Bicara Therapeutics Inc. ($BCAX)

Hello, everyone. I'm Etzer Darout, 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, if you could just give us an overview of Bicara and progress that you've made in upcoming milestones.

Yes. Great. 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. And so our lead program is an exemplary of that. It's an EGFR TGF-beta again, where we're using EGFR to bring TGF-beta to the tumor microenvironment. We founded the company in 2020, where we actually were able to license intellectual property from an organization, Biocon back in 2020 and have since over the last 4 or 5 years, continue to develop that. And we're now at a point where we've seen substantial activity with that molecule, which I'm sure we'll speak about 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 early last year and are going to be in a position where we expect to have top line data in mid-2027 in the head and neck market.

Great. So you're looking at an 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.

Yes, absolutely. And so as part of our rationale, again, when we design the molecule is, there's no synergy between EGFR and TGF-beta. 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 higher levels of TGF-beta. And our rationale early on, again, in the development was there have been a number of historical approaches and where companies have tried to use TGF-beta in the cancer setting and have been unable to see activity there. And really, our view there was you weren't able to see adequate levels of TGF-beta in the tumor microenvironment. So we're using EGFR to get there and to be able to get TGF-beta into the tumor. What we know is that TGF-beta, if you look at the biology of TGF-beta, what it does is it helps overcome acquired resistance mechanisms with EGFR. So there's this duality of effect as you think about EGFR and TGF-beta together. And that's why we paired the 2 together. Not only to be able to get to the tumor, but we also know that there's kind of synergistic activity of the two and working together. And we've seen that. I think the first real signs of the contribution of TGF-beta was as we started to present data around our early signals of activity that we were seeing, we were seeing these really deep and durable responses. When we first presented our data in the 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% to 7% complete response rate. We now, as the data has continued to mature, we're showing in the 1,500-milligram dose, which is the dose that we 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 100% reduction in their primary tumor. So you're seeing that TGF-beta effect where you're seeing 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, 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%. So we have nearly tripled the responder population. And what we showed was a 21.7 month median duration of response. And so what we had known all along is that, that responder population that would have responded to pembro monotherapy was still going to exist within our trials. But what about the next 30%, 35%, what's going to happen to their duration of response. What you've seen with cetuximab, what you've seen, I would say, even with petosemtamab is you actually see in that those additional responders EGFR-like duration. And that's where, again, we think 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. And I guess one of the things we've seen with FICERA, as well is just the improved toxicity profile for FICERA versus sort of traditional or classic TGFR-beta. What do you owe that phenomenon to? Is it just the EGFR localization? Is it maybe a finer or more tuned TGF-beta?

I'd say, it's probably more of the latter, more fine-tuned. So what we did, the trap that we have in our molecule is the extracellular domain of TGF-beta receptor 2. So if we look at some of the older TGF-beta programs, you saw some cardiomyopathy there, which was attributed to TGF-beta 2. And by using the extracellular domain of 2, what we see is greater specificity for 1 and 3, which are also the cancer-associated forms of TGF-beta. So again, I think we've been able to be a bit more targeted there, which I think it definitely has helped mitigate some of the historical TGF-beta tox that we've seen with other programs.

Got it. And for folks less familiar, can you give a sense of the proportion of patients that are HPV-negative head and neck versus HPV positive?

Yes. One of the important distinction, there are multiple subtypes of head and neck cancer. There are four main subtypes. The one subtype that is where you have a mix of positive and negative is the Oropharyngeal or OPSCC. Overall, as you look at the totality of the various four subtypes, in the U.S., for example, the 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 the Asian countries where the incidence of smoking tends to be pretty high. Again, one of the questions that we often get is, are we seeing an evolution in the epidemiology. 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. So you're seeing a pretty consistent proportion of the Fab and 80% negative, 20% positive.

Got it. You mentioned the 21-month OS that you've seen 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?

Yes. So actually, one of the things -- so Merck never disclosed the breakdown of positive versus negative for overall survival. If you look at the pooled population and CPS greater than 1, what you see with pembro monotherapy is around 12. In the real-world data, there's been a pretty -- about a 600-patient real-world study that Flatiron published, there does show around 9 months. So you are seeing -- and what we were able to see in that data set is they actually broke out positives versus negative. So that 12.3%, it's really hard to understand what do you get from the positive versus negative. What we know in the data, the real-world data that we've seen is you see a lower overall survival in HPV-negative patients and higher in the positive. What we also know is that many patients actually, if they're diagnosed, HPV-positive patients, if they're diagnosed in the locally advanced setting, many of those patients don't recur. So 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 if you're HPV negative.

Got it. And -- as far as 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 a question, is this sort of EGFR plus? Or what's the contribution of TGF-beta for this population and maybe how the clinical studies, the trials, the data have answered those questions.

Yes. There's a couple of investigator-sponsored studies that really we use to help guide our thinking. One was cetuximab plus pembro. The other was cetuximab plus nivo. And in both of those cases, what you see there from a duration of response is around 13 months. And so I would say purely, 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. And again, I think that 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. And again, there's a lot of biological rationale for why that's happening. And again, you think back to the biology, we know that TGF-beta is helping to overcome the acquired resistance mechanism. So even as we started this program, what you anticipated was TGF-beta, if you're going to see a clinical contribution, it was going to be on those durability endpoints, duration of response, PFS, overall survival. And that's exactly what we've seen. We've seen it not only at the 1,500-milligram dose, which is what we have in the pivotal trial, you see it at 750. You see it -- we presented data a couple of weeks ago of 2,000 milligrams every 2 weeks. So regardless of dose or schedule, you're seeing a real characterization of the pharmacodynamic benefit of TGF-beta. And again, with our molecule, we fully saturate EGFR at 750. So as you look at doses beyond 750, it's 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. And maybe a little bit more details about the Phase III, the ongoing Phase III and then also the endpoints that obviously you're going to be looking at for FICERA.

Yes. So we initiated a trial again in the first quarter of last year. We initiated it as a 3-arm trial at the beginning because we had not yet met the FDA's Project Optimus. They wanted us to do additional dose optimization work. So we had aligned with the FDA to look at two different doses of FICERA and then the control arm of pembro monotherapy. We actually -- early this year, we aligned with the FDA and we're able to move forward with the 1,500-milligram dose. So we have now formally moved to the Phase III component of the trial 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 is they continue to look at innovative ways and trial design to facilitate and speed up earlier -- getting drugs into earlier lines of therapy is under Project Front Runner, we've got a design where 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. So we'll follow patients, 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. And so the total trial size is around between 600 and 650 and we will get both an accelerated approval potentially off of ORR and then following a full approval on OS 1.5 years or so later than that. Again, so it's a way for us to 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 6 months of follow-up on the majority of patients to make sure that a large proportion of your patients have maintained their response at 6 months and also expect that they will do their own sensitivity analysis around the trend of overall survival at that time.

Got it. And have you disclosed powering assumptions around overall survival?

We've not. Again, I think our view -- what was interesting KEYNOTE-048 trial, again at 12.3, a, 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 we -- that informed our view on how we size the trial is that there was data from the lenvatinib LEAP-010 trial, which is lenvatinib plus pembro. There -- in that trial, all of a sudden, we saw pembro monotherapy at 17.8. I think there are a lot of rationale to -- 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 going to -- in our trial, we'll see 17.8. We also -- knowing that we are in a negative population only. What the data would suggest is the bounds there are probably anywhere from 8 to 18. And again, I think we looked at all the various data as we size the trial. That being said, the confirmatory endpoint for full approval will be in OS, we make sure that we size it in a way that, a, was not only clinically meaningful, but also we derisked the trial in terms of overall, it was worth 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. And any differences in sort of inclusion/exclusion criteria from sort of the Phase Ibs into the Phase III or just very similar?

Very, very similar. In fact, if you look at the patient demographics in our trial in our Phase Ib compared to KEYNOTE-048, very similar. We would expect the same thing as we have our pivotal trial.

Great. And for the 2,000 mg once every 2 weeks, how do you plan to leverage that profile? Is it maybe a maintenance post the 1,500? Is it completely sort of shift the market to 2,000 mg? Like how do you think about that?

Yes. So we -- I think looking at the totality of the data across our various cohorts, we now have close to 100 patients across three different cohorts, 750 milligrams weekly, 1,500 milligrams weekly and then 2,000 every 2. So we've been able to do really robust exposure response modeling and to understand the contribution of the two different components of the drug, what's driving activity on the EGFR side versus the TGF-beta. Using all of that information, what we know is that we get very rapid deep responses at 1,500 milligrams weekly. So our plan is to continue to initiate therapy with a loading phase 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. And so you'll have significantly reduced the tumor size. That gives us the opportunity then to stretch the interval. And 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 C-trough basis. We think not only does that will allow us to maintain a best-in-class efficacy profile with a very durable response. We think it actually has a 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 as your TGF-beta tumor dramatically reduces, you need less drug. And so we're going to -- 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. And so you think across kind of the three dimensions of efficacy, safety and administration. This weekly loading phase into a every 3-week maintenance, we think optimizes across all three dimensions and gives us a best-in-class profile across all three areas.

So would that entail a new study, a bridging study?

It is, yes. One of the things that we -- on the heels of presenting the data at the head and neck meeting -- what we guide to 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. 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. And the HPV testing, how routine is that in head and neck? And then also with the testing, how you plan to move that into sort of a commercial setting?

Yes. It's super routine. In fact, most guidelines, going back to the comment I made earlier, the vast majority of patients, probably more than 80% of patients are actually diagnosed in the locally advanced setting. It's during that initial diagnosis that 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, by the time they come in and they recur, the physician will already know their HPV status. So we've not seen it to be an impediment in enrollment at all. We don't expect it to be a commercial impediment. We also from a payer perspective, what we know -- the feedback that we've gotten is actually that payers are comfortable using the IHC testing that they already have. And so there won't even be this element where they will need to get our PCR test in order to be able to be reimbursed.

Great. And how are you thinking about the commercial infrastructure and maybe the ongoing work in trying to build out a commercial infrastructure?

Yes. We -- about, I guess, 1.5 weeks ago or so, we raised an additional $172 million. The use of proceeds on that fund raise was to begin to build our commercial and medical affairs infrastructure. As you look at head and neck, for a company who will be launching for the first time, head and neck is actually a pretty approachable tumor type. The prescriber universe is relatively concentrated. But you also have from an approval perspective, we will be approved first in the U.S. and then ex U.S. on overall survival. So it gives us our ability to build a commercial infrastructure to launch in the U.S. We will maintain optionality as we think about whether we want to build our own infrastructure outside the U.S. or whether we'll partner. But we absolutely are going to build the organization and feel that we've got the capability and the know-how to be able to launch in the U.S.

Right. And you're looking at FICERA and opportunities beyond frontline head and neck cancers. If you could maybe talk about those opportunities in the remaining time that we have?

Yes. 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 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 and even within head and neck, I think locally advanced is a really interesting opportunity. One of the things that is known is radiation actually increases TGF-beta levels. So when you think about even there, we think that in that setting in patients who were radiated in the locally advanced setting that we are mechanistically differentiated to -- again, where TGF-beta kind of stand apart from the other EGFR bifunctionals.

Great. And 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 kind of get the...

Yes. And 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. And so we use that work and our own work to really guide the way we're thinking. One of the things that we don't want to just chase EGFR. What we know is that TGF-beta is a really important component of this molecule. And so we are looking for those tumor types where both EGFR and TGF-beta play a critical role.

Great. We're up on our time. Thank you, Ryan, for your time. Thank you for our listeners on the line, and we'll be back soon with our next session. Thank you.