Good morning, everybody. Welcome back to the Bank of America Healthcare Conference. I'm Tazeen Ahmad, one of the Senior Biotech Analysts here at the bank. It is my pleasure to have our next presenting company, Bicara Therapeutics. Up here on stage with me is Ryan Kohlhepp from Bicara. Ryan, good morning. Thank you for making the trip over from Boston.
Thank you. Thank you for having us, and, you know, appreciate the opportunity to meet with you here today.
Maybe for those who aren't as familiar with the Bicara story, can you just give us a quick overview of the company and your lead program, and then we can go into some questions from there?
Yeah, absolutely. Bicara Therapeutics, we're a company focused on large molecules, bifunctional antibodies, focused in solid tumor oncology. Our lead program is ficerafusp alfa, which is a EGFR TGF-beta. We, you know, the company was founded in 2020. We're based in Boston, Massachusetts, and today we're a development phase company, and have about 100 employees. We've grown fairly rapidly over the last 2 to 3 years, following going public in 2024. Our lead program, again, you know, as I had mentioned, our focus is on bifunctionals, where what we're looking to do is use tumor targeting to get things like TGF-beta to the tumor.
Early on, when the asset was being developed, one of our views was that TGF-beta had a lot of promise, but we had seen very limited activity, particularly in the oncology setting, with TGF-beta. I think the most notable was the Merck KGaA GSK molecule, bintrafusp alfa, that ultimately, you know, had to be discontinued. Our view was the what the shortcoming was there, you weren't able to get adequate levels of TGF-beta to the tumor. We were using, EGFR cetuximab as our mechanism to get to the tumor, ultimately to deliver, TGF-beta there. I think ultimately we've now seen that that has played out clinically, with the data, which I'm sure we'll get into in, into more detail.
You know, overall, kinda that's the concept and the, and the focus that we have, as a company.
Okay. Your leading indication is for head and neck cancer. How did that become your first, you know, optimized indication?
Yeah. As we evaluated, you know, one of the things that we have done, continue to do is to evaluate those tumor types where there's both a role for EGFR and for TGF-beta. There are a handful of tumors. I think a couple of the more obvious ones are head and neck cancer, colorectal cancer. There's a clear view for EGFR. Wasn't always clear whether there was a TGF-beta signature there. Early on, you know, one of the things we wanted to be able to characterize is the contribution of TGF-beta. You know, with molecules like ERBITUX, you know, there was clear view that, you know, you had activity in head and neck cancer.
In CRC, as we looked at that development landscape, it's likely one where we would have to go head to head against ERBITUX given, you know, kinda where it is in the treatment paradigm. Head and neck, you know, we look there, the standard of care in the recurrent metastatic setting was pembro monotherapy or pembro plus chemo, has a 19% response rate. There had also been investigator-sponsored studies, one by Dr. Assuntina Sacco at UCSD, another by Christine Chung at Moffitt, who showed when you added pembro to cetuximab, you were able to, you know, increase response rates pretty significantly. We looked at, you know, the, you know, the standard of care, where the opportunity was.
We also felt that it gave us an opportunity, where based upon the IST data, that the likelihood that we were gonna be active was very high and would give us the opportunity to understand what we were getting from TGF-beta before going into a tumor type like colorectal cancer, where we were gonna have to go head to head against cetuximab. I think we clearly have now been able to do that. We've seen in our data, you know, of a particular interest is we're seeing deep responses. You know, our complete response rate in head and neck cancer, we have, you know, 21%, which again, is kinda unprecedented in the head and neck space.
That really was ultimately in terms of where we thought we could develop the drug, where we thought we could be able to characterize the contribution of both EGFR and TGF-beta. We thought head and neck was a good opportunity.
Okay. You talked about the targets that you've got for your bispecific. There's another asset that is now part of, it's the old Merus asset, PIDO, and it's been acquired, and the acquirer, Genmab, has made some changes to the trial design. Maybe let's start with, how do you think your molecule is differentiated from theirs? Maybe why do you think that they've decided to upsize that study, which is their pivotal study for frontline?
Yeah. I'll start with the differentiation. You know, I think it really comes down to we all have EGFR as a component of the molecule. You know, another, you know, molecule that is also developing in that space is J&J's AME, which is an EGFR c-Met. The petosemtamab molecule, their secondary component is LGR5, and then with Ficera, it's TGF-beta. We really think that it's that secondary component where you see differentiation clinically. You know, what we've seen in our data is, you know, more than 80% of our patients who respond will have a reduction of their tumor of 80% or greater. We're seeing really deep responses. We believe that that depth of response is ultimately delivering durability.
We presented at ASCO 2025, median duration of response of over 21 months, again, which is unprecedented. In those investigator-sponsored studies that I had mentioned, you see with cetuximab plus pembro around a 13-month median duration of response. With some of the other investigational EGFRs, you're seeing similarly kinda in that teen range.
What really stands out with our molecule is the duration of response. We believe that ultimately is predictive and has translated into the median overall survival, which again is approaching 22 months. At the end of the day, you know, we believe that the depth is driving durability, the durability is driving overall survival, and where ultimately our molecule will separate and differentiate from an efficacy perspective. You know, you, you pointed out the recent changes that we saw on ClinicalTrials.gov in the petosemtamab, LiGeR-HN1 trial. What we see there is, you know, an increase of the total N of about 200 patients. I think that trial is now at 700 patients.
One of the key areas of difference between the way we designed our program and the way that program and that trial was designed is they included HPV positive patients. We made the decision to focus our trial exclusively on HPV negative based upon our own data as well as data from other EGFR monoclonal antibodies. You see historically, you know, whether it be with cetuximab, you know, Vectibix, and Panitumumab had done a study, there was an EGFR monoclonal that Genentech had been developing. In all of those cases, with close to 1,000 patients worth of data, you consistently see that with EGFR monoclonal antibodies, you see far better activity in HPV negative patients than what you do in HPV positive patients.
You know, you see the response rates, you know, more consistently kind of in the 30% range. Based upon that, you know, we wanted to develop our molecule where we thought you were gonna have the ability to see the most profound benefit, which is in HPV negative. Do we work in HPV positive? Yes. You know, again, we had 11 patients in our phase I-B experience. 3 of those 11 responded.
Two of our 3 responders were complete responses. The drug is absolutely active there. We made the decision to, you know, do a biomarker selected population based on HPV negative. You know, I think, you know, ultimately, you know, we've not heard exactly what was behind the thinking in terms of why Genmab decided to increase that. You know, I think what they have stated publicly is they're looking to do so to increase probability of success.
I think to some degree, that is validating of our approach, again, where we thought the greatest benefit was gonna be in the HPV negative patients. It's likely that, you know, there was that recognition by Genmab as well.
Okay. For clarification, head and neck cancer can be caused by HPV. If you're HPV positive versus HPV negative, for those that may not know this story. What % of the population is HPV negative based on your research?
Yeah. If you look at the recurrent metastatic setting, about 85% is HPV negative. As you break down, there are multiple subtypes of head and neck cancer, 4 specifically. 3 of those 4 are presumed to be HPV negative. The only one the testing is required is in the oropharyngeal subset. In that case, you know, that accounts for about 30% of the subtype, and about a third of oropharyngeal is HPV negative. You've got, again, you know, I think, you know, 70% that is presumed to be negative. Of that last 30%, you have an incremental 15%, gets you to 85% that are HPV negative.
Okay. As of right now, I don't think Genmab has made any statements about timing for the readout for phase III. When it was part of Merus, I think the expectation was it would read out like at year-end this year. Let's say that by adding more patients, that might increase the time to readout for them. Just remind us of when you expect your pivotal study to read out, and maybe just remind us also of the study design for that.
Yeah. We, what we have guided to is that we will have top-line data from our study, middle of next year. You know, enrollment continues to be on track. The other thing we have guided to is that we will be substantially enrolled by the end of this year.
data cut middle of next year. The design of our trial is, you know, we initially actually started with 2 different doses of Bicara to satisfy Project Optimus by the FDA. Earlier this year, we were able to announce that we had met with the FDA and were able to move forward with the 1,500 milligram dose, so the higher of the 2 doses, and formally transition to the phase III component of the trial. We now, in the phase III portion, we're randomizing 2 to 1 to Bicara 1,500 milligrams plus pembrolizumab versus pembrolizumab monotherapy. With, you know, the first interim analysis is look at overall response rate with 6 months of durability.
You know, we'll do a data cut once we've had about 350 patients with 6 months of follow-up to assess the durability of those responses. That's what will yield the top-line data cut middle of next year.
Okay. What would you consider to be good data, competitive data?
Yeah. You know, again, you know, you go back to benchmarking, you know, pembro monotherapy, Merck never broke out HPV positive versus HPV negative. There are multiple real world data sets.
You know, Flatiron had done a study of about 600 patients. There you see an HPV negative pembro monotherapy doesn't do quite as well as the 19% that we see in the KEYNOTE-048 study. You know, I think, a roughly doubling of response rate is clinically meaningful. You know, ultimately at the end of the day, what matters is getting overall survival.
Yeah.
You know, I think that's one of the things that, you know, if you look across, you know, even the KEYNOTE-048 study, you know, there when you added chemotherapy, what you saw is you were able to increase response rates, and then, you know, the response rate when you added chemotherapy went from 19% to 36%. It didn't really have a meaningful increase in overall survival. That overall survival went from 12.3 months to 13 months.
While a doubling of response rate is clinically meaningful and, you know, based on feedback that we have from the FDA, will be supportive of being able to get that accelerated approval. At the end of the day, being able to deliver a meaningful benefit in overall survival, again, which we think the early, you know, predictor of that is gonna be the durability of those responses, is what really is gonna be the most important.
Okay. In terms of the market opportunity for head and neck, I think people have been trying to back out KEYTRUDA sales and what proportion of it is head and neck, and that number seems to be increasing. I think the latest I've heard is that head and neck sales for KEYTRUDA are around somewhere between $3 billion-$4 billion.
I don't know what you're hearing, but would love to hear the latest on any market data that you've enlisted.
market data research.
Yeah. We've heard similar. We've heard anywhere from 5%-10% of global KEYTRUDA sales are in head and neck.
I think, you know, it's interesting to think about that. What we know, particularly in head and neck, is you don't have great response rates. You know, again, in the monotherapy setting, only 1 in 5 patients are responding, and that duration tends to be relatively low.
Yeah.
You know, pembrolizumab monotherapy has a good duration, but when you add chemotherapy, that duration goes down to about 7 months. You know, you think a, you know, a scenario where, you know, Keytruda sales globally for head and neck are $3 billion-$4 billion, and you've got a real opportunity. You know, based upon our phase I-B data, you know, we see the opportunity to both expand the responder population and to meaningfully expand the duration of therapy. Yeah, we really see the opportunity here. You know, I envision, you know, probably by 2030, the EGFR bifunctional class in head and neck probably equally easily exceeds $5 billion, you know, as you think about the opportunity of adding these into the treatment and being able to both.
Obviously expand the responders and the duration.
Okay. Given that it's seemingly becoming a more crowded market, so if you think about PIDO, if you think about ficerafusp, let's also talk about J&J and some recent data that was released from ENHERTU. How, how do you think about the sizing of the opportunity relative to the number of players that are trying to enter head and neck?
Yeah. I think, you know, the, you know, the interesting thing, and you know, I think we're J&J also is developing an HPV-negative population. You know, I would say that the trial approach they are taking is slightly different than what ourselves and Genmab are taking. Again, with what we've seen from J&J is they are developing in combination with chemotherapy. You know, one of the things that we know in terms of the treatment decisions is those patients who today are getting chemotherapy often are patients with lower CPS scores, CPS 1 to 19, but also have bulky disease.
What we hear consistently from oncologists is, you know, if you have a patient that has, you know, high tumor burden, that they're looking to debulk that pretty quickly, that's today where they're using pembro plus chemo, or they're using cetuximab plus chemo. You know, one of the things that we've been able to demonstrate is the consistency of our data, regardless of CPS score. You see very consistent overall response rates, regardless of whether it's CPS 1 to 19 or CPS 20 or greater. The other thing that we've been able to demonstrate, and we broke it out, and we have begun to show it this way as recently as ASCO of last year is the activity based on the sum of the target lesions.
You know, 1 of the things that early on, people were questioning based upon our complete response rate is were we seeing CR only in those patients with really small tumors? What we've been able to demonstrate is even if you have bulky disease, we're able to get rapid responses, so I think, you know, even though the trial's designed with pembro monotherapy as the control arm, the data that we have demonstrated, and we will continue to build on that data, is the ability to also have activity in those patients today who are getting chemotherapy. 1 of the things, you know, I had mentioned the lack of the response reading through to better overall survival.
One of the reasons we believe that happened is about 30% of patients on the pembro chemo arm ultimately had to discontinue early because of adverse events associated with chemotherapy. you know, with a regimen like ficerafusp alfa plus pembro, we've got the ability to see those long durations, not add the toxicity of chemotherapy. We really believe that, you know, we are positioned to be able to compete both in that chemo market.
as well as the pembrolizumab monotherapy market, whether it be And I think that that's where we're able to kind of straddle both relative to some of the other EGFR bifunctionals.
Okay. Any thoughts on the OX40?
Yeah, I think, you know, we saw data on Monday. You know, that data, you know, came out at the same time we were doing our earnings call. We were kind of multitasking.
trying to look at that data at the same time. I think, you know, the data they demonstrated is in the population of CPS 20 or greater. I thought that, you know, for that mechanism, I think it probably exceeded expectations for the mechanism. That being said, you know, that response rate, it doesn't really, you know, stand up to what other, the other EGFR bifunctionals have been able to demonstrate, ourselves included. You know, I think there's still some questions, you know. I don't think we've yet seen detailed safety data.
You know, I think the, in terms of, you know, both the data as well as where they are in terms of overall development, I think they have publicly declared, you know, enrollment will finish in that trial for, in 2029.
It puts them well behind where we are. You know, I think it could be an option for some patients. Again, I think that, you know, so far the data package doesn't look quite as competitive as some other agents.
Okay. Wanted to maybe touch on the safety profile of the drug. What's your view of the profile so far? I think earlier on, there was some concern that there might be a bleeding signal, but, you know, as you've collected more data on more patients, how have doctors' response been to the overall profile of the drug, specifically on safety? What are your expectations of what the phase III readout could show?
Yeah. On the tolerability side, you have, you know, the on-target EGFR.
acneiform rash that you see very consistently with historical EGFRs and the other EGFR bifunctionals. I think one of the interesting things, you know, in our molecule, the mAb portion of it is cetuximab. The molecular kind of composition, 80% of our overall molecule is cetuximab. You think about that, you know, at a 1,500 milligram dose, we're getting 1,250 milligrams of cetuximab on board, which is almost 3X what ERBITUX was able to do, yet you're seeing a similar rash profile. One of the things that was interesting about that is we've seen preclinically is that TGF-beta actually is playing a role around neutrophil trafficking that is mitigating some of that severity of rash, which allows us to get more EGFR on board.
I think very, very consistent with what we expected. In fact, you know, maybe even a little bit better than what we expected because we were given such a much higher dose of cetuximab. On the TGF-beta side, early approaches to TGF-beta, there were concerns, cardiac concerns, that was focused on TGF-beta 2. In the design of our trap, we actually, you know, designed it in such a way to dial out some of that cardiomyopathy that was seen in earlier versions of TGF-betas. I think there were, you know, perceived concerns around bleeding risk. What we've seen in our molecule is we see some nosebleeds, some gingival bleeding. The one thing to note is in head and neck cancer, there's a lot of disease-related bleeding.
We've been really pleased, in those events where we do see some mucosal bleeding, it tends to be very transient at grade 1, and those cases haven't required discontinuations or dose holds. I think we've been able to dose, and we now have dosed up to 2,400 milligrams, as we continue to explore alternative doses for less frequent.
You know, one of the things that we announced on our call on Monday is we've aligned with the FDA on a maintenance regimen where we will start with weekly therapy for 12 weeks, and then we will transition to 2,250 every 3 weeks, which gives the ability for patients to synchronize their dosing with pembrolizumab, which is every 3 or every 6 weeks. Even at doses exceeding 2,000 milligrams, we still see a safety profile that is very tolerable, that keeps people on therapy. That's the, I think, real key here. I think you go back to studies even like the lenvatinib plus pembrolizumab study, where a lot of patients had to come off because of AEs. At the end of the day, pembrolizumab monotherapy did better than pembrolizumab plus lenvatinib.
In head and neck, we need to keep people on therapy, and we've been able to do that with our tolerability profile.
Okay. In terms of the data readouts for 27, of course, is the pivotal, have you guided to when next year?
mid next year.
Middle of next year. Okay. Between now and then, let's talk about, you have a poster update, I believe, coming up at ASCO. Can you just remind us what you're gonna show?
Yeah. We're gonna show. We have 2 posters. One is focused on longer-term follow-up with all of our cohorts. The 3 main cohorts patients we have are the 750 milligram cohort, the 1,500 milligram, which is the selected dose, and then we had a cohort of 2,000 milligrams every 2 weeks. What we've demonstrated last year at ASCO was at the 1,500 milligram 2-year follow-up, and that's where we had a stable median overall survival, median duration of response. We now will have 3 years of follow-up in that patient population. You'll be able to further characterize the tail, and, you know, by comparison, you know, pembro monotherapy in an HPV-negative population at 3 years, their survival is about 15%, you know, from a benchmarking perspective.
For our other two cohorts, the data wasn't mature enough when we first presented it, so you haven't yet seen duration of response.
PFS or overall survival. We will update the data with those durability endpoints, at ASCO. That'll be, you know, part of what you'll be able to see there is, again, we wanna continue to characterize the clinical contribution of TGF-beta, because we think that is so critical, in our differentiation and ultimately what's gonna deliver better overall survival. Again, what you saw for response rates between 750 and 1,500 milligrams were similar response rates, and that makes a lot of sense because at 750, we have fully saturated EGFR, and you think mechanistically what EGFR is gonna deliver versus TGF-beta. TGF-beta is really, it doesn't overcome de novo resistance.
It overcomes acquired resistance, it'll contribute to durability endpoints. You know, what, you know, you would, you know, really expect is, you know, that you're gonna see, you know, you saw similar response rates. You would expect to see better durability than what you would see with just an EGFR mAb, probably not as good as 1,500 milligrams. Again, what that allows you to do is really begin to demonstrate the real benefit and the contribution-
of TGF-beta, that's what those posters will really be able to demonstrate.
Okay. Any other updates at any other medical meeting this year planned?
You know, we have the possibility. We have, you know, we're accruing to CRC cohorts-
The possibility of being able to show our first CRC data in the second half of this year at a medical meeting.
Okay. The inevitable comp will be versus what PIDO had shown early-stage CRC data. You know, I think it came in probably below expectations. Based on that, what level of confidence do you have that you'd be able to show higher quality efficacy?
Yeah. You know, the third-line population's a tough one. You know, again, I think, you know, Pedo is able to demonstrate 10%. You know, historically, with cetuximab retreatment, you see about 13%, which is small and a really difficult patient population. We know the drug is active, you know, with the EGFR component. You know, as we look at that, you know, in CRC, we're taking a fairly measured approach.
Not only, you know, do we want to ensure that we have a competitive profile within CRC, but we also know we have a lot of other opportunities with this molecule. We've shown activity, monotherapy activity in cutaneous squamous cell. We've seen anal canal activity. We know that there's a huge opportunity in locally advanced. For our internal bar not only is, you know, being competitive in CRC, but it has to be competitive with our other options as a company. You know, as we look at that data in the second half of this year, it really will be, you know, from the perspective of where we think we have the best opportunity to demonstrate a benefit for patients and the highest probability of success relative to the other opportunities that we have.
I think we're looking forward to seeing that data. Again, you know, we have two cohorts, both a monotherapy cohort and one in combination with Pembro. That cohorts may not be as obvious 'cause you haven't really seen much activity of Pembro there. What we're looking for is, again, using with the TGF-beta mechanism and the hypothesis we have around being able to alter the immune environment. We wanna see whether our molecule in combination with Pembro actually is able to also do that in, you know, late-line CRC the way it has in head and neck cancer.
Okay. How many patients worth of data will that be?
You know, we're expecting probably around 15-20 patients per cohort when we present it at a medical meeting.
Okay. It's not gonna be in a PR, it'll be at a medical meeting.
It'll be at a medical meeting.
Okay. As you think about the sizing of that opportunity, where do you think it could fit in CRC?
Yeah. Again, I think, you know, for us from that perspective, you know, third line again is not as huge of an opportunity. I think we also are seeing, you know, is there a signal there that would, you know, put us in a position where we would wanna move into earlier lines more rapidly? Which obviously is huge, but also competitive. As we think about, you know, again, some of those other opportunities, you know, a key for us not only is gonna be response rates, but also is the durability of those responses in PFS.
You know, a 30% response rate with only a 2-3 month PFS, probably isn't nearly as interesting as being able to go into locally advanced head and neck where you have the opportunity to have a meaningful benefit for a longer duration.
Okay. Maybe before we wrap up, just wanted to get a sense of your balance sheet, cash needs, and how far it could take you.
Yeah. We reported on Monday cash at the end of the quarter of $540 million that gets extended to 2029. For me to be able to fully execute on the pivotal trial, the randomized trial with every 3-week schedule, as well as beginning to build out our commercial and medical affairs organization. We also announced on Monday the hiring of our Chief Commercial Officer, Chris Sarkey, who joined us last week. We're well-funded, have the ability to execute on the trials that we have ongoing, as well as to begin to plan and build for our commercial launch.
Okay. How big of a commercial organization do you think you would need? Do you have a sense for that?
Yeah. You know, again, our base case expectation is we will launch first in the U.S. off the accelerated approval. You know, I think that, you know, head and neck, as you look at it, you know, definitely is an approachable for a company who will be launching for the first time. I, you know, would fully expect that, you know, we would be over time adding an additional 100-150 people into the organization, inclusive of additional medical affairs and commercial team members.
Okay. Last question from me is what are your thoughts on business development bringing in external assets, or do you feel like you have enough momentum on your internal efforts?
Yeah. I think we're super excited about the opportunity with ficerafusp. I think there are a lot of opportunities there and, frankly, more opportunities than the capital that we have. That being said, we're always looking. As we think about building a sustainable company that will, you know, win and succeed in the future, you know, we continue to look at opportunities that fit with what we're looking for. Again, you know, I think what, you know, large molecule solid tumor assets are something that we, you know, continue to explore and look out for, to enhance the what we already have with ficerafusp.
Mm-hmm. Okay. With that, we are out of time. Thanks very much, Ryan.
Thank you.
for spending the last half hour with me on stage, and thanks everybody for joining.
Sure. Thank you. If you've ever done something. Only in dreams. Just one look at you you haven't done it alone.