All right, we're going to go ahead and get started. Welcome to Day Two of the Stifel Healthcare Conference. I'm Stephen Willey, one of the senior biotech analysts here at the firm, and glad to have with us providing an overview of the company. We have Bicara, CEO Claire Mazumdar, CFO Ivan Hayap, COO Ryan Cohlhepp. I think this is their first presentation as a public company, so we're all kind of privileged here. Appreciate you guys coming. They're going to give an overview of the company. We'll have some time for Q&A. If you have a question, feel free to raise your hand. Claire, I'm going to hand it over to you.
Perfect. Thank you, Steve. Hi, everyone. My name is Claire Mazumdar. I'm the CEO of Bicara Therapeutics. And thank you, Stifel and Steve, for hosting us today at our first public company presentation. Today, I will be making forward-looking statements. Those statements are there are risks and uncertainties with those statements. Please refer to our SEC filings for additional information. Bicara Therapeutics is a clinical stage biotech company focused at the intersection of what we call targeted tumor modulation. The idea in the molecules we develop are that one arm gets you to thee tumor, and the other arm is some type of tumor modulator that, when delivered directly to the tumor microenvironment, should not only provide better efficacy and durability, but improve tolerability. This is exemplified by our lead program with the name ficerafusp alfa.
For the sake of today's presentation, I'll refer to it as ficerafusp alfa, which is an EGFR-directed antibody with a TGF-β ligand trap. It was really in the summer of 2023 at ASCO in an oral presentation where we presented Phase IB data, looking at combining ficerafusp alfa plus Pembro in frontline head and neck, where we showed that in the HPV-negative subset of the recurrent and metastatic setting of head and neck, we could close to triple response rates compared to standard of care, which is Pembro monotherapy. As that data has matured, it has built a confidence in Bicara that we have a potential for a registration-enabling study. Based off of feedback and alignment with the FDA, we believe that there is a path to accelerated approval to change the standard of care in frontline head and neck.
We remain on track to initiate that study in the near term. Head and neck is a significant market opportunity with close to 23,000 cases in the US alone each year and a significant unmet medical need with only a 13% five-year overall survival. What we'll show you is that, given the biologic rationale of this molecule and the expression of EGFR and TGF-β, there's a strong opportunity to expand into other squamous cell carcinomas, and we've seen some encouraging preliminary activity in other tumor types, such as cutaneous squamous cell carcinoma. As Steve alluded to, on September 13, we had our public offering. Today, we have north of $520 million that should fund our studies into the first half of 2029, so we're very well capitalized.
The idea behind ficerafusp alfa was really this idea of being able to maintain the functionality of an EGFR inhibitor, but using the EGFR arm to direct TGF-β inhibition directly to the tumor microenvironment, and that inhibition of TGF-β is really predicated on two important synergies we were going after with our mechanism of action. The first is that it's been shown by a number of labs, especially in the immunotherapy space, that in particular in these more immunosuppressive or so-called cold tumors, where immunotherapy or checkpoint inhibitors have not been as effective, that if you can inhibit PD-1 and TGF-β in the same setting, you can actually turn these cold tumors hot and improve the efficacy of checkpoint therapy, a key rationale for going in combination with pembro from the very onset of our clinical development.
The other important synergy we're going after with our molecule is that it's been shown that a key driver of resistance to EGFR-targeted therapies, such as cetuximab or the approved Erbitux, as well as panitumumab, is actually through the upregulation of TGF-β and the EGFR and TGF-β pathways that drive something known as the epithelial-to-mesenchymal transition or EMT phenotype. That's a key driver of resistance. The way we think about it is really this triple inhibition of EGFR, TGF-β, and PD-1 that will lead to an increased depth and durability of response compared to standard of care. Today, it's really this increased depth and duration of response that we believe differentiates our molecule from the EGFR class. When we began our dose escalation studies, we began both in monotherapy and in combination with Pembro.
Today, we chose 1,500 milligrams q weekly of ficerafusp alfa as the dose we took into our dose expansion cohorts. Importantly, we did not achieve maximum tolerated dose. Our rationale for our dose expansion cohorts was to go into tumor types where there's a strong biologic reason for inhibiting EGFR and TGF-β at the same time. This really led us to this Venn diagram of squamous-like carcinomas that tend to have high EGFR overexpression, typically greater than 90%, and a known role for TGF-β. Given the underlying synergy with PD-1, you'll see that our expansion cohorts are predominantly focused in combo with Pembro, with our most mature data set being in frontline, head and neck, and the data I'll walk you through today. So, as I mentioned, head and neck is a common cancer with a significant unmet medical need.
In the U.S. alone, there are more than 20,000 patients each year with recurrent and metastatic disease, and they have typically about a 12-month overall survival. The disease is subsetted into two distinct subsets: HPV-positive disease, which is driven by the HPV infection, and makes up only a small minority of the frontline recurrent and metastatic patients, about 15%. The vast majority are HPV-negative, which are patients with a history of smoking or chewing tobacco. Here in the U.S., it's about 80%, and the predominance globally is close to 90% in Europe and Asia, where there's a higher history of smoking. Today, treatment decisions are not guided by HPV status, but instead CPS or combined PD-L1 score, where Pembro is approved in the CPS greater than or equal to 1, which is where our initial focus is of our proof of concept data as well as our pivotal study.
As I mentioned, a key reason for moving into frontline, head and neck from the very onset of our clinical development was very much predicated on this underlying synergy that comes with inhibiting TGF-β and PD-1 in the same context. The real idea here was that by inhibiting both, we could go after this more immunosuppressive tumor type like head and neck, where Pembro today has a low response rate of only 19% and a 12-month overall survival. In addition, there were two investigator-initiated studies that published around the time that we began our clinical development that really, in some ways, created a precedent for what we believed we could achieve.
As you may be aware, since the approval of Pembro in the frontline setting of head and neck, there have been a number of immunotherapy combinations that have been studied, most notably the IDO inhibitors, TIGIT, and most recently lenvatinib. And while those showed modest improvements in response rate, none of those translated to meaningful improvements in overall survival. In fact, the only two studies that have showed meaningful improvements in OS are the cetuximab investigator-initiated studies. We felt that if at a minimum we were equivalent to cetuximab, there was a path to approval in the frontline setting of head and neck, as neither Merck nor Lilly were moving forward with registrational studies for cetuximab.
What I'll show you today is that our data has meaningfully differentiated from cetuximab, both on a depth and durability that we attribute to the TGF-β arm of the molecule and really speaks to our underlying mechanism of action. So here's the data from our phase IB study in frontline recurrent and metastatic head and neck. Today, we see more than a 50% response rate in a typical patient population where the Pembro monotherapy response rate is 19%. But maybe the most noticeable thing about the waterfall plot I'm showing you here is the depth of the response. Typically, head and neck is not a tumor type where you expect complete responses. It's not like melanoma where immunotherapy leads to high complete responses.
In fact, if you look at prior data sets, either with Pembro, Pembro plus chemo, or even Pembro plus cetuximab, the complete response rate is really in that 3%-5%. So to see a 15% complete response rate with four additional patients achieving complete tumor regressions at 100% PRs really speaks to the depth of the response that we attribute to the TGF-β arm of our molecule. As we look at the distinct subsets of head and neck, as I mentioned, the etiology of HPV-positive and HPV-negative head and neck is quite distinct. Typically, HPV-negative patients are patients with a history of smoking and chewing tobacco, and they're known to have a distinct biology and mutational burden than their HPV-positive counterparts. Also importantly, they're known to have a worse prognosis, both in terms of response rate but as well as overall survival.
What's important about this disease from a Bicara perspective is that HPV-negative patients are known to have higher levels of both EGFR and TGF-β, which we hypothesize would make them better targets for a molecule like Bicara. Indeed, if you zoom in only on the HPV-negative patients, you do see an outsized efficacy, both in terms of response rate as well as complete responses. This also translates to improved median PFS in the more difficult-to-treat HPV-negative patients. Today, Pembro has a median PFS of just about three months, while today, with our molecule in combination with Pembro, we're seeing about a 10-month median PFS. Importantly, despite the fact that these patients have 12 months of follow-up at a minimum, we have not yet achieved median DOR or median overall survival, really speaking to the outsized durability we're seeing with our molecule.
I should again highlight that median overall survival with Pembro or Pembro plus chemo is about 12 months. So really speaking to the outsized durability. From a safety perspective, ficerafusp has been generally well tolerated with no treatment-related deaths. We would attribute our safety profile to the EGFR-related toxicity, so our patients do see the cetuximab-associated rash. What I will say is those have typically been less severe than what you typically expect with cetuximab, despite the fact that we are dosing above the approved dose of cetuximab with our molecule. On the TGF-β side, we do see transient low-grade mucosal bleeds or epistaxis, which are nosebleeds, but those have not been dose-limiting or required dose interruptions.
Given the strong clinical profile of ficerafusp, our high response rate, our incredibly high complete response rate, median PFS, and safety profile, we started to build a confidence that there was a path to an accelerated approval in the frontline setting of head and neck. We've reached alignment with the FDA on our registrational trial design and again believe there's a path to an accelerated approval. Here is the design of our FORTIFY-HN01 study that we are on track to initiate in the coming weeks. This study really speaks to the accelerated approval based off of a response rate endpoint. It is a double-blind placebo-controlled study where we compare ficerafusp plus Pembro versus Pembro monotherapy plus placebo. Based off of guidance on Project FrontRunner and alignment with the FDA, the confirmatory endpoint for this study is overall survival.
Beyond frontline recurrent and metastatic head and neck, we believe that there are opportunities in earlier stages of disease within head and neck where, again, there's a strong biology that really speaks to the TGF-β arm of our molecule. In particular, with the proceeds from our recent public offering, we will look to signal-seek in the locally advanced setting of head and neck in combination with radiation therapy. As you may be aware, radiation is known to lead to significant TGF-β upregulation, so there is a strong rationale to move into this earlier stage of disease, which could potentially triple our addressable patient population. Beyond head and neck, there are a number of other tumor types, which I alluded to, which have a strong role for the inhibition of both EGFR and TGF-β.
We do have one monotherapy expansion cohort in cutaneous squamous cell carcinoma where, in the first stage of our Simon two-stage study, we saw a 42% response rate in a post-PD-1 and typically highly PD-1 refractory population. We plan to present a larger data set at a medical meeting next year, so we really believe that there are opportunities both within head and neck as well as other tumor types where there's a strong rationale for ficerafusp, really speaking to its pipeline within a product focus, and we are initiating colorectal cancer cohorts, which we believe really speak again to the EGFR precedent in that tumor type.
And so with that, just to conclude, today we believe that there's a strong clinical profile of our molecule, in particular in the HPV-negative subset of the recurrent and metastatic setting of head and neck, seeing a 64% overall response rate, 18% complete response rate, and a 9.8-month PFS. We've reached alignment with the FDA on our Phase I, III trial design and are on track to initiate that very soon. And from a financial position, we have, as I mentioned, north of $520 million in cash equivalents from our upsized IPO this September. And with that, thank you for your time.
All right. That was great. Thank you.
Thank you.
So I think the Phase III trial that you're highlighting now is maybe a little bit smaller relative to the one that was being outlined previously. Can you just kind of speak to what informed the change here, how that may or may not impact disclosure timelines at all, and just whether any of the underlying powering assumptions of the study have changed at all as a result of the sample resize?
Yeah. Great question, Steve. So you're correct. When we initially presented the Fortify study, we were presenting about a 750-patient study that has since been reduced to north of 600 or just about 650. The idea here is that the endpoints and the statistical assumptions underlying those endpoints have not changed from a powering assumption standpoint. Based off of our conversations with the FDA, the one underlying assumption for the study that has changed was our dropout rate. Initially, we were assuming a more conservative 10% dropout rate every six months. And based off of conversations with the FDA and also precedents around the KEYNOTE-048 study, we reduced that to a 10% dropout rate yearly, and that actually reduced our sample size.
So while I think it's too early to really speak to the differences in data disclosures, there may be small adjustments in terms of when, again, the confirmatory endpoints will come.
Okay. So there's obviously a couple of competitive development programs that are also in Phase III. They're seemingly leveraging smaller trials in more heterogeneous patient populations. So can you just kind of speak to why you've taken a different approach here? And I guess, to what extent was this approach at all informed by results from the LEAP-10 trial?
So it very much was. What you're alluding to is if you look at historical Pembro overall survival or Pembro plus chemo, that typical median OS has been about 12 months or 12.3 months. There was a recent study called the LEAP-10 study, which combined Pembro plus lenvatinib, a multi-VEGF inhibitor, and showed, interestingly, in the control arm, Pembro outperformed historical data sets and showed about an 18-month overall survival. While what I can allude to is there are many reasons to believe that the patient population for the Fortify study is distinct from that of the LEAP-10 study in that we are only looking at HPV-negative patients, and the patients in the LEAP-10 study were typically healthier than the KEYNOTE-048 48 population because of the toxicities associated with lenvatinib. We are taking a more conservative assumption than the 12-month KEYNOTE- 48 study.
What I can allude to is a back-of-the-envelope calculation is that anything less than about a 600-patient study, based off of powering on overall survival, would assume about a 12-month OS on the Pembro arm. So we felt it was necessary, again, to take a slightly more conservative assumption, despite the fact that data sets support HPV-negative patients having worse overall survival than their HPV-positive counterparts.
Okay, and then just any thoughts on what this additional Phase III competition will mean for enrollment?
Yes.
How are you thinking about where your trial sites are relative to some of the rest of the competitors and if there's going to be any kind of impact here?
Yeah. So I think, to my knowledge, there are anywhere between four or five frontline Pembro studies initiating in the next year or so. So this includes two EGFR plus datasets by Bicara's as well as Merus's. There is an Exelixis molecule, and there are a few ADCs that are potentially moving to the frontline setting. If you look from a geography standpoint, Bicara has built our organization very much focused on head and neck since the very beginning. We have a strong presence in the U.S. where we began our Phase IB studies, and we are today anticipating north of just about 200 clinical trial centers globally to enroll this study. I think that's consistent with what we've seen historically.
When KEYNOTE-048 was being run in the late 2010s, there were, I believe, three or four late-line studies of other PD-1s, and all of them showed about a two-year enrollment for those large studies, which were on similar patient numbers. I think there will be distinct geographies for some, and it will really likely be that, at least in the case of the EGFRs, sites will not enroll both frontline EGFR studies, but there are sites we've heard from that are enrolling, for instance, Bicara's Fortify and Merus's second-line monotherapy data.
Okay. And then have you given any thought about how you're going to update enrollment progress to the investment community?
That's a great question. So I think today our first important data disclosure for this study will be our dose selection, where we'll be able to disclose what the dose was that was selected. I think that will be an important timeline to at least indicate where we lie in terms of enrollment, but that will be likely the first.
Okay. And then you talked about the interim analysis that you've built into the trial here on the basis of response rate. Have you solicited any feedback from the treating community just with respect to the willingness to prescribe on response rate data alone? And I know there's a little bit of skepticism out there maybe as a function of the LEAP-10 data in terms of the surrogacy of response as an indicator for survival.
So what I will highlight is while we're listing response rate as a primary endpoint, this is overall response rate with six months of durability. The FDA has alluded to needing to see a descriptive analysis of OS or at least no detriment to the OS endpoint at the time of granting accelerated approval. We really believe that that's based off of their learnings from the LEAP-10 study. At that time point, there will be a descriptive look at overall survival, which I think will, again, the time differential between the accelerated and full approval, given we will be fully enrolled for the confirmatory, speaks to, I think, being able to convince prescribing physicians around the OS benefit as well.
But also speaks to our data disclosure next year around two-year OS rate, which will be our first look at median durability likely and median OS, which we think will be very important to inform the community.
Okay, so we have seen a fairly recent data point in head and neck from Merck. They announced data from the KEYNOTE-689 trial, which I believe was neoadjuvant, adjuvant, and maintenance. They're guiding towards regulatory submissions. How do you think that Pembro label expansion into the pre-metastatic may or may not change how frontline patients are treated? And I guess, do you think that there would be any disproportionate impact to a patient population that is either HPV positive or negative?
Yeah. So my understanding for the Merck study, I think the best responses were actually in the negative as well, in the HPV negative. There is a wealth of literature that actually shows that patients who present with recurrent and metastatic disease after being treated with a PD-1 in the adjuvant or neoadjuvant setting will still respond to PD-1s in the recurrent and metastatic setting. So typically, it's both that it's presenting as a different disease, but also that time from treatment is typically more than six months. And so while I don't think it will distinctively change the opportunity in the recurrent and metastatic setting, to us, it builds an important precedent that if we can combine with Pembro in the neoadjuvant, adjuvant, and maintenance setting, it grows our addressable market population pretty distinctively. So we plan on initiating distinct signal-seeking studies in all three of those distinct timelines.
And do you think that 689 trial provides a template for how you would like to tackle that pre-metastatic label? Would you like to go after all of those opportunities within the same trial design, or do you think you're better off maybe trying to carve out adjuvant and maintenance from neoadjuvant?
It's a great question. It's the debate we're having internally. I think today, from a signal-seeking perspective, we would separate all three of those. But it may be if we see a signal on all three that the registrational trial design will include all three. I would say the largest opportunity is clearly in the maintenance setting just from a time of treatment perspective.
Okay. Then you got into the update in the frontline Phase I occurring in the first half of the year. I think you've also indicated there should be some updates from the anal squamous cell carcinoma study, cutaneous squamous cell carcinoma study. Can you just provide a framework around what those updates for each of those opportunities might look like in terms of patient numbers, duration of follow-up, etc.?
Yep. So I'll start with the head and neck Phase Ib data. So this is the same data that you saw here today, but with two years of follow-up. So we anticipate while there's maturity to the response rate and the median PFS, this will likely be a first look at median DOR and potentially median OS, at least with a two-year OS rate at a minimum. In terms of the anal canal cancer, that was a dose expansion cohort in second line in combination with Pembro, which is about just a bit more than a 20-patient data set. That really speaks to the opportunities outside of head and neck. And then the cutaneous data set will also be an update to the data I disclosed on the prior slide of the 12 patients. So this will be a minimum 20-patient study looking at cutaneous monotherapy in second line.
Our approach there is waiting for a more fulsome data set to mature and determining whether there is a potential single-arm opportunity in cutaneous second line and/or moving to frontline in combination with PD-1, where both Pembro and Regeneron Libtayo is approved.
Okay. So you obviously have a pretty healthy balance sheet here post-IPO. How do you think about prioritizing all of the opportunity for ficerafusp alfa, both within these additional head and neck patient segments that you talked about, but also outside of head and neck and some of these other EGFR-driven solid tumors?
Yeah. I think by being able to upsize our IPO, we are able to meaningfully signal-seek in all of the indications I highlighted here. I would say that allows us to signal-seek in the locally advanced neoadjuvant setting and head and neck, but also meaningfully look at a number of different expansion cohorts in colorectal. In none of those scenarios, should we see a strong signal, would we be able to do a large registrational study in either the locally advanced setting or colorectal without additional financing? But it does allow us to look at a number, be broader in our prioritization opportunity.
Okay. And then I think in addition to the adjuvant setting, which you highlighted here, I know you've also talked about maybe pursuing patients who don't have PD-1 expression at baseline, patients who are HPV positive, but are.
Smokers.
Ex-smokers. Are those areas you can gain traction from a prescribing perspective just by kind of running a Phase II study, getting a compendia listing, or do you feel that you need to kind of pursue a formal label expansion for each of those subgroups?
No. For both of those subgroups, we really do see it as a potential expansion from a compendia listing perspective. I think, importantly, we need to begin with 20 to 30 patients in each of those subsets to see if there is a chemo sparing regimen, but should we get the approval in HPV negative, CPS greater than or equal to 1, I think this allows us to broaden our market organically.
Okay. And I know you're dosing once weekly in the Phase III. That was the dosing regimen in the Phase I but I think you're also doing some work looking at dosing every other week. Should we expect to hear an update there, and how big of a priority is that for you?
I think given the data that we've seen, we feel confident in the efficacy of the Q-week standpoint. We do think, given many cases, Pembro is moving to an every six-week, by being able to reduce the number of clinic visits would be important for patients. Our data supports moving to every two weeks. I think in terms of updates to those expansion cohorts, it is dependent on the dose that is selected as part of Project Optimus in our 45 study. So I think you should expect updates once we've disclosed the dose. And then today, we are at least considering a PK bridging study outside of the 045 study that would run in parallel and potentially allow us to move to an every two-week dose in advance of approval for launch.
Maybe just last question. So I mean, you're obviously juxtaposed relative to Merus in a lot of conversations. Do you think that there's an opportunity to sequence these agents? And if so, is there evidence from other tumor types where you can resequence an EGFR-targeting drug?
Yeah. So, interestingly, we may move to a world that way. From what I understand, I think it will really depend on the underlying EGFR targeting of both drugs. We have seen with our molecule that we can see responses in patients who are cetuximab refractory and in combination with the PD-1. From my understanding, Merus's molecule does potentially lead to internalization of the EGFR receptor. So I think today it's too early to say because nobody has done the clinical experiment just yet. But there may be a sequencing rationale to move to have Merus in a monotherapy opportunity. There are data sets that show that re-challenging with cetuximab does work in some patients. I think it's been shown in colorectal cancer.
All right. Any other questions? Claire, Ryan, Ivan, thank you very much.
Thank you.