All right, we're live. Good afternoon, everyone. Tyler Van Buren here, Senior Biotech Analyst at TD Cowen. Thank you very much for joining us at TD Cowen's 45th Annual Healthcare Conference. For our next session, very excited to have a hybrid presentation and Q&A with Bicara, and it's my pleasure to introduce Claire Mazumdar, the CEO. Claire, privileged to have you here. Thank you very much for joining us.
Thank you, Tyler, and thank you to you and the whole Cowen team for allowing us to present today and share some exciting updates to Bicara. As part of today's presentation, I will be making forward-looking statements. There are a number of risks associated with that. You can read them here. Bicara is a clinical stage biotech company focused at the intersection of what we call targeted tumor modulation. The idea behind Bicara is that we develop bifunctional or multifunctional antibodies where one arm gets to the 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 but improve tolerability and durability. This is exemplified by our lead program, ficerafusp alfa, which I'll refer to as Ficera, which is our bifunctional EGFR-directed antibody bound to a TGF-β ligand type.
Ficera, in combination with Pembro, at ASCO in 2023, we shared some exciting data showing that if you could use this combination in frontline recurrent and metastatic HPV-negative head and neck, we could close to triple response rates compared to standard of care. As our data has matured, we have built a confidence that it will show a distinct standard of care profile on durability and overall survival. As of last month, we started our FORTIFI- HN01 study, a seamless phase two-three study for the potential accelerated approval of Ficera plus Pembro in frontline recurrent and metastatic head and neck. Head and neck remains a significant market opportunity with a significant unmet medical need. There are about 23,000 cases of recurrent and metastatic head and neck in the U.S. alone each year, with a dismal five-year overall survival of only about 13%.
What we'll show you today is that there's a potential for Ficera far beyond head and neck and other squamous cell carcinomas and other tumor types where there's a strong rationale for the dual inhibition of both EGFR and TGF-β. Today, we at Bicara are in a good financial position with an IPO in September of 2024, which allows us to fully fund our study. I apologize, I have the flu. Today, if we look at Ficera, we have a number of important data catalysts that will be coming our way. The most important remain within head and neck, with an important update expected at ASCO this year for our data set at 1,500 mg weekly in combination with Pembro.
At this time point, we will be showing a long-term follow-up with more than two years' worth of follow-up on the data set that we've presented in the past, and I'll update you on today. There are a number of other data cohorts that will be presented over the course of the next several years at other doses and in other subsets of head and neck beyond the HPV-negative CPS positive. In addition, we have some important data catalysts outside of head and neck coming early this spring. At AACR this year, we will be presenting an update to our second-line cutaneous squamous cell carcinoma monotherapy data set, which we think will continue to speak to the potential of this molecule outside of head and neck.
We also will be initiating studies this year both in colorectal cancer as well as in the locally advanced setting of head and neck in combination with radiation therapy and in combination with anti-PD-1. Going back a little bit to speak to the design of the molecule of Ficera, Ficera was very much designed to maintain the functionality of an EGFR inhibitor while using the EGFR arm to localize TGF-β inhibition directly to the tumor microenvironment. By doing so, this was really predicated on two underlying synergies we were going after, the first of which is that it's known that inhibiting TGF-β and PD-1 in more immunosuppressive or so-called cold tumors can lead to the improved efficacy of checkpoint therapy. The other synergy we're going after is the synergy that comes with inhibiting EGFR and TGF-β in the same setting.
It's known today that the most common resistance mechanism to EGFR-targeted therapies is actually through the upregulation of TGF-β, leading to the epithelial to mesenchymal transition or EMT phenotype. That's a key driver of metastasis and progression. We've shown preclinically that we can reverse this phenotype with the use of ficerafusp alfa and have shown responses in both PD-1 and EGFR refractory patients during our dose escalation studies. Seen another way, we think of this really as a triple inhibition in frontline head and neck. By inhibiting both EGFR, TGF-β, and PD-1 in the same setting, we can increase the depth and durability of response and delay that onset of resistance. It's really this increased depth and durability of response that we believe differentiates our molecule from other EGFRs, including cetuximab as well as other novel EGFR derivatives.
The reason for going into head and neck in frontline head and neck from the very onset was, again, predicated on this underlying synergy that comes with inhibiting TGF-β and PD-1 in the same setting. In addition, there were two investigator-initiated studies that in many ways set a precedent for what we believe we would be able to achieve with our molecule. As you may know, Pembro is the approved standard of care in frontline head and neck, showing about a 12-month overall survival and a response rate of 19%. In 2021 and 2022, two papers were published, one from Dr. Sacco combining cetuximab plus Pembro and the other from Dr. Chung, combining cetuximab plus Nevo that showed if you combined cetuximab plus a PD-1, you could close to double response rates, which translated to a six- to eight-month overall survival improvement.
This was really the first time that in head and neck we saw that an improvement in response rate translated to a meaningful OS improvement. As you know, cetuximab was not going into registrational studies with an anti-PD-1. We felt that at Bicara, if our molecule was equivalent to cetuximab, there was a path to approval in the frontline setting if we could show this type of meaningful OS improvement. What we'll show you today is that ficerafusp alfa has meaningfully differentiated from cetuximab both on a depth and durability that we attribute to the TGF-β arm of our molecule, and we believe will continue to differentiate on overall survival in our pivotal study. In addition, we focused in on the HPV-negative subset of head and neck. These are the patients who make up the vast majority of the frontline recurrent and metastatic setting, at about 80% in the U.S.
and over 90% in the rest of the world where there's a higher rate of smoking. These patients are known to have a distinct biology from their HPV-positive counterparts and a worse overall prognosis. They're known to do worse on both response, PFS, as well as overall survival. Importantly, from a Ficera perspective, they're known to have higher levels of both EGFR and TGF-β than their HPV-positive counterparts. We hypothesized we would see better efficacy in this patient population. Indeed, if you look at our data set in the HPV-negative patient population, we see a 64% response rate, which is more than tripling of the response rate in HPV all-comers with Pembro monotherapy. Maybe most importantly, if we look at this waterfall plot, it's just the depth of the responses that we see.
Today, we're seeing an 18% complete response rate, which continues to mature, really speaking to that outsized depth, which has also translated to improved durability if we look today, our median PFS of just under 10 months. Pembro monotherapy shows a three-month median PFS, again, in HPV all-comers, really showing that with the addition of TGF-β, we can almost triple median PFS. Importantly, as the time of this data cut, we have not yet achieved either median duration of response or median overall survival despite the fact that these patients had at least 12 months' worth of follow-up. We anticipate, again, at ASCO this year, being able to share two years' follow-up and far more extended durability and overall survival. From a safety standpoint, today, Ficera has been well tolerated in head and neck patients with no treatment-related deaths.
Our AE profile is predominantly associated with EGFR-related AEs of dermatitis acneiform. What I would highlight is while the majority of our patients do get the associated cetuximab rash, the severity of those has been less than what's expected with cetuximab, despite the fact that at 1,500 mg of Ficera, we're actually providing patients with almost 50% more cetuximab than the approved dose of cetuximab. On the TGF-β-related AEs, we do see transient low-grade mucosal bleeds or epistaxis, which are nosebleeds, but those have resolved themselves without the need for a dose interruption or any type of intervention. Given the clinical profile, we saw Ficera with a strong response rate, a high complete response rate, which has not been seen in head and neck today with prior therapies, as well as an extended median PFS.
We have moved forward with our FORTIFI- HN01 study, which, as I mentioned, began enrolling last month. This is a seamless phase two-three study, which begins as a three-arm study looking at two different doses of Ficera, both at 1,500 mg and 750 mg weekly to satisfy Project Optimus. In the phase three portion, it continues for response rate for potential accelerated approval based off of a response rate interim. The way we've designed this study is as, again, a seamless study. By doing it in the phase two-three format, we will continue enrolling without any stopping to enrollment in the Project Optimus portion of the study. I anticipate being able to disclose our selected dose early next year.
The data set that will go into the optimal dose for data package will include not only the FORTIFI randomized studies of 10-20 patients in each arm, as well as two open label cohorts. You've seen the data from the open label cohort at 1,500 mg, and we do have an equivalent 30-patient cohort at 750 mg, which has finished enrollment and continues to mature. Beyond head and neck, as I mentioned, we have data sets coming out next month at AACR in cutaneous squamous cell carcinoma. We presented data earlier this year at ASCO GI in squamous cell carcinoma of anal canal and will be initiating colorectal studies later this year. The anal canal data we shared at ASCO this year really continues to speak to the potential of this molecule in combination with Pembro.
The bar is quite low for second-line anal canal patients, with Pembro response rates being really in the low 11%, with a 12-month PFS of only 15%. What was exciting about this data set is despite we were able to double response rate, show almost a tripling of 12-month PFS, but heard from many investigators that patients with liver metastases were able to completely resolve their liver metastases, which is exceedingly rare in anal canal cancer. Again, another data set that really speaks to the potential of this molecule in an important tumor type with a high unmet medical need. In conclusion, before we go to the fireside chat portion of the presentation, Bicara has showed some significant progress in the last year in both our clinical data as well as our being able to initiate our pivotal study.
We are currently enrolling patients and have built strong site activation and continue to build very strong momentum in this study. We have a robust financial position and are excited to share some important data catalysts this year.
Wonderful. Thank you very much for that presentation, Claire. Split the time right down the middle. That was great. Ryan's going to be joining us too. Ryan Cohlhepp is the President and Chief Operating Officer at Bicara. Naturally, starting in head and neck, you guys have kind of led the way in the frontline in combination with Pembro. You put up a 9.8-month median PFS that you referred to on the slides in HPV-negative frontline patients. Can you just elaborate on your confidence in that number and how it was calculated as opposed to just picking a middle point on the swim lane? Thank you.
That number was calculated using, again, Kaplan-Meier analysis. The way we went about this was, I would say, in the most conservative approach, the similar way you would do it with an FDA submission. There are many cases where we did not censor patients. We counted those as events if we knew that they had progressed beyond their treatment.
Okay. At ASCO, you mentioned an important update that you guys are going to be having with the two-year overall survival data. Can you help, I guess, provide some context as to what the appropriate benchmarks are for survival and therefore what would be impressive when we see that data?
Yeah. Two-year OS will be an important landmark. We anticipate potentially having median OS and median DOR.
I think the totality of that package will really speak to the improved durability and the TGF-β hypothesis. If we look at OS benchmarks for two-year overall survival, whether it be with Pembro, Pembro plus Chemo, or even recent data sets, they are exceedingly low, really, in the 20% standpoint, 20-30%. I think really being able to show that we are able to, we know today, if we can really show even a 10-20% improvement beyond that and show that our Kaplan-Meier curve is above that, it would really put a stake in the ground as to what to expect. I think we saw, if we look at one-year OS rates, you can see those anywhere from 50-80%, depending on what clinical trial you have looked at in head and neck.
Those have actually not translated to anything beyond a median OS of 12 months. We think two-year OS is really the key indicator for what to expect in improvement.
Okay. That's helpful. The 12-month median overall survival, is that in all patients or HPV-negative?
In all comers. That's not even looking at subsetting it by HPV status.
You would expect HPV-negative patients to do worse?
Correct. If we look at real-world data today on subsetting median OS for these patients, there are two recent publications, one from Kevin Harrington in the U.K. with about 300 patients followed since the approval of Pembro, and another Flatiron data set of about 600 patients in the U.S. here that showed that overall survival in HPV-negative patients tends to be closer to nine months, while the total population is closer to 11-12 months. You really have those HPV-positive patients pull out the median.
I think, odd to that, I think at this point, trying to understand what the Pembro monotherapy is going to do has been a bit of a moving target over the last year, particularly after the lymphadenom data and LEEP-010 came out and really showed Pembro monotherapy did far better than any of us expected it would. We've done a lot of work on our side, not only trying to understand, again, what patient characteristics that were in that study that may be different than what we have in FORTIFI, but also the differences based on HPV status. Again, in those two reports that Claire referenced with Harrington and Flatiron, what you do see is we do fully expect to see differences in survival outcomes based upon HPV status.
It has informed the way we've thought and we've designed our trial around effects. I think that with the likelihood that in an HPV-negative only, the Pembro mono will probably do potentially even worse than what it did in KEYNOTE-48.
I guess just to double-click on that, for FORTIFI, for the final median OS analysis, how did you factor all of that into the way that it's powered and designed?
We haven't disclosed our stats plan. What we can say is, at the time, to Ryan's point, especially with the LEEP data, we took a slightly more conservative estimate than KEYNOTE-48. We have every reason to believe that, again, our patient population is quite distinct from that of LEEP. I would use that 12 versus 18-month almost like bookends and realize, though we know HPV-negative patients tend to do slightly worse. Those are the bookends that I would point you to land somewhere in the middle.
Perfect. That's helpful. The phase III, III, FORTIFI- HN01 trial, early days, I know, but obviously enrollment is kicked off and dosing. Maybe you could talk about early progress there if possible and what proportion of patients need to be tested for HPV status and if that's going to get in the way of your enrollment.
It's gone incredibly well. I mean, in terms of site activations, we're ahead of where we thought we would be at this point in time. There's a great deal of enthusiasm as we've been able to get the trial out. It's resonated well with both the design, but also our data with investigators. I think a really strong uptake. It's your question around the testing for HPV.
One of the things is it's consistent across guidelines that testing at diagnosis for P16 is kind of standard of care. We don't anticipate we're going to see an impediment to screen fails because most of these patients, they already know P16 status, so they're going to be P16 positive or negative. In most cases, and the investigators, when they know that they've got a P16 negative, they'll be confirming that in the oropharynx only. That's the only place that you need to test for. It's presumed to be negative everywhere else. There's a small proportion of patients that will need to be tested with a diagnostic. Again, you have that kind of baseline P16 status that will guide investigators on the likely outcome of that patient anyways.
I guess just to clarify, what percentage of patients have oropharyngeal head and neck, and how many of those are positive?
Yeah. That represents about 30% of the subtypes, the various subtypes. Within that particular subtype, HPV-negative is about 30% of that subtype, so 30% of 30. As you think about the overall cross various subtypes, roughly 75%-80% of recurrent metastatic patients are HPV-negative.
Got it. Okay. The final dosing decision after that initial phase II portion, can you talk about how that's been optimized to ensure that it's not going to delay the readout and what you're going to use to make that decision?
Yeah. I'm happy to jump back to the prior slide, but the data set that will be used to inform that dose selection are 10-20 patients in each of the ficerafusp-containing arms of FORTIFI with 12 weeks of follow-up. We have a sense of, again, response rate and safety. To really better understand durability and depth of response, we will have two open label cohorts, the 30 patients at 1,500 and 30 patients at 750, which will be part of the full data package we present to the FDA around our dose recommendation.
I guess to make the decision, is it going to be response rate or durability response?
It'll be a number, kind of the totality of the evidence across several different measures. We initiated that lower cohort in an open label context because duration of response is incredibly important.
Even if you look at other trials, DOR, again, referencing back to the LEEP-010, their lymphadenom Pembro did better in response rate. They did better in PFS. Ultimately, we were inferior in overall survival. What you see there also in that study is the duration of response with the lymphadenom arm is really low. We wanted to make sure that our decision on dose is going to be guided not only by response rate, but probably even more importantly is duration of response, particularly also as we think with our molecule and the TGF-β adds to that durability. Making sure that we're picking a dose that optimizes durability was critical to us.
Remind me, the phase one expansion cohort at 750, will that data come before you make that decision, or do you think we might hear about it at the same time?
I would say likely same time.
Yeah. That would make sense. Right. Okay. Wonderful. And then for the FORTIFI trial, getting back, I guess, to the potential for approval, the overall response rate that could be used for accelerated approval potentially coming out in 2027, what do you need to show on response rate to file for accelerated approval?
Yeah. What the FDA had guided for Project Front Runner is looking for an approximate doubling of response rate. I think the important piece is it's not only response-based. You would need to show, again, to Ryan's point, durability, at least six months durability around the responses. I think given the recent lymphadenom failure, one of the pieces that the FDA is definitely looking for is a descriptive look at overall survival.
What we saw in the LEEP-010 study is, in fact, at the time that they were probably doing their data cut for accelerated approval, their KM curves crossed for overall survival. There are so many examples where response hasn't translated to OS that I think OS will be an important aspect of really being able to show that delta.
How large do you believe the frontline head and neck cancer opportunity is?
It's big. I mean, I think one of the proxies we look at is I think Merck has disclosed that somewhere between 5% and 10% of global Pembro sales are in head and neck. You can do the math there pretty easy. It's big. That's with short durations of therapy. You think about adding a drug like ficera and being able to significantly increase duration of therapy. I think you very easily could see this turning into being a $3 billion-$4 billion market pretty easily globally.
Okay. We talked about the patients that might need to be tested in the pivotal trial. Just as we think about the launch, is testing available in all of the practices outside of those academic sites? Is it readily available in the community?
Yes. Again, as part of the launch, there will be a companion diagnostic, which the field has been initially immunohistochemistry, even done in community centers. The test is moving over to a PCR test, which, again, as you know, is a much easier test to do and much cheaper and rapid. We feel very confident that this is going to have no impact on launch.
Yeah. I think a question is always, does the CDX, is there a commercial implication of that? Certainly, I don't think 22C3 hasn't been an impediment to Pembro use. I think having a CDX there, and again, I think most of those patients who are even in the commercial setting within label will have had P16 on board already, and then you'll just confirm with a PCR.
Okay. As you think about the pivotal trial or commercialization, does P16 status versus a true HPV-positive patient, does that matter? Obviously, some KOLs have discussed that in the context of some of the data that we've seen reported. Is that something that you're?
I mean, we know that with P16, there's, I think, about a 10% both false positive and false negative. You see it on both sides. I do think that as you think about if there truly are differences in outcomes based on HPV status, you could see differences in efficacy by actually testing using PCR versus just P16 based on the false positive negativity rate of P16.
Okay. We've got a couple of minutes, so we'll move to some of the other indications. Cutaneous, AACR, what should the expectation be for this readout? What data will we get, and what would be considered a success?
I think, yeah, hopefully what that data will show is that some of the, I think, the naysayers around monotherapy activity, that is a monotherapy data set that is showing that will show and has shown, we've disclosed previously, monotherapy activity in patients who are second line post-PD-1. The vast majority of those were PD-1 primary non-responders.
I think hopefully it'll definitively demonstrate monotherapy activity of our molecule where we've tested it. We have not tested monotherapy in head and neck because our approach there is in combination in the frontline setting. Doesn't mean that if we didn't test it, we would not see activity in second line monotherapy, EGFR naive. Again, that data set will, again, demonstrate the monotherapy activity that our drug delivers.
I t's too early for PFS? It'll be more response rate based?
Yeah.
Okay. Moving forward, phase two, three, potential pivotal plans, would it be as a monotherapy, in combination, or both? Okay. Good. I know who the likely partner is there. All right. The anal canal data that you guys showed that you covered from ASCO GI, what's the pathway forward there? Obviously, standard of care is horrible. These were super late line patients. There appears to be an improvement. It's enticing to go into earlier line patients and see what that data shows. How are you thinking about moving that program forward, or what are you weighing?
Yeah. I mean, I think we've seen recent data from Insight in the frontline setting. I think one of the things we continue to engage with our investigators to think what the most prudent path forward is. We've seen, I think, preliminary data from that. We've not yet seen the more mature data. I think we are taking a bit of a pause there to figure out what the most appropriate, whether it's in a PD-1 exposed, whether it's PD-1 naive. I do think we have the possibility to see an evolution in the treatment landscape, and we want to make sure that we're doing the right study in the future landscape.
What other ficera indications and development are you guys most excited by?
I'd say for me, it's definitely earlier stages of head and neck, especially in combination with radiation therapy. There's a strong rationale for upregulation of TGF-β. I think given some of the recent pembro data, there's a large opportunity in the locally advanced setting. Colorectal, I think, is also a lot to work with.
Yeah. Maybe just to wrap up, what do you believe is the most underappreciated aspect of the Bicara story by investors right now?
I think at the end of the day, there are two EGFRs being developed in head and neck. I think they have fundamentally different mechanisms of action and quite different clinical development strategies with different risk profiles and different probabilities of success. I think that's being lost in just a discussion around one versus the other.
It is also going to be a massive market. Both are successful. It is pretty appealing.
They are likely both approvable molecules.
Yep. Wonderful. Thank you very much for the time, guys.
Thank you.