STIFEL 2026 HEALTHCARE CONFERENCE - BICARA THERAPEUTICS INC

All right, we're going to go ahead and get started. I'm Stephen Willey, one of the senior biotech analysts here at Stifel. I'm glad to have with us Ryan Kohlheap, who is the CEO of Baikara Therapeutics. We're just going to have a casual discussion. If anyone has a question, feel free to raise your hand and we'll get you acknowledged and your question answered. Ryan, thanks for being here. Anything you want to say from an opening statement perspective before we jump into Q&A? Yeah, sure. Maybe just to step back and ground for those who may not be as familiar with the Bicara story is our lead program that we have been developing over the last several years is Fisera First Alpha. It's a EGFR TGF beta trap that we're developing in a pivotal study in recurrent metastatic head and neck cancer. As we go back to even the design of that molecule and what we were looking to accomplish is TGF-beta for almost 40 years now has been considered a target that should work. I think there have been many in oncology TGf-bета is one of them. And I think there were some notable failures, one of which Merck KGA They had BenchVest Alpha, which was a PD-L1 TGF-beta. When we were designing the molecule, you know, we felt that the shortcoming with TGV-bета was getting adequate levels of it to the tumor. And I thought, you Know, if we are able to localize and direct it to, to the tumor, we could see activity that, you know, ultimately fulfill the promise of, of TGP-bete in the biology, the, the underlying biology. Yeah, and I think we've absolutely been able to do that. You know, we've demonstrated in the head and neck population the ability to almost triple response rates. We've got mature follow up in our phase one cohorts now out beyond three years where we're showing a median overall survival and an HPV negative population of close to 22 months, which is 10 months greater than what you see with the standard of care right now. And at the three-year mark, we've been able to demonstrate that we have twice as many patients alive at the three- year mark that would have been alive otherwise with Keytruda. So I think that was all, that data was the basis for investing in and initiating the pivotal trial, the Fortify HNL1 trial, which we are anticipating data top line middle of next year, which we're really excited about. And again, based on the data that we've seen for ourselves and the class in general, I do believe that we have a profile based onthe depth and durability that TGF-Beta delivers that will allow us to show meaningful and a best in class overall survival profile. Okay, great. I generally don't like to start off talking about other people's drugs during these things, but so let's do it. Just given that seems like a very appropriate place to start here, given the GenMab disclosure from a couple weeks ago. So how are you and, I guess, your team just interpreting kind of the headline response rate and OS statistics that were provided in the Phase 3 frontline trial press release? And we'll have some follow-ups from there. Yeah, so, you know, with that release, again, I think there was fairly limited data that GMAT put out there. You know, as we've evaluated that, both in terms of, you know, what we believe, you know, that data tells us from a differentiation perspective and how we ultimately will stack up against the pitot-symptomatic molecule, but also probably even more importantly is what can we read through as we think about our own study, what мы want to do, how we're executing, and how wir operationalizing the Fortify HNL1 study. At the end of the day, we can only control what we can control, and the conduct of the Fortify trial is one of those things. So as we look at that, the two key pieces of data were on response rate. They chose to present the data based on an odds ratio, so you have to make some assumptions based on the control arm. And what we did here from GENMAB is that it was consistent with what you've seen historically with PEMBRO as a control arm in these types of trials. And so I think the range that we would model there would be somewhere between 19% and 25% on a response rate basis. What that tells us is it's likely in a blended population. And again, that's a key difference between our trial and the GENMAB trial is based upon historical data. we made the strategic decision to develop an HPV-negative population alone. We felt that both the data from our own trial as well as the historical data, you know, that was prospectively evaluated across multiple trials with EGFR monoclonal antibodies suggests that these molecules aren't going to work as well on HPV positive patients. And so we chose to develop it in the population where we expect the most profound benefit. When you look at, in that pool of population, we fully anticipate that inclusion of the HPV positive will cause some level of deterioration in the response rate data. But what that data tells us is that even in an HPV negative population where you're trying to compare apples to apples, you probably have seen in that trial, you know, pedosymptomab delivering data consistent with what they had seen previously, probably in the mid-50s, maybe into the low 60% range on a response rate perspective. And so that, I think, again, one of the scenarios that could have played out was they put up a big number in the 70s for HPV negative. And again, we think that that scenario is very unlikely based on the data that we saw. As you move to overall survival, which I think that's where the market has shifted to and their focus around, how are these drugs ultimately gonna differentiate in survival? What we saw is a hazard ratio of 0.5, but not much beyond that. The confidence intervals that they showed would suggest that it was a fairly early analysis with about 175 death events and a total trial of 700 patients. But we don't know how many of those death events we're in HPV positive patients versus HPV negative patients, which we know will have a significant influence ultimately in what that looks like. You also, you know, you think about where, you know if you look at the Keynote 48 trial, which was a study that Merck had to support the approval of Pembroke in this population, the Kaplan-Meier shows a pretty aggressive decline in the first 30 to 40 percent of patients. And so our view, based on the number of events that are in the current analysis, is you're probably on the front end of the curve. And as you think about these agents, particularly IO-based therapies, TGF-beta in particular, as you think about where is that contribution going to come from, I think you start to see in the later phases of the curve. And I would say even as you think about where HPV positive patients are likely to sit in that curve, we know that HPV-positive patients live longer. And so we do think that there's a high probability that that hazard ratio will deteriorate over time, which I think as you play that forward from a regulatory path perspective, I think the jury is still out in terms of ultimately what the initial approval or label will look like for pidosymptomab. That being said, as we read that through to our own trial, we've got greater confidence and an ability to see a statistically significant benefit with a smaller sample size. So as we think about the allocation of alpha and where you spend it, one of the things at earnings this week, we communicated is we've committed to an interim analysis for overall survival. And I think we've got additional data to inform the way we think about that, which I'd much rather have that data now when we still have runway on these decisions versus seeing it on the other side of a top line where I think just we came out of that with more information for us to inform our own strategy. So maybe you can talk about a little bit about the interim analysis that you're now committed to conducting on survival. And just, you know, I think a lot of the questions that we get now is, okay, how is this going to align with the response rate interim analysis? That I think you've pre-specified based upon a 350 or so patient fraction. You do have, as you said, exclusively HPV-negative patients in this trial. Presumably, historical outcomes would suggest that you're going to accrue death events faster. So do you think that there's an opportunity whereby you can get to that event trigger number that informs an interim by time of the response rate look? Yeah, I think it's absolutely a viable scenario. And again, what we did not, I think, pin ourselves down to on Monday was when we're going to do that interim analysis for overall survival. There's additional data that we're going to see both in our own trial, one that we continue to evaluate the rate at which we are accruing death events in the trial in a blinded, aggregated way. And so we can run scenarios off that and you know seeing continued maturity of that i think will help inform ultimately where we think that analysis will land we also expect that we may see data from genmad that would give us a better view on you know what that curve looks like for them the one thing that the key guiding principle in the way we're approaching this is we continue to have a high degree of confidence in our ability to get this drug approved. The the war is not going to be won on top line data releases. It's ultimately what label we are able to put in the hands of our sales representatives and our medical team that will live with this label for a long time. And so you know we're not going to, you know, be reckless and go too early. That being said, the scenario that you painted, again, given the population in our study, we do expect to be able to accrue those death events at a rate faster than what the pedosymptomab trial did. And so I think there are various scenarios on the table, and we certainly will, you knows, communicate as as appropriate. And one of the things that I think ourselves and GenMab can definitely agree on is this is a highly competitive space. And so in terms of, you know, what we disclose when we obviously know that there are many stakeholders here, including the investor community. And I think we'll, you now, I think do make that disclosure and communicate that when it's fitting. Okay. Yeah, I think your point around concentrating the benefit of what they're seeing from a survival perspective into that front end of the Kaplan-Meier curve is a really important one. And it kind of aligns with this notion of, okay, they upsized the study by 200 patients, but then didn't change the underlying statistical protocol, which meant that they were able to accelerate the number of events that occurred in that top half, right? And we know that if you target EGFR, if you debulk, you're going to have an advantage over Pembro and that top-half. We saw that with cetuxen chemo and keynote, right. and so i guess in that sense where you have an io comparator right it gets really hard to compete on on the tails of those curves and that presumably feeds into your uh deterioration hypothesis but i guess do you think that having tgf beta on board allows you to be more competitive on those tails Absolutely. And I would say that the data that we've demonstrated out of our phase one cohort is supportive of that. You look at the three-year landmark where twice as many patients are alive compared to PEMBRO. And again, you've got the PEMBO-IO tail there where we know that those patients who respond on PEMRO generally do pretty well. Their duration of response is out to around 24 months. And one of the questions as we came into the trial was, we knew we were going to be able to increase response rates, but what was the durability of those additional responders going to look like? And you go back to the Keno48 trial where you added chemotherapy and you were able to add 17% response rate, but you didn't really see anything on a DOR. In fact, DOR declined dramatically. You saw a little bit of an uptick in PFS and only less than a month improvement in overall survival. The fact that we've been able to see expand the responder population by almost 3x and still deliver IO-like durability absolutely speaks to where the tail effect that we're likely to see as you compare the ultimate medians from an overall survival perspective between the drugs. Okay. So the depth and durability of response of Fifarifis really kind of seems to be the defining characteristics of that molecule. When you talk to KOLs, how do those two things inform clinical decision-making? Yeah, I think, you know, and we can separate the depth in durability. I mean, the depth, even from a symptomatic improvement perspective. Both the rapidity of response that we're seeing, we're hearing anecdotes from physicians where within two to three weeks, patients who had airway obstructions, who weren't able to eat, had to eat through feeding tubes, were seeing significant reductions in tumor that allowed them to remove trachs and for them to resume normal eating. From a durability perspective, I think the key, and this has been informed by trials like the LEPO-1O trial where durability was really low, or even the addition of chemotherapy where durability dropped down by two-thirds when you added chemotherapy, is physicians know in order to see these long-term outcomes, they need to keep patients on therapy. And so the durability of response is critical and a read-through ultimately to longer-term outcomes for overall survival. So as we show our profile, and we've also at ASCO last year, one of the things that we were able to show is in those patients who have a reduction of their tumor of 80% or greater, what do their outcomes look like? You know, we were able to demonstrate that you see outsized benefits and DOR, PFS, and with over three years of follow-up, we still haven't met the median overall survival in those patients who had a tumor reduction of 80% or greater. And as a reminder, that's not just a couple patients. We had 15 responders in our phase one data set. 12 of the 15 had a reduction of 80% or greater. So the vast majority of our responders are those deep responders. And you're seeing outsized benefits in overall survival. Okay. So I guess we could sit here and probably statistically speculate for the next hour like we did this morning. But let's just try to keep this moving. So how are you thinking then about just kind of the size of the HPV negative market in the U.S. and kind of The Revenue Opportunity that you see that's up for grabs here? Yeah, you know, as we model and look at the epidemiology in the US, HPV-negative with a CPS of greater than one, so the population that sits within the potential label for the drug, about 18,000 patients. And you think about the ability to, you know, it's a sizable population. And you now, with a drug like Viscera, you're going to be able to significantly enhance the responder population. And you're able to significant increase across that population their duration of therapy. And even Merck has publicly disclosed in the past that for Keytruda, the head and neck population accounts for somewhere between 5% and 10% of global Keytrude sales. So you think about that where only one in five patients are responding to a Keytrudabase therapy with a relatively short duration, depending on whether it's with chemo or not. The ability to grow that market based on greater durations, more responders, we look at this market by 2030 and I think easily anticipate that you're going to have a $5 billion EGFR market in the recurrent metastatic head and neck population in pretty short order. I think what we consistently hear from KOLs is that upon approval, they see this class being used in the vast majority of their frontline patients. Maybe you could talk a little bit about the Fortify Flex trial, which you're running in parallel. This is intended to move patients to a less frequent once every three-week dose after induction. Maybe you can just kind of talk about the trial, what you're hoping to achieve here and how some of the dose ranging data you've generated to date strengthens your confidence in this induction maintenance strategy that you're proposing. Yeah, we chose, you know, an approach where we're initiating with 12 weeks of weekly therapy before we transition to every three weeks. And the reason we're doing that is the efficacy profile that we've demonstrated with weekly therapy is a really high bar. We didn't want to do anything that would potentially deteriorate from the speed of response, the depth of response and ultimately the durability. You know, what we know in our data from 1,500 milligrams is by that point in time where we're transitioning, the vast majority of patients will have already responded and hit kind of their maximal depth of response. You know and you've got a time to response of 1.4 months or six weeks where we scan for the first time. So more than half of our patients are already in response at their first scan six weeks into therapy. And so, you know, wanted to ensure that that profile was maintained. What we've seen in other data sets, particularly the 750 milligram data set, and I call that out because the every three week dose is 2250 every three weeks. That dose replicates the pharmacokinetic exposure profile of 750 weekly. What we know is, in looking at the 750 data, is our ability to maintain those responses once you capture a response. You actually saw similar levels of response between 750 and 1,500 milligrams. The key difference was the depth. So we did, in data that we presented last year, we had a landmark at 24 weeks. And what you saw at 24 weeks is you had a significant higher number of patients with a deep response at 24-weeks with 1,500 milligrams in comparison to 750. And, again, that was why we didn't start with 2,250 every three from the outset. And so by doing it this way, we believe that we have been able to maintain the efficacy profile that we believe has the potential to be best in class. You have increased or improved on the administration schedule, which now synchronizes with K-3, true to either every three or every six weeks. And one of the less obvious things that we think we're going to be able to accomplish there is potentially to shift the tolerability profile. And the reason we believe that is as we looked at our 1,500 milligram data, some of the AEs that would be attributed to TGF-beta, like anemia, like the mucosal bleeding that we've seen in some patients, you often see those in your best responders and late in the course of therapy. And our perspective on why that's happening is because at that point, you have significantly debulked the tumor, and you now have more TGF-beta in the periphery because you don't have tumor for the molecule to bind to. And so by lowering the exposure of the 12-week mark, we actually think that there's an upside in tolerability, which gives us the ability to maximize the profile of the agent across efficacy, safety, as well as administration. The trial that we've conducted, which we initiated in the third quarter, starts patients at 12 weeks. At the 12-week mark, we're going to randomize those patients to either remaining on weekly therapy or transitioning to every three-week therapy. And what we're looking for there is the proportion of patients that remain in response at a 24-week landmark. And basically, the endpoint objective there is that you're not losing responses by transitioning people to a lower exposure and to a less frequent dose. It's not a pure non-inferiority with the line with the FDA. Basically, the way the endpoint is designed is the point estimate on every three-week arm needs to sit within the confidence interval of the weekly, which allows us to do that trial with about 150 patients. Okay. There is another competitor molecule. Again, you spoke to the size of the market opportunity, right? So not surprising. J&J is amivatinib. They're pursuing phase three development at Frontline, but with the addition of chemo on top of Pembro and AMI. We just saw that data presented at ESMO. Just any thoughts on what you saw there? Yeah. I mean, we had seen the top line response rate number in the high 70s, which I think, again, is a number you pay attention to in this class where even ourselves and PETA demonstrated in the mid-50 to low 60% range for a response. I think what was a little surprising in that data, and definitely as we have gotten feedback from KOLs that stood out, is a couple of things. What you consistently hear from treating physicians is they give chemotherapy because they want to debulk tumors fast and they want a rapid response. What we saw in that data with the triplet was a time-to-response that exceeded nine weeks. By comparison, you know, our median time-of-responce is six weeks. And so you've now added chemotherapy, which is notorious for rapid responses, but you didn't see any acceleration in time-To-Response with that triplet regimen. The other thing, you know, that origami has multiple cohorts. Cohort two, I believe, is the cohort with Pembro plus AMI. If you look at that data from a PFS perspective to the cohort five, which is the triplet, PFS looks basically identical at around seven months. by comparison at, you know, we've showed with Fisera in an HPV negative population, a PFS of 9.9 months. And so I think it's not clear what the added benefit of, you know, putting chemo into that regimen. And again, that's their pivotal trial that they are choosing to conduct. Andso the one thing that is clear that you do get is a lot more tox. You know, what we saw in that data set is I think 26% of patients had to discontinue at least one study drug. You had more than 10% of patients who had a grade five event. And so, you know, I think what we saw in that data set at ESMO this year was surprising on the efficacy side with the lack of time to response and PFS, but what you would expect on the talk side. So, you Know, one of the areas of feedback, I Think people came out of that, You know, and as we talk to physicians, I think their view on where they see utilizing a triplet regimen shifted and see less of a place for that regimen compared to, you know, a Fisera or Pembro regimen. Okay. And I know J&J actually just secured an accelerated approval of AMI in second-line patients. We've gotten this question a little bit, but do you see any impact of that drug now being available in the second line in the U.S. only? Is there any impact to Fortify, I guess, specifically with respect to this notion that a control arm patient in Fortify could progress and then subsequently receive AMI as a second line therapy? Our view is that the risk is limited to very minimal. And part of that is the indication what they were approved for were in those patients who had progressed on chemotherapy plus PD-1. Again, the two arms in the Fortify trial are Viscera plus Pembro and Pembromanotherapy. therapy. And so I know that potentially you could get reimbursement or you could get use there if they had seen a Pembroke chemo regimen in the adjuvant setting, in the locally advanced setting. But we do believe that there's going to be limited second-line use of patients that would come off of the four-to-five trial. I think the other thing that, as you think about, probably roughly 25% to 30% of our phase three is going to be enrolled in the U.S. That actually was front-loaded. We started the trial there. As you think about, you know, and a lot of those patients who came on early in the trial, we initiated the trial in February of last year. A lot of the patients who have come on early likely will have already progressed. And you're now seeing a disproportionate amount of our enrollment that sits outside of the U。S. So overall, our view on it is, again, very limited to potentially no impact from a subsequent therapy confounding concern. Maybe we can spend a few minutes that we have left on colorectal. So you have a couple of cohorts that you're looking at in the third line setting or third line plus setting. I thought the commentary you made around perhaps maybe some of the early signals of safety and efficacy appeared to be pretty constructive. You can correct me if I'm wrong. But just how are you now thinking about communicating this data to investors? I think you got it to something maybe early next year. And then what are the efficacy benchmarks that you kind of have in mind here? Yeah, you know, on Monday at earnings, you said that we would be presenting that data in January. Since that call, we actually have received our acceptance at ASCO GI. So we can now be clear in terms of where in January that's going to be presented. so it'll be presented at ASCO GI. Does that mean I have to go back to San Francisco after J.P. Morgan? I'm sure you can see it virtually. And if not, we can talk about it. So in terms of efficacy benchmarks, what we saw from the pitocinemab in a comparable data set in the third-line plus setting was 10%. I think the other data that we find intriguing is Insight's TGF-beta PD-1, where you were able to see a slight increase off of that to 15%. When they added Avastin to it, again, they presented this data at ESMO, that response rate data went up into the high 20s, I think around 27%, 28%. So as we look at it, we think that those are the relevant benchmarks, the 10% to 15% What's really important for us in that data set is, is there some level of activity? We know the third-line setting is a very difficult population, But we've seen how a 10 to 15 percent can translate into a 70 to 80 percent in the front line and the second line setting. And so, you know, not only so I think our data from an efficacy perspective, it's less around how much data do you need to see there unless the path is a registration approach in the third line setting? And I think the other key element there is what is the tolerability profile? Is the tolerability profile consistent with what we've seen in head and neck cancer? Because what we know as we move into earlier lines of CRC, it means you're going to do it in combination either with chemotherapy or other novel mechanisms. So, you know, I think some level of activity, but frankly, the more important element for us is can we safely move this into the earlier lines in combination with other regimens and other drugs? Yeah, that insight data has kind of piqued my interest, not only just because of the response rates that you just referenced, but there's no fall-off in patients with liver mets, right, which is where you just wouldn't expect. Yeah, and if you recall, you know, we presented data in an anal canal cohort, I believe it was at AACR, where we showed in a number of our patients in that population who had liver metastases resolution of those liver mets. And so, you know, we do think that, you know, as we play that forward and read it through into the colorectal population, do think the, you know, that TGF beta mechanism will, you know. Potentially have a differential effect in that population that, you know has liver mets. Okay. Maybe you can just lastly speak to the balance sheet and just kind of what that allows you to execute on here going forward. Yeah, we reported 442.3 million at the end of the quarter. And what we have guided to is that That takes us into early 29 to fund enrollment of the Fortify trial through the survival endpoint. The Fortify Flex trial, some of our initial medical affairs and commercial build, as well as a little bit of signal-seeking work and other indications like colorectal cancer. So we're, again, continuing to focus and execute on getting those patients enrolled in the Fortify trial and the Fortify Flex trial as quickly as possible and look forward to our top line data in the middle of next year. All right. Anything we didn't talk about that you want to quickly highlight before we wrap up? No, I think we've covered the basis. We did. All right, thank you, Ryan. Thank you, everyone. Thanks a lot, Steve.