One, Carter Gould, Senior Biotech Analyst at Barclays. Happy to have Bicara Therapeutics with us for our next session. We have Ryan Cohlhepp, President and Chief Operating Officer. Ryan, maybe for those less familiar with the story, could you just give us an overview of Bicara and progress that you've made in upcoming milestones?
Yeah, great. Now, thank you for the invitation and having us here at the conference. So Bicara Therapeutics is a company focused on bifunctional antibodies that are tumor-targeting. Our lead program is an example of that. It's a EGFR TGF-beta. Again, where we're using EGFR to bring TGF-beta to the tumor microenvironment. You know, we founded the company in 2020, where we actually were able to license intellectual property from an organization, Biocon, back in 2020, and have, you know, since over the last 4 years- 5 years, continued to develop that.
You know, we're now at a point where we've seen substantial activity with that molecule, which I'm sure we'll speak about, you know, a little bit later, and have been able to embark upon a registrational trial in the recurrent metastatic head and neck setting. We initiated that trial in early last year and are gonna be in a position where we expect to have top-line data in mid-2027.
Mm-hmm.
in the head and neck market.
You're looking at a HPV-negative population in head and neck cancer. Historically, that's been a segment that's been sort of viewed as being immune excluded, right? Where it's difficult to get drugs, effective drugs in that population. Maybe just talk about the EGFR TGF-beta mechanism and how that's been able to really make and show clinical activity in that population of patients.
Yeah, absolutely. You know, part of our rationale, again, when we designed the molecule is there's known synergy between EGFR and TGF-beta. You know, you speak to the HPV negative population in particular. What we know of the negative population is that, A, there's higher levels of EGFR expression, but also the higher levels of TGF-beta. You know, our rationale early on, again, in the development was, you know, there had been a number of historical approaches, you know, where companies have tried to use TGF-beta in a cancer setting.
Mm-hmm.
have been unable to see activity there. Really, our view there was you weren't able to see adequate levels of TGF-beta in the tumor microenvironment. We're using EGFR to get there and to be able to get, you know, TGF-beta into the tumor. You know, what we know is that, you know, TGF-beta, if you look at the biology of TGF-beta, what it does is it helps overcome acquired resistance mechanisms with EGFR. There's this duality of effect as you think about EGFR and TGF-beta together, and that's why we paired the two together. Not only to be able to get to the tumor, but we also know that there's, you know, kind of synergistic activity of the two when in working together. We've seen that.
I think the first real signs of the contribution of TGF-beta was as we started to present data around you know our early signals of activity that we were seeing these really deep and durable responses. You know, when we first presented our data in head and neck population at ASCO 2023, at that point, we already had a number of patients with really deep responses and several patients with complete responses. If you look at in that HPV negative population, the historical data for Pembro, you typically only see at best about a 4%-7% complete response rate.
We now, as the data has continued to mature, we're showing in the 1500 mg dose, which is the dose that it will carry forward into the pivotal trial, is a 21% complete response rate. We have another 9% of patients who they weren't upgraded to complete responses, but they had a 100% reduction in their primary tumor. You're seeing that TGF-beta effect where you're seeing, you know, really, really deep responses. I think the other notable thing here that stands out relative to other EGFR bifunctionals or EGFR monoclonals is the durability. What we know with Pembro is in those patients, you know, about one in five patients respond to Pembro monotherapy. Those who do pretty well on it. They get about a 24-month duration of response.
The issue is you're just not seeing many patients respond. What we were able to see is we have a confirmed response rate in that same population of 55%. We have nearly tripled the responder population. What we showed was a 21.7-month median duration of response. What we had known all along is that responder population that would've responded to Pembro monotherapy was still gonna exist within our trials. But what about the next 35%? What's gonna happen to their duration of response? What you've seen with Cetuximab, what you've seen, I would say even with pembrolizumab, is you actually see in that those additional responders EGFR-like duration.
That's where again, we think the, you know, the TGF-beta has been able to distinguish itself and differentiate from the other mechanisms and really being able to drive not only depth, but durability.
Great. I guess one of the things we've seen with ficerasfusp alfa as well is just the improved toxicity profile for ficerasfusp alfa versus sort of traditional or classic TGF-beta. What do you owe that phenomenon to? Is it just the EGFR co-localization? Is it maybe a finer or more tuned TGF-beta molecule?
I'd say it's probably more the latter, a more fine-tuned. What we did, the trap that we have in our molecule is the extracellular domain of TGF-beta receptor two.
Mm-hmm.
If we look at some of the older TGF-beta programs, you know, you saw some cardiomyopathy there, which was attributed to TGF-beta 2. By using the extracellular domain of two, what we see is greater specificity for one and three, which are also the cancer-associated, you know, forms of TGF-beta. Again, you know, I think we've been able to be a bit more targeted there, which I think definitely has helped mitigate some of the historical TGF-beta toxicities that we've seen with other programs.
Got it. For folks less familiar, can you give a sense on the proportion of patients that are HPV negative head and neck versus HPV positive?
Yeah. You know, one of the important distinction. There are multiple subtypes of head and neck cancer.
Mm-hmm.
There are four main subtypes. The one subtype that is where you have a mix of positive and negatives that oropharyngeal or OPSCC. Overall, as you look at the totality of the various four subtypes. In the U.S., for example, 80% of patients are HPV negative. It's actually a little bit higher as you go into Europe, even a touch higher as you get into, you know, the Asian countries where the incidence of smoking tends to be pretty high. You know, again, one of the questions that, you know, we often get is, you know, are we seeing an evolution in the epidemiology? You know, we now have Gardasil, so you have HPV vaccinations, you see smoking rates beginning to decline. Actually, what we're seeing is those two phenomena are neutralizing each other.
You're seeing a pretty consistent proportion of the HPV in 80% negative, 20% positive.
Go ahead. You mentioned the 21-month OS that you're seeing median OS, pembro monotherapy about 9- months, combination with chemo about 7 months. Do you have a sense of how that sort of plays out in the real world setting? Are patients actually seeing the 9- months and the 7- months in the real world relative to what we observed in the clinical?
Merck never disclosed the breakdown of positive versus negative for overall survival.
Mm-hmm.
You know, if you look at the pooled population and CPS greater than one, what you see with pembro monotherapy is around 12. In the real world data, there's been a pretty you know, about a 600 patient real-world study that Flatiron published.
Mm-hmm.
There it does show around nine months. You are seeing what we were able to see in that data set is they actually broke out positives versus negatives. That 12.3, it's really hard to understand, you know, what do you get from the positive versus negative. What we know in the data, you know, the real-world data that we've seen is you see a lower overall survival in HPV negative patients and higher in the positive. You know, what we also know is that many patients, actually, you know, if they're diagnosed HPV positive patients in the locally advanced setting.
Mm-hmm.
Many of those patients don't recur. You start to also see the skewing towards the negative population as you get into recurrent metastatic disease, and again, they don't do as well, you know, if you're HPV negative.
Got it. You know, as far as for the depth of response, which I think has been pretty unique and differentiated in the population, can you sort of relate that to what we would know or see from EGFR monotherapy in these populations? Because there has always been questions, is this sort of EGFR plus or is what's the contribution of TGF-beta for this population? Maybe how the clinical studies, the trials, the data have answered those questions.
Yeah. You know, there's a couple of investigator-sponsored studies that you know really we use to help guide our thinking. One was Cetuximab plus pembro, the other was Cetuximab plus nivolumab.
Mm-hmm.
In both of those cases, what you see there from a duration of response is around 13- months. I would say, you know, purely, you know, if you don't have that secondary component, you could expect to get about 13- months. I think even as you begin to look at some of the other EGFR bifunctionals, there's an ongoing question in terms of what does LGR5 or c-Met or TGF-beta deliver? I think you know, what we see here is that of those three secondary components, thus far, the only one that really has been able to demonstrate the clinical benefit related to durability is TGF-beta.
Mm-hmm.
Again, there's a lot of biological rationale for why that's happening. Again, when you think back to the biology, we know that TGF-beta is helping to overcome the acquired resistance mechanism. Even as we started this program, what you anticipated was, you know, TGF-beta, if you were gonna see a clinical contribution, it was gonna be on those durability endpoints.
Mm-hmm.
Duration of response, PFS, overall survival, and that's exactly what we've seen. You know, we've seen it not only at the 1500 milligram dose, which is what we have in the pivotal trial. You see it at 750, you see it. You know, we presented data a couple weeks ago of 2000 milligrams every two weeks. Regardless of dose or schedule, you're seeing a real characterization of the pharmacodynamic benefit of TGF-beta.
Mm-hmm.
With our molecule, we fully saturate EGFR at 750. As you look at doses beyond 750, we're able to isolate the benefit of EGFR versus TGF-beta, and you're seeing this really nice contribution in depth and durability from the TGF-beta component.
Great. Maybe a little bit more details about the phase III, the ongoing phase III, and then also the key endpoints that you obviously you're gonna be looking at for ficerasfusp alfa.
Yeah. We initiated the trial again in the first quarter of last year. We initiated it as a three-arm trial at the beginning, because we had not yet met, you know, the FDA's, you know, Project Optimus. They wanted us to do additional dose optimization work. We had aligned with the FDA to look at two different doses of ficerasfusp alfa, and then the control arm of pembro monotherapy. Early this year, we aligned with the FDA, and we're able to move forward with the 1,500 mg dose. We have now formally moved to the phase III component of the trial.
Mm-hmm.
with 1,500 milligrams being the chosen dose. The study is designed in such a way that it's got two primary endpoints. It's got overall response rate, and then we will continue to follow patients for OS. One of the things that the FDA, as they continue to look at innovative ways and trial design to, you know, facilitate and speed up earlier getting drugs into earlier lines of therapy, is under Project FrontRunner, we've got a design where, you know, instead of having to do a randomized phase II and then do a confirmatory phase III, we're doing it all in a single trial.
Mm-hmm.
We'll follow, you know, patients, you know, probably roughly 350 patients will trigger the analysis for overall response rate. Those patients will continue to be followed. This trial will remain blinded, and they'll be followed all the way to the survival endpoint. The total trial size is around between 600 and 650. We will get both an accelerated approval potentially off of the ORR, and then following, a full approval on OS, you know, a year and a half or so later than that. It's a way for us to, you know, get out there earlier.
What we also know, the FDA not only will be looking at the accelerated approval, the ORR data, they will also look, and are asking to have at least six months of follow-up on the majority of patients to make sure that a large proportion of your patients have maintained their response.
Mm-hmm.
at six months. Expect that they will do their own sensitivity analyses around the trend of overall survival at that time.
Got it. Have you disclosed powering assumptions around overall survival?
You know, again, you know, I think our view, you know, what was interesting, you know, the KEYNOTE-048 trial, again, at 12.3, you know, we didn't know the proportion of negative versus positive, so we didn't have complete information to do sizing. The other thing I think, you know, that informed our view on how we size the trial is that there was data from the lenvatinib LEAP-010 trial, which was lenvatinib plus pembro.
Mm-hmm.
There, you know, in that trial, all of a sudden we saw pembro monotherapy at 17.8%. I think there were a lot of rationale to, you know, as you look at the inclusion/exclusion criteria, a number of reasons, patients were excluded based upon toxicity from lenvatinib. So we don't think that it's gonna. You know, in our trial, we'll see 17.8%. We also, you know, knowing that we are in a negative population only, you know, what the data would suggest is the bounds there are probably anywhere from 8%-18%. I think we, you know, we looked at all the various data as we size the trial.
That being said, you know, the confirmatory endpoint for full approval being OS, we made sure that we sized it in a way that A was not only clinically meaningful, but also we de-risked the trial in terms of overall it was worth, you know, an additional 100 patients or so to make sure that we had a high degree of confidence in our ability to meet the OS endpoint.
Got it. Any differences in sort of inclusion/exclusion criteria from sort of the phase IBs into the phase III or just is very similar?
Very, very similar. You know, in fact, if you looked at the patient demographics in our trial and our phase I-B compared to KEYNOTE-048, very similar.
Mm-hmm.
We would expect, you know, the same thing, you know, as we, you know, have our pivotal trial.
Great. For the 2000 mgs, once every two weeks, how do you plan to leverage that profile? Is it maybe a maintenance post the 1500?
Yeah.
Is it to completely sort of shift the market to 2000 mgs? Like, how do you think about that?
Yeah. You know, I think looking at the totality of the data across our various cohorts, we now have close to 100 patients across three different cohorts, you know, 750 milligrams weekly, 1,500 milligrams weekly, and then 2,000 every two. We've been able to do really robust exposure-response modeling and to understand the contribution of the two different components of the drug, you know, what's driving activity on the EGFR side versus the TGF-beta. Using all that information, you know, what we know is that we get very rapid, deep responses at 1,500 milligrams weekly. Our plan is to continue to initiate therapy with a loading phase.
Mm-hmm.
of up to 12 weeks, at 1,500 milligrams weekly. At that point, we know that the vast majority of patients will have not only responded but have hit their best response.
Mm-hmm.
You'll have significantly reduced the tumor size. That gives us the opportunity to stretch the interval. What we are looking to do is to match the PK profile of the 750 milligram weekly, both on an exposure as well as a Ctrough basis. We think not only does that will allow us to maintain a best-in-class efficacy profile with a very durable response.
Mm-hmm.
We think it actually has benefit from a tolerability perspective. Because as you reduce the overall size of the tumor, again, you think back to, again, the rationale for this molecule. We're using EGFR to get TGF-beta. The tumor is your TGF-beta tumor dramatically reduces, you need less drug.
Mm-hmm.
We're gonna, you know, with a very good understanding of the biology of our molecule as well as the disease, we think we have the ability to stretch that interval out, to now sync up with pembro.
Mm-hmm.
You think across kind of the three dimensions of efficacy, safety, and administration. This weekly loading phase into a every three-week maintenance-
Mm-hmm.
We think optimizes across all three dimensions and gives us a best-in-class profile across all three areas.
Mm-hmm. Would that entail a new study, a bridging study?
It is. Yeah. One of the things that, you know, we, you know, on the heels of presenting the data at the head and neck meeting, what we guided through is we will be doing another trial, which will run in parallel to our pivotal trial. We anticipate doing a randomized trial. We still need to align with the FDA on the exact design of that trial, and so we will disclose the full design. But we do anticipate that we'll be able to have data in hand from that trial to inform the way we are thinking strategically around pricing and other things at our first approval.
Got it. The HPV testing, how routine is that in head and neck? Then also with the testing, how you know you plan to move that into sort of a commercial setting where
Yeah. It's super routine. You know, in fact, you know, most guidelines, you know, going back to, you know, the comment I made earlier, the vast majority of patients, you know, probably more than 80% of patients are actually diagnosed in the locally advanced setting. It's during that initial diagnosis that, you know, they do HPV testing. Historically, they've used p16 IHC. We are actually developing with a partner a PCR HPV test that we'll get a co-approval with. That being said, you know, by the time they come in and they recur, you know, the physician will already know their HPV status. You know, we've not seen it to be an impediment in enrollment at all. We don't expect it to be a commercial impediment.
Mm-hmm.
We've also from a payer perspective, you know, what we know, you know, the feedback that we've gotten is actually the payers are comfortable using the IHC testing that they already have. There won't even be this element where they will need to get our PCR test in order to be able to, you know, be, you know, reimbursed.
Great. How are you thinking about the commercial infrastructure and maybe the ongoing work in trying to build out a commercial infrastructure?
Yeah. We, you know, about a week and a half ago or so, we raised an additional $172 million. The use of proceeds on that fundraise was to, you know, begin to build our commercial and medical affairs infrastructure.
Mm-hmm.
You know, as you look at head and neck, you know, for a company who will be launching for the first time, head and neck is actually a pretty approachable tumor type.
Mm-hmm.
The prescriber universe is relatively concentrated. What you also have, you know, from an approval perspective, we will be approved first in the U.S. and then ex-U.S. on the overall survival. It gives us our ability to build a commercial infrastructure to launch in the U.S. We will maintain optionality as we think about, you know, whether we wanna build our own infrastructure outside the U.S. or whether we'll partner. We absolutely are gonna build the organization and feel that, you know, we've got the capability and the know-how to be able to launch in the U.S.
Right. You're looking at ficerasfusp alfa and opportunities beyond frontline head and neck cancers. If you could maybe talk about those opportunities in the remaining time that we have.
Yeah. I think there are a lot of opportunities. I mean, I think there are probably. There are more ideas and opportunities than the capital available. You know, you think about where EGFR expresses, where TGF-beta plays a role. I mean, we have cohorts open in colorectal cancer. We also have demonstrated activity, monotherapy activity in cutaneous and anal canal. Even within head and neck, I think locally advanced is a really interesting opportunity. You know, one of the things that is known is radiation actually increases TGF-beta levels.
Mm-hmm.
You think about even there, we think that in that setting, in patients who were irradiated in the locally advanced setting, that we are mechanistically differentiated, to, you know, again, where TGF-beta is kinda stand apart from the other EGFR bifunctionals.
Great. I think for head and neck, the EGFR TGF-beta story, I mean, I think it's pretty clear. Have you looked at sort of these other tumors in terms of the TGF-beta component and how those are expressed there to kinda get the-
Yeah.
-great-
There's a fair amount of work that actually has been done. A researcher, Shannon Turley, who I believe is still at Genentech, has done a lot around TGF-beta signatures.
Mm-hmm.
We use that work and our own work to really guide the way we're thinking. You know, one of the things that we don't wanna just chase EGFR. What we know is that TGF-beta is a really important component of this molecule. We are looking for those tumor types where both EGFR and TGF-beta play a critical role.
Great. We're up on our time.
Great. Thank you.
With that, thank you, Ryan, for your time. Thank you for our listeners. Line in, we'll be back soon with our next session. Thank you.