Bicara Therapeutics Inc. ($BCAX)

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 Cohlhepp from Bicara. Ryan, good morning. Thank you for making the trip over from Boston.

Thank you. Thank you for having us, and I appreciate the opportunity to meet with you here today.

So 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.

Yes, absolutely. So Bicara Therapeutics, so we're a company focused on large molecules, so bifunctional antibodies focused in solid tumor oncology. Our lead program is ficerafusp alfa, which is an EGFR TGF-beta and we -- 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, as I 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 had to be discontinued. And our view was that what the shortcoming was there, you weren't able to get adequate levels of TGF-beta to the tumor. And so 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 has played out clinically with the data, which I'm sure we'll get into in more detail. But overall, kind of that's the concept and the focus that we have as a company.

Okay. So your leading indication is for head and neck cancer. How did that become your first optimized indication?

Yes. So as we evaluated, one of the things that we have done and continue to do is to evaluate those tumor types where there's both a role for EGFR and for TGF-beta. And 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. It wasn't always clear whether there was a TGF-beta signature there. And early on, we -- one of the things we wanted to be able to characterize is the contribution of TGF-beta. With molecules like Erbitux, there was a clear view that you had activity in head and neck cancer. And 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 kind of where it is in the treatment paradigm. And head and neck, 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 have also been investigator-sponsored studies, one by Dr. Tina Sacco at UCSD another by Christine Chung at Moffitt, who showed when you added pembro to cetuximab, you were able to increase response rates pretty significantly. So we looked at 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 going to be active was very high and it 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 going to 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 of particular interest is we're seeing deep responses. Our complete response rate in head and neck cancer, we have 21%, which, again, is kind of unprecedented in the head and neck space. So 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. So you talked about the targets that you've got for your bispecific. There's another asset that is now part of -- it's the Merus assets, peto, and it's been acquired and the acquirer Genmab has made some changes to the trial design. So maybe let's start with how do you think your molecule is differentiated from theirs? And maybe why do you think that they've decided to upsize that study, which is their pivotal study for frontline?

Yes. So I'll start with the differentiation. I think it really comes down to we all have EGFR as a component of the molecule. And another molecule that is also developing in that space is J&J's Ami, which is an EGFR/c-MET. The petosemtamab molecule, their secondary component is LGR5 and then with Ficera, it's TGF-beta. And we really think that it's that secondary component where you see differentiation clinically. And what we've seen in our data is more than 80% of our patients who respond will have a reduction of their tumor of 80% or greater. And so we're seeing really deep responses. We believe 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 kind of 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. And so at the end of the day, 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 pointed out the recent changes that we saw on clinicaltrials.gov in the petosemtamab LiGeR-1 trial. What we see there is an increase of the total in of about 200 patients. I think that trial is now 700 patients. And 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, whether it be with cetuximab, 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 see the response rates more consistently kind of in the 30% range. Based upon that, we wanted to develop our molecule where we thought we were going to have the ability to see the most profound benefit, which is in HPV negative. Do we work in HPV positive? Yes. Again, we had 11 patients in our Phase Ib experience. 3 of those 11 responded. 2 of our 3 responders were complete responses. So the drug is absolutely active there. We made the decision to do a biomarker selective population based on HPV negative. I think ultimately, we've not heard exactly what was behind the thinking in terms of why Genmab decided to increase that. 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 going to be in the HPV-negative patients. And so it's likely that there was that recognition by Genmab as well.

Okay. So for clarification, head and neck cancer can be caused by HPV. So if you are HPV positive versus HPV negative for those that may not know the story, and what percent of the population is HPV negative based on your research?

Yes. 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. Three of those 4 are presumed to be HPV negative. The only one the testing is required is in the oropharyngeal subset. And in that case, that accounts for about 30% of the subtype and about 1/3 of oropharyngeal is HPV negative. So you've got, again, I think, 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. So 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 of this year. So let's say that by adding more patients that might increase the time to read out 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.

Yes. So we -- what we have guided to is that we will have top line data from our study middle of next year. And 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, which will enable that top line data cut middle of next year. The design of our trial is -- we initially actually started with 2 different doses of Ficera to satisfy Project Optimus by the FDA. Earlier this year, we were able to announce that we had met with the FDA and we're able to move forward with the 1,500-milligram dose, so the higher of the 2 doses and formally transitioned to the Phase III component of the trial. We now, in the Phase III portion, we're randomizing 2:1 to Ficera 1,500 milligrams plus pembro versus pembro monotherapy with the first interim analysis is look at overall response rate with 6 months of durability. And so 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, and 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?

Yes. Again, if you go back to benchmarking pembro monotherapy, Merck never broke out HPV positive versus HPV negative. There are multiple real-world data sets. 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. But I think a roughly doubling of response rate is clinically meaningful. Ultimately, at the end of the day, what matters is getting overall survival. And I think that's one of the things that if you look across even the KEYNOTE-048 study, there, when you added chemotherapy, what you saw is you were able to increase response rates. The response rate when you added chemotherapy went from 19% to 36%, but it didn't really have a meaningful increase in overall survival. That overall survival went from 12.3 months to 13. And so while a doubling of response rate is clinically meaningful and 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 predictor of that is going to be the durability of those responses is what really is going to be the most important.

Okay. So 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 and $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.

Yes. We've heard similar. We've heard anywhere from 5% to 10% of global KEYTRUDA sales are in head and neck. And I think it's interesting to think about that. What we know, particularly in head and neck is you don't have great response rates. Again, in the monotherapy setting, only 1 in 5 patients are responding and that duration tends to be relatively low. Pembro monotherapy has a good duration. But when you add chemotherapy, that duration goes down to about 7 months. So you think in a scenario where KEYTRUDA sales globally for head and neck are 3 to 4 and you've got a real opportunity based upon our Phase Ib data, we see the opportunity to both expand the responder population and to meaningfully expand the duration of therapy. So we really see the opportunity here. I envision probably by 2030, the eGFR bifunctional class in head and neck probably easily exceeds $5 billion 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. So given that it's seemingly becoming a more crowded market. So if you think about peto, if you think about Ficera, let's also talk about J&J and some recent data that was released from Inhibrx. How do you think about the sizing of the opportunity relative to the number of players that are trying to enter head and neck?

Yes. I think the interesting thing, I think we're -- J&J also is developing an HPV-negative population. And 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're developing in combination with chemotherapy. 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 if you have a patient that has 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. 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 over the last year is the activity based on some of the target lesions. One of the things that early on, people were questioning based upon our complete response rate is where we see in CRs only in those patients [Audio Gap] molecular kind of composition, 80% of our overall molecule is cetuximab. And so you think about that 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 the 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, 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 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 perceived concerns around bleeding risk. What we've seen in our molecule is we see some nose bleeds, some gingival bleeding. The one thing to note is in head and neck cancer, there's a lot of disease-related bleeding. And we've been really pleased in those events where we do see some mucosal bleeding, it tends to be very transient grade 1 and those cases haven't required discontinuations or dose holds. So 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 -- one of the things that we announced on our call on Monday is we have 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 milligrams every 3 weeks, which gives the ability for patients to synchronize their dosing with pembro, which is every 3 or every 6 weeks. And even at doses exceeding 2,000 milligrams, we still see a safety profile that is very tolerable, that keeps people on therapy. That's, I think, real key here. I think you go back to studies even like the lenvatinib plus pembro study where a lot of patients had to come off because of AEs. And at the end of the day, pembro monotherapy did better than pembro plus lenvatinib. And so in head and neck, we need to keep people on therapy, and we've been able to do that with our tolerability profile.

Okay. So 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. And then 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 going to show?

Yes. We're going to show we have 2 posters. One is focused on longer-term follow-up with all of our cohorts. The 3 main cohorts of 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 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 by comparison, pembro monotherapy in an HPV-negative population at 3 years, their survival is about 15% from a benchmarking perspective. For other 2 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. And so that will be part of what you'll be able to see there is, again, we want to continue to characterize the clinical contribution of TGF-beta because we think that is so critical in our differentiation and ultimately, what's going to deliver better overall survival. And 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 going to deliver versus TGF-beta. TGF-beta really doesn't overcome de novo resistance. It overcomes acquired resistance. So it will contribute to durability endpoints. And so what you would really expect is that you're going to see -- you saw similar response rates, you would expect to see better durability than what you would see with just an EGFR mAb, but probably not as good as 1,500 milligrams. But again, what that allows you to do is really begin to demonstrate the real benefit and the contribution of TGF-beta, and that's what those posters will really be able to demonstrate.

Okay. Any other updates at any other medical meeting this year planned?

We have the possibility -- we have -- we're accruing to CRC cohorts and the possibility of being able to show our first CRC data in the second half of this year at a medical meeting.

Okay. So the inevitable comp will be versus what peto had shown early-stage CRC data. I think it came in probably below expectations. So based on that, what level of confidence do you have that you'd be able to show higher quality efficacy?

Yes. The third-line population is a tough one. And again, I think peto was able to demonstrate 10%. Historically, with cetuximab retreatment, you see about 13%, which is small in a really difficult patient population. We know the drug is active with the EGFR component. As we look at that, in CRC, we're taking a fairly measured approach and not only 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 is a huge opportunity in locally advanced. So for us, our internal bar not only is being competitive in CRC, but it has to be competitive with our other options as a company. And so as we look at that data in the second half of this year, it really will be 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. And so I think we're looking forward to seeing that data. Again, we have 2 cohorts, both the monotherapy cohort and one in combination with pembro. That cohort may not be as obvious because you haven't really seen much activity of pembro there. But 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 want to see whether our molecule in combination with pembro actually is able to also do that in late-line CRC, the way it has in head and neck cancer.

Okay. And how many patients worth the data will that be?

Yes. We're expecting probably around 15 to 20 patients per cohort when we present it at a medical meeting.

Okay. So it's not going to be in a PR, it will be at a metical meeting?

It will be at a medical meeting.

Okay. As you think about the sizing of that opportunity, where do you think it could fit in CRC?

Yes. And again, I think for us from that perspective, third line, again, is not as huge of an opportunity. I think we also are seeing -- is there a signal there that would put us in a position where we would want to move into earlier lines more rapidly, which obviously is huge, but also competitive. And so as we think about, again, some of those other opportunities, a key for us not only is going to be response rates, but also is the durability of those responses in PFS, a 30% response rate with only a 2- to 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, I just wanted to get a sense of your balance sheet, cash needs and how far it could take you.

Yes. So we reported on Monday cash at the end of the quarter of $540 million. That gets us into 2029. So 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 Sarchi, who joined us last week. And so 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. And then how big of a commercial organization do you think you would need? Do you have a sense for that?

Yes. Again, our base case expectation is we will launch first in the U.S. off the accelerated approval. I think that head and neck, as you look at it, definitely is an approachable for a company who will be launching for the first time. So I would fully expect that we would be, over time, adding an additional 100 to 150 people into the organization, inclusive of additional medical affairs and commercial team members.

Okay. And then last question for 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?

Yes. I think we're super excited about the opportunity with Ficera. 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 win and succeed in the future. We continue to look at opportunities that fit with what we're looking for. Again, I think large molecule solid tumor assets are something that we continue to explore and look out for to enhance what we already have with Ficera.

Okay. With that, we are out of time. So thanks very much, Ryan, for spending the last half hour with me on stage, and thanks, everybody, for joining.

Thank you.