you know, so that you have clarity, and you don't have a black box on what the likely data is at either dose. So, investors will be able to see, again, what the data looks like, both at 750 and 1,500.
I think additionally, regardless of what dose is selected, one of the things that data set at 750 will do is we see it as a de-risking cohort. You know, even if you see a lower overall response at 750, which you would expect, you know, I think it, you know, people would naturally expect at a lower dose, you would see probably less activity. We do still think that as you combine those data sets, it will tighten the confidence intervals around overall response rate.
Mm.
And you know, given that that is the endpoint for accelerated approval, I think what investors will be able to look at at that 750 cohort, they'll look at it and again be able to increase probability of success of our ability to demonstrate a meaningful difference at the accelerated approval.
Okay, excellent, and maybe we can talk about the market. Like, how big is the market in HPV negative?
Yeah. So HPV negative in the U.S. accounts for about 85% of overall head and neck cancer in the recurrent metastatic. It's a bit lower if you look at earlier stages of disease. You know, often, HPV-positive patients are cured in the locally advanced setting, you know, in Stage I, II, and III. And so as you get to recurrent metastatic, it begins to skew a bit higher towards the HPV negative. But, you know, the vast majority of patients in the recurrent metastatic setting are HPV negative. And again, there's multiple subtypes of head and neck cancer, and in fact, in all of the subtypes but one, patients are presumed to be HPV negative. So in fact, you only have to even test for HPV status in the oropharyngeal subtype.
Okay. And would you do a companion test for that, or is that-
We do.
Okay.
We are working in partnership to develop a PCR-
Okay
... HPV test. So historically, what has been done and is currently in the ESMO guidelines and, you know, multiple guidelines is, you know, typically, patients are tested in the locally advanced setting when they're first diagnosed, and they're doing it with p16 IHC. You know, the issue with the IHC is there's about a 10% both false negative and false positive rate, so the PCR has better, you know, sensitivity. And so, you know, we will have that test as part of a companion diagnostic at our approval.
... And would you go after the locally advanced setting?
We absolutely are. We've got a number of studies that are currently in planning right now with large cooperative groups. You know, I think there are a couple studies within locally advanced. You know, again, you know, we saw recently, you know, the data from pembro and KEYNOTE-689 study, where, you know, those are patients that were surgically resectable. Again, that's probably about a quarter of the patients that fall under the KEYNOTE-689 population. So we are looking there, you know, in those patients that are eligible for surgery. But we're also, I think, even more intrigued by patients who are getting radiation. What's known is that radiation increases levels of TGF-beta, so we think that we are mechanistically differentiated-
Mm.
given, you know, the TGF-beta component of our drug to show a differential effect in a locally advanced setting in those patients who also have radiation.
Super interesting. And I guess, by how much do you think that could expand, kind of the TAM?
Considerably. So, you know, in the U.S., you know, we just look at U.S. numbers, the recurrent metastatic accounts for about 23,000 patients. The total annual incidence in the U.S. across all stages is around 67,000 .
Okay. Okay.
Not insignificant.
I wanna just in the last couple of minutes move over to colorectal cancer, but are there any questions in the room? Yeah.
Yeah,
On that, I-
Say it one more time, and then I'll-
We anticipate that we'll be able to initiate that trial either later this year or early next year.
There will be combination with them or alone?
Likely in combination.
Okay, and then for the webcast, so this is a question about the locally-
Yes
... advanced pursuits, and, when you would start it, and whether it be in combination with pembro? Awesome.
Can I ask one more?
Absolutely.
You have your current program that you have a certain population, it's just greater than one. Do you have a differentiation between CPS less CPS?
What we demonstrated, so the question for those on the webcast is, in our population, we are studying patients with CPS 1 or greater. Is there differentiation based upon CPS score? What we showed at ASCO this last year is actually we see very similar activity regardless of CPS score. So we're seeing high response rates, both in the way we subset it, is CPS 1 to 19, and then CPS 20 or greater. And the reason we did that is that's actually in KEYNOTE- 48 on the initial approval from pembro. That's the way Merck had subsetted it. So we wanted to use kind of that historical control data to evaluate differences. In most cases, and in fact, in the pembro monotherapy, we actually do see better activity in the CPS 20 or greater.
With our drug, you saw similar activity regardless of CPS score.
Okay, great. Yeah, so let's move on to colorectal cancer. Maybe, can you just talk about the mechanism of action as it relates to colorectal cancer? I guess the question is, are you dealing with a patient population that may have some resistance to EGFR?
Yeah, so we're initially doing signal seeking in a third-line plus population.
Okay
... where, you know, probably everyone will have seen EGFR in the past. You know, especially, you know, we're initiating that in the U.S., so my expectation is that they all have had some exposure to EGFRs. And that, you know, mechanistically, again, what we saw in our dose escalation data is patients who had prior exposure to EGFR, the TGF-beta was able to overcome that. And what we were able to see in multiple patients is we were able to recapture responses even after they progressed. One patient in particular that I think, you know, demonstrated this, had seen Erbitux in two previous lines, and then ultimately responded as a fifth-line patient-
Wow
... to ficerafusp alfa. So again, we do believe that the TGF-beta will allow for, you know, an immune environment that will allow patients to recapture the response even after they've progressed on previous EGFRs.
What do you think the bar is in this setting?
You know, it's pretty low. I mean, you know, in third- line plus, you know, you see single-digit response rates, you know, PFS in the five-month range. You know, I think for us to pursue that signal, obviously, you know, we're looking to, you know, probably something in the mid-teens in order to... But I think also, even from that perspective, you know, for us internally to invest additional capital in CRC, really what we're looking to do here is, you know, is the compound active?
Mm-hmm.
you know, we know that it's a tough population. It's a heavily pretreated population. It has prior EGFR exposure. So are we seeing enough activity to give us the conviction, to move into earlier lines where the drug is able to actually probably demonstrate, you know, its true utility?
Excellent. And when do you expect to have that info?
We anticipate we should have preliminary group of patients, you know, sometime in 2026.
Okay. Okay. And if that's positive, like, what would that kind of market opportunity potentially be? I mean, I guess it depends on sort of how far up the treatment line you go, but yeah, how are you thinking about that?
Yeah, I mean, I think, you know, you'll likely, you know, move to the front line pretty quick there in combination with chemo. I think there's gonna be some interesting data that emerges. You know, I think we anticipate we'll see data from J&J's EGFR c-Met.
Mm.
I think that'll continue to help inform.
When is that?
What? The bar. I think we expect to see it at ESMO.
Okay.
And Merus is developing in CRC as well. So I think there are a number of data sets out there that will, you know, continue to define what the bar is, and where the most viable path is. You know, for us, one of the things that's really important is identifying populations where TGF-beta plays a role, where there's a you know. And another area outside of CRC is pancreatic. Pancreatic, we know that, you know, there's been a fair amount of data that there are TGF-beta signatures within populations in pancreatic cancer. And we will be similarly looking for those populations within CRC, same way we did in head and neck to identify where we think, you know, our molecule is most likely to benefit patients.
Okay, excellent. I guess the last question from me is just around cash and kind of what kind of clinical catalysts do you think you're currently funded for?
Yeah. So, you know, at the IPO last year, you know, we were able to raise $362 million at the IPO. We've, our most recent earnings have, I think, $437 million of cash on hand at the end of the quarter, which we've guided, that gives us runway to 2029. So, you know, we're able to see our current pivotal trial through with that amount of cash. And, you know, we'll be looking, you know, if we see a signal in CRC, obviously we'll need to raise more capital to go into a pivotal trial there, but are fully funded for our head and neck registrational trial.
Okay, excellent. And are there any other questions in the audience? Okay, Ryan-
Great.
Thank you so much.
Thank you.