Perfect. Let's get started. Welcome, everybody, to the next session. My name is Kelsey Goodwin. I am one of the analysts here at Piper Sandler. Our next session, we have Bicara. We have the President and COO, Ryan Cohlhepp. Thanks for joining us.
Thank you.
Let's start with a quick summary of Bicara, where we stand heading into year-end and 2026.
Yeah. So for those of you who are not familiar with Bicara, we are a company that is focused on developing bifunctional, trifunctional, multifunctional agents across solid tumors. Our first program that we developed, and we actually launched the company and formed the company around, was a TGF-β EGFR bifunctional. And our concept here as a company is to utilize tumor targeting to get things like TGF-β to the tumor. We started here really with a concept. We thought that there was a lot of promise with TGF-β. It really has been unrealized promise, particularly as it relates to oncology. And our thinking from the onset was what the limitation has been there is getting TGF-β to where it matters, which is at the tumor level.
One of the things that a number of companies have been able to demonstrate is peripheral neutralization of TGF-β, but have never really been able to demonstrate a change in the tumor microenvironment, and we used EGFR in order to do that, and so have built kind of our company around that. We did have other programs that were in our research portfolio with a similar concept, but our lead program, ficerafusp alfa, again, that TGF-β EGFR, is the furthest progressed, and we've now demonstrated pretty substantial clinical data there, and that data has catalyzed the start of a pivotal trial. We embarked upon a phase II/III trial in February of this year in the frontline recurrent metastatic head and neck cancer market, and again, that was coming off the data that we presented first in ASCO 2023, and then we're able to present data with two years of follow-up.
That cohort of patients at our most recent ASCO is showing really meaningful improvements in response rate and PFS and duration of response and overall survival.
A perfect segue to my next question, which is mainly, for ficera , what have been the key clinical learnings to date? How do they support the design and the mechanism of action? And maybe let's just say as of ASCO 2025, and we'll pause into ESMO after.
Yeah. Yeah. One of the things, again, with the concept is, again, we had conviction around TGF-β, but to be really transparent, early on in the early stages of the program, we weren't sure what the clinical contribution of TGF-β was going to be. And that's why we went into head and neck cancer. It's an area that made a lot of sense for us on a number of different dimensions. One is EGFR is overexpressed in about 90%-95% of patients with head and neck cancer. So we felt comfortable empirically treating with our agent without having to prospectively test for EGFR expression. Secondly, the current standard of care is pembrolizumab therapy, which only has about a 19% response rate. So the ability to show meaningful improvements in response rate, we felt were pretty high.
There were also investigator-sponsored studies that utilized Erbitux in combination with pembrolizumab, which showed a doubling of overall response rate there. We thought that the head and neck population would be a good area for us to where we thought probability of success was high. We were also able to demonstrate and evaluate what kind of clinical benefit are you able to get from TGF-β. What we showed at the most recent ASCO was, again, we confirmed almost a tripling of response rates. But even, I think, more meaningful was you tripled the responder population, but we showed median duration of response of over 20 months. One of the things what's interesting when you look at pembrolizumab is while only one in five patients respond, those patients who respond actually do really well. You have about a 24-month duration of response.
So one of our questions was, as you expand the responder population, that 19% that sat there with pembrolizumab therapy as responders, that population still exists within our study. What was the next 35% going to do? And we were really, I think, encouraged when we saw that you basically saw pembrolizumab-like response, duration of response, even in that extra 35%. And that's where we were able to show a median DOR of over 20 months, median overall survival in that population of close to 22 months. And again, I think mechanistically, what that has told us is what you're seeing, even in the cetuximab plus pembrolizumab, you only see about a 12-month duration of response. So you see a significant drop-off as you add on 20%-25% of responders, you see a significant drop-off in that 25% on their duration of response. We didn't see that.
We completely attribute the duration of response and the depth of primary tumor reductions that we're seeing to the TGF-β. I think we now have a very clear view of the clinical benefit that you're getting from TGF-β. And again, I think we also will be showing, I think, some really compelling translational data, even as we now are looking at multiple doses. And as you're seeing increased inhibition of TGF-β at the tumor, we're seeing a lot higher reductions in pSMAD2, which is a downstream marker for TGF-β. So I think a very clear distinction not only between our doses, but I think even more importantly, we're seeing that differentiation across the EGFR bifunctionals as people begin to try to understand what is TGF-β bringing versus LGR5 versus c-MET. And I think that we've been able to do a nice job of characterizing the contribution of TGF-β.
Great. And that primarily was at the 1,500 mg. Obviously, you'll be presenting the 750 mg data later this weekend. We saw the abstract over this past weekend. Just remind us, how does a 750 mg dose fit into kind of the development strategy for ficera ? And what were the key takeaways from the brief abstract that we saw?
Yeah. So as part of our clinical development strategy, one of the things that FDA had requested from us is that we do dose optimization, and we decided from an efficiency perspective to incorporate that into our pivotal phase II/III trial. The two doses that we took into that trial were 750 and 1,500, so in the phase II portion of our pivotal trial, we've got both of those dose levels. Knowing that we were going to be doing that, we enrolled 30 patients in an open-label cohort, which will allow us to have greater than a year of follow-up at the 750 mg dose. We have over two years of follow-up at the 1,500 mg dose that will help inform and be important supportive data when we go to the FDA to make a dose selection.
And the reason we picked 750 is we know that at 750 mg, we have fully saturated the EGFR target. And what the data that was released in the abstract over the weekend showed is that we have a confirmed response rate of 55% at the 750 mg dose, which is very similar to the 1,500 mg. In a lot of ways, that was completely in line with our thinking in terms of understanding the pharmacodynamics of the two components of our drug. Knowing that you have saturated the EGFR target at 750, what we know is that the overall response rate we believe is being driven from EGFR. Because TGF-β, what it does biologically is it overcomes acquired resistance mechanisms and pathways, but doesn't overcome de novo resistance.
So where we think that EGFR is delivering on response rate, TGF-β is delivering on the depth of that response, the durability of that response, and ultimately the median overall survival. So one of the things that was also seen in that abstract is what we've been able to demonstrate with our data at ASCO is a 21% complete response rate at 1,500 mg. We also had three additional patients that had 100% reductions in their primary tumor that were considered PRs. They weren't classified as CRs. Whereas at the lower dose, we only are seeing a 10% complete response rate. And really, you think about, again, where is TGF-β contributing? We know that at the 1,500 mg dose, you're getting higher levels of TGF-β inhibition. Again, you're seeing from a clinical endpoint perspective those differences in complete response rates.
Again, we will be hosting a corporate conference call on Saturday where we'll provide more data around the differences between the doses, particularly as it relates to the pharmacodynamics of TGF-β.
Got it. And maybe just specifically in terms of the full presentation, just confirm the data cut and anything else we might expect in the full presentation.
Yeah. So, Dr. Deborah Wong from UCLA will be presenting the data on our behalf at the meeting on Saturday. And that data, so the data cut and the abstract was from July. The presentation will have the same data cut. It'll be a July data cut. What will be additive to that, there will be more information kind of on the tolerability profile, the AE profile, as well as we'll have the waterfall showing the depth of response. So you'll be able to better characterize and understand, again, in the abstract, you saw a 55% confirmed response rate, but you'll also see across the range of patients, 30 efficacy evaluable patients, the depth of those responses.
Okay. Got it. And then I guess the other side of TGF-β, obviously, there's the potential or investors think there's a potential for bleeding risk. Maybe just remind us what you've seen so far at the 1,500 mg dose and to what extent the 750 mg dose might help further contextualize that.
Yeah. The bleeding that we've seen has been a, transient, low grade, predominantly grade ones. What we've seen is epistaxis or nosebleeds. And we've also seen some gingival bleeding. The gingival bleeding in particular is common in head and neck patients in general. And I think what we see there at 1,500 mg, you don't really see a meaningfully different profile with the 750 mg. I think, again, given the transient nature of it, I think it often is in early cycles, early doses that you see the bleeding. The one area that you do see some differentiation, as you would expect, is on anemia because anemia is on target with TGF-β. The hypothesized mechanism of that anemia is an impact on red blood cell maturation. And so we are seeing higher rates of anemia at 1,500 mg.
The positive perspective on that, though, is even at 1,500 mg, it has not led to discontinuations. You haven't needed to see significant reductions in dose intensity. And in most cases, investigators have been able to start patients on oral iron and overcome the anemia. I think one of the things that is notable is anemia is very common in head and neck cancer patients in general. 52% of our patients who came on to study with a grade two anemia. And so the vast majority, over half of our patients started at a grade two. And in some cases, even small changes and small reductions in hemoglobin led to kind of those patients going on to a grade three.
Understood. Okay. So those two doses are both in the pivotal phase II/III trial. Maybe just remind us how this trial was designed and your base case assumption for timelines.
Yeah. I think the easiest way to think about it is really kind of in three different buckets. The first objective in the trial, the phase II component, will be making a determination on dose between the 750 mg and the 1,500 mg. We have agreed on a certain number of patients with the FDA that at what point we'll go back with our open-label data, the 750 and 1,500+ data from the run-in of the pivotal trial to make a decision to drop one of the two doses. The dose that is selected, the patients that are enrolled in the phase II component will contribute to all subsequent efficacy analyses, both for overall response rate and overall survival. The design that we have agreed to with the regulators here is a seamless design. So at approximately 350 events, we will be doing a data cut for overall response rate.
Consistent with the Project FrontRunner construct, the FDA has guided that that would be a sufficient number of patients to potentially facilitate an accelerated approval on overall response rate. All of those patients will continue on to the confirmatory endpoint for overall survival. Rather than having to do an additional confirmatory trial, we will get both the accelerated approval and a confirmatory full approval on the single trial.
Okay. Got it. In terms of first half of 2026 choosing the dose, how will you communicate with the street? And what would kind of be included in that update?
Yeah. So the plan is to meet with the FDA in the first half. And at the time of dose selection, what will be publicly disclosed is which dose was selected. There won't be any data because given that those patients will contribute to subsequent analyses, that data will remain blinded. And so in order not to contaminate or to potentially affect the conduct of the trial, we will not be publicly disclosing the data and the response rate data. We will only disclose which dose was selected.
Okay. Understood. So also in early 2026, you'll also provide an update from the 2,000 mg Q2W expansion cohort. So that dosing schedule is not in four to five. Maybe just remind us, what do we gain from this update? How should we benchmark it now to the 750 and the 1,500?
Yeah. I think that data, I think, has two things. One, it provides kind of reason to believe that we can get to a less frequent dosing administration to help synchronize with pembro. Pembro now is given either every three weeks or every six weeks. I think more and more you're seeing it given every six weeks. So being able to go to every two weeks will reduce the number of times that a patient will have to come into the clinic. And the estimated half-life of our drug is around eight days. So there's a lot of rationale to get to every two weeks. Even if you look at Erbitux, they initially were approved weekly and then subsequently got a label expansion to every two weeks.
So again, I think it'll be the preliminary data to demonstrate that we don't have Cmax-related toxicity that would limit us to go to higher doses at every two weeks. I think the other really nice thing about it is you'll now have a dataset at 750 mg, 1,500 mg, and 2,000 mg. I think what is beginning to build there is a really nice story around the contribution of TGF-β. You're going to see it for the first time meaningfully when we show the 750 mg versus 1,500 mg and what you see from a TGF-β perspective as it relates to depth. As you dose even higher and you get a dose up at 2,000 mg, I think what that data has the ability to demonstrate is the continued dose responsiveness of the TGF-β clinical contribution.
Okay. Understood. In terms of moving forward with this dosing schedule, I guess, is there still potentially a plan to try to get this longer term into the label? What does that kind of process look like?
Yeah. We absolutely are. I mean, one of the things that our pharmacology team is doing a lot of work on right now is really characterizing the exposure-response relationship with different pharmacokinetic parameters, whether you're looking at Cmax, AUC, Ctrough, which of those we think is the key driver to activity. We will ultimately look to, once we declare the weekly dose, look to do a pharmacokinetic bridge that would enable subsequent label expansion to less frequent dosing.
Okay. Understood. And sorry, the timing of that would be alongside four to five or after the fact?
Our plan is to get that up and running, to have that running in parallel with four to five. And assuming that we're able to do it based on pharmacokinetics, those trials, there's a lot of regulatory precedent of being able to do that on PK endpoints of anywhere from 80 to 120 patients if you're able to do it with a PK bridge.
Okay. Understood. Okay. Great. Shifting to the competitive landscape, you've mentioned it. I think you kicked it off with this. Based on what we have seen now, how do you think about comparing the different arms, TGF-β, LGR5, or c-MET? Which appears to be most promising? What are you looking at?
Yeah. Again, purely based on clinical demonstration, our view obviously is TGF-β has been able to show what it's adding into the molecule, what it's adding for patient benefit. We've shown, I think, the duration of response data that we showed at ASCO was meaningful. I think it really begins to set itself apart. If you look at, again, the study that was conducted with cetuximab plus pembro, there you saw a median duration of response in a similarly sized trial of around 12 to 13 months. We were able to extend that out to in excess of 20, with the key difference there being TGF-β.
I think as you continue to see other EGFR bifunctionals, I think the data that we have yet to see in comparison to our own is anyone being able to show duration of response in a large responder population similar to what we've been able to do with TGF-β. So I think, again, I think everyone's pretty clear what EGFR brings to the party, what the other component of these drugs is. Again, I think there's growing clarity that TGF-β is bringing depth and durability.
Understood. In terms of the frontline trial designs across kind of the three lead programs in the space, we have ficera, we have [phyto], and amivantamab. I guess, how do you think about the three kind of approaches to frontline head and neck and why ficera's trial might be best designed?
Yeah. Looking at the historical data with EGFR, and we've looked at a lot of the cetuximab data. Amgen had done a study that ultimately failed with panitumumab. Those trials in close to 1,000 patients have consistently demonstrated that EGFR monoclonal antibodies do better in an HPV-negative population. Is there activity in positive? Yes, there is. Even in our own, we had three patients out of the 11 that responded. Two of those three had complete responses. So could we have added the positives? 100%. We could have done it. Do we think it would have been dilutive to the effect both in overall survival and response rate? We believe that it would have been and why we excluded the HPV-positive population. We do believe that there is a subset within HPV-positive that are more likely to respond to these agents.
Our hypothesis there is that patients who have a history of smoking. And we think that the smoking is what's driving the biology more so than what the HPV infection is. And so we are doing a cohort where we think that we can use smoking as a patient selection identifier to identify a subset of patients in the positives that will respond. We took an approach that we wanted a population that we thought had the best chance to respond. And we enriched for our pivotal study in the population that we think are the patients that will respond the best. In comparison, what we understand from the ami trials that they're likely to do that in the recurrent metastatic in combination with chemotherapy. There you see a real diversity across the world in terms of what patients are getting chemotherapy.
In the U.S., what we know is it tends to be a smaller subset of patients where physicians are looking at this bulky disease and they're looking for rapid responses, and more and more, I think that that is a diminishing population, particularly as you have agents like ficera that are potentially going to show meaningfully higher overall survival and better response rates with a better safety profile. What we know in pembro chemo is that almost 30% of patients discontinue early because of AEs, and so I think what we have done in our trial is we have gone with, I think, the larger population, which is also consistent with a population that is most likely to benefit the greatest from our therapy.
Understood. All right. One minute left. Maybe just final thoughts heading into this weekend and then also into 2026.
Yeah. I think we're super excited with the data being able to demonstrate. And again, what we'll show on the call is the difference across doses and kind of where our heads are as we move to make that dose determination. We continue to, from an operational perspective, I know one of the, I think, the real areas of focus is on our execution as a company, particularly as the competitive space continues to heat up. We continue to add sites on. We are now open in North America and Europe. We will quickly begin opening up sites in Asia and South America. And so the team continues to execute and to bring patients on to trial and look forward to making that dose declaration as we've guided to in 2027 and move to the phase III component of this trial.
Perfect. All right. Right on time. Thank you so much.
Thank you.
Thanks everyone for joining.
Great.