Okay. Yeah.
Hi. Good afternoon. Welcome to this session of the Morgan Stanley Global Healthcare Conference. I'm excited to welcome Bicara with Claire representing the team here. Let me just read a quick disclosure before we get started. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. With that out of the way, Claire, again, thanks for being here. Maybe up front, for those who may be less familiar with this story, can you give us a brief introduction to Bicara and your lead molecule, ficerafusp alfa?
Happy to. And thanks for having me. Bicara Therapeutics is a clinical stage biotech company focused on what we call targeted tumor modulation. We develop molecules where one arm gets to the tumor, and the other arm is some type of tumor modulator that delivers not only improved efficacy and durability but an immunotherapy-like response. This is really exemplified by our lead program, ficerafusp alfa, which is a bifunctional EGFR-TGF-β1/3 inhibitor that entered the clinic in the summer of 2020. The most recent update to that dataset was we shared a dataset at ASCO in an oral presentation this summer showing that if you combine ficerafusp alfa plus pembrolizumab in first-line, HPV-negative recurrent/metastatic head and neck squamous cell carcinoma, we could triple response rates, but more importantly, double overall survival compared to the standard of care with pembrolizumab monotherapy.
Okay. Great. We will get into all that, I promise. Just on the targets, TGF-beta is a fairly well-known target in oncology. Can you talk about historical efforts to target TGF-beta and how your molecule might be differentiated in that respect?
Happy to. As you said, TGF-β is one of the best validated oncology targets, but it's been very difficult to drug in a way that actually delivers strong efficacy in the context of oncology. What I would say the field has come to realize is that some of the earliest approaches, some 20 years ago, were these pan-TGF-β inhibitors that targeted both the active and latent forms and all three isoforms of TGF-β. There were a lot of toxicities at the time attributed to TGF-β2, which is predominantly expressed in cardiac tissue, and that led to significant cardiotoxicities. Since then, the field has moved to realize that there's isoform-specific inhibition, which is how we think about it. Our trap specifically binds TGF-β1 and TGF-β3, which are the known cancer-associated isoforms.
Importantly, I think the most important differentiation from Physera compared to all other TGF-β inhibitors has been the fact that we're the only tumor-targeted. We're using the EGFR arm to localize TGF-β inhibition directly to the tumor microenvironment. In fact, we've been able to demonstrate very clearly that we're able to inhibit TGF-β in the tumor compared to patient biopsies and translational data.
Okay. That makes sense. With that in mind, kind of both arms of the bifunctional molecule, your lead indication is first-line, sorry, RM head and neck cancer. Can you tell us about the unmet need that you're trying to address here, and maybe even more specifically, HPV-negative versus positive?
Happy to. I think head and neck is still one of those indications where it's really considered an immunosuppressive or so-called cold tumor. While pembrolizumab was approved earlier this decade, it really still has pretty poor prognosis, in particular in the HPV-negative subtype. Patients, you know, it's about a 19% overall response rate across both HPV subtypes. In HPV-negative patients, the median overall survival is still only about nine months, so quite bad. What people have come to realize is in some ways we should think of these as two very distinct diseases. HPV-negative head and neck is really driven by a history of smoking or chewing tobacco and alcohol use. You predominantly in the U.S. see it in the Southern Tobacco Belt, and in Europe and Asia where you see much higher rates of smoking.
What's important from a biological standpoint is that these tend to be more EGFR overexpressing and also have a very high level of TGF-beta, which in fact is what makes them immunosuppressive. We always hypothesized that our molecule would see outsized efficacy in that subset, and indeed that's what we've seen. While we have seen some activity in HPV-positive, we see far more in the HPV-negative subset, which is where we went into.
Okay. Maybe just to set the stage a little bit further, I think you're into investigator-led efforts, CTOXINLAB with pembrolizumab. Can you talk about what brought you to?
Yeah. I would say it was a combination exactly of that. A, knowing that there's a clear biological synergy with TGF-β inhibition in the PD-1, but importantly, there was in some ways almost a proof of concept or a precedent from two investigator-initiated studies that had shown that if you could combine ficerafusp alfa with the PD-1, this is really the first time that we saw improvements in response rates translate to improvements in overall survival. We felt, given ficerafusp alfa had gotten off patent years ago and neither Merck nor Lilly were moving that regimen forward in a pivotal study, that there was a path to approval in the frontline setting. I think what we've shown to date is that ficerafusp alfa meaningfully differentiates from ficerafusp alfa both on depth of response and durability and higher response rates, and that is what has led to really outsized overall survival.
Okay. You know, one question I think we got around IPO time, but less now. Just the decision to pursue frontline and not go monotherapy in second line is probably worth revisiting.
Yeah. Happy to. I mean, again, it goes back to the TGF-β arm of the molecule. We knew that TGF-β and PD-1 together synergize to give you that one-two kick or one-two punch of reactivating the immune system. We also felt that, you know, in a world where we had such strong data in first line, the EGFR-naive second-line population was always going to be a diminishing one. I think at the time there have been, and today what we have seen is a lot of competition, especially with the ADCs for that second and third line, while the vast largest market and synergy is PD-1 really comes from the front line.
That makes sense. You touched on it at the top, but you did have an important update at ASCO earlier this year, where you did give us some survival data. Can you recap that update for us and contextualize it with historical outcomes in the setting?
Happy to. As I alluded to before, in HPV-negative head and neck, patients typically have a median overall survival of only about nine months. This is really based off of real-world datasets of close to 600-plus patients that have really shown consistency in this. HPV-positive patients, on the other hand, have median overall survival closer to 14 to 20 months, depending on what you look at. What we shared with ASCO was really our first update at achieving median overall survival at greater than 21 months, as well as a median durability or duration of response of greater than 21 months. I think the important aspects of both of those are just the consistency that durability really matched overall survival, but more importantly, what we saw was that durability was something very akin to immunotherapy.
If you look at EGFR inhibitors in development, that durability has been really short, very almost chemo-like. We felt that the key best predictor of why we would see overall survival benefit would come from durability. I think the other important aspect of the dataset we presented at ASCO is that we weren't just seeing these in the patients who tend to respond to pembrolizumab, which are the CPS high patients or the combined PD-L1 score high patients. We are seeing this, if anything, even more in the CPS low, which are the PD-1 refractory patients. Really seeing the TGF-β effect across the board.
Okay. Great. You've got an internal oral readout in 2027 for your Phase 2/3 for ficerafusp alfa in a one study. Is there anything you can share on progress around getting sites up and running and enrollment? Did the ASCO update have any impact on cadence or is it too early to tell that?
No. I think we really did see strong momentum with investigators coming out of ASCO. I think one of the things that has always resonated is just how strong and mature our dataset is and that we designed this study really with a pretty significant amount of data in hand to help inform how we would appropriately size the study. That has really resonated as we spoke site engagement. We continue to build really strong momentum. I would say we're very much on track in terms of site activation and enrollment. We continue to guide to being fully enrolled in 2027 as well.
Okay. Great. Maybe taking a step back here, you're addressing Project Optimus requirements with the Phase 2/3. Can you remind us of why the trial was designed as it was, and also the process and timeline specifically for selecting pivotal dose and where we are there?
Yeah. Happy to. As you said, to satisfy Project Optimus, we designed it as a seamless Phase 2/3. The way to think about it is that the first patient enrolled at what we think will be the selected dose, even in the Phase 2 portion, will contribute to the interim analysis for overall response rate as well as the confirmatory analysis for overall survival. By doing it in such a way, we wanted to not delay the potential accelerated approval. We felt more comfortable in some ways over-enrolling the non-optimal dose or the non-selected dose. We anticipate having anywhere between 60 to 80 patients who are enrolled at the non-optimal dose. By doing so, we kept to our aggressive, accelerated approval time or potential accelerated approval timelines.
To your question of where we are today, the way we've thought about Project Optimus is while there is a blinded Phase 2 portion of the study, we also have two open-label datasets in the Phase 1b that will help contribute to that dose selection decision. Later this year or early next year, we will be presenting at a medical meeting the dataset, the preliminary dataset in terms of response rates, from the 750-milligram cohort, to help really inform how we're making that decision and how we think about ficerafusp alfa across doses.
Okay. Perfect. Like you said, you're going for an accelerated approval based on internal or. Can you comment on the regulatory path for ficerafusp alfa beyond that? Have you had any recent interactions with the FDA or read-throughs from other programs that reinforce your confidence in the accelerated pathway?
I would say we are lucky to have a good dialogue with the FDA. The way we've designed this study is to satisfy something known as Project Front Runner within the FDA. What we'll be looking at at that time, unfortunately, there aren't too many precedents of Project Front Runner. The only that we're aware of today is Breakwater, for encorasamib. There are some similarities, but not all, given they have slightly different endpoints. The focus, and I think others going for the similar approach have guided to very similar, is we're looking for an approximate doubling of responses with a look at durability at that time, ensuring that those responses are durable. Importantly, I think, and my sense is this will continue to be a key piece of the FDA's guidance as they dig in more into overall survival.
At that time, we'll have a look at least a descriptive overall survival as well.
Okay. Great. Like you said, the Phase 2/3 is only enrolling patients that are HPV-negative. Can you tell us about the reasoning for that decision, which you did touch on mechanistically, but maybe adding on to that, how does that affect commercial opportunity for ficerafusp alfa? I think there's probably some misconceptions about how largely addressable the market is if you do, in the end, exclude HPV-positive patients.
Happy to. To your question, let's look ahead and begin with what people, you know, I think there's sometimes a misconception of just the size of the HPV-positive and HPV-negative population. While both are growing in theory, most patients who are HPV-positive are cured in the locally advanced setting from radiation and surgery. If you end up in the recurrent and metastatic setting, that is heavily skewed towards HPV-negative. In the U.S., it's close to 80% to 85%. In Europe and Asia, it's closer to 95%. In some areas, it's close to 99%. The way I like to speak to it is if you think about the patient's journey, if you have 10 patients entering a community clinic in Tennessee, for the sake of argument, 7 of those 10 in the locally advanced setting are assumed to be HPV-negative in the get-go.
Those are three subsets: the oral cavity, the hypopharynx, and the larynx. Only in 3 of those 10 patients do you test for HPV status in the oropharyngeal subset, and one and a half of those are HPV-positive. Typically, their status is already known in the locally advanced setting. By the time they come to the recurrent and metastatic setting, there is no additional testing that is typically done. We are developing a companion diagnostic in parallel with our pivotal study, and that's really, in some ways, to harmonize how we think about HPV testing. I'd say today, most academic centers you go to have developed their own HPV PCR, which is far more broad across all different types of HPV, and it has a higher rate of concordance and is more accurate.
Typically, in community centers, they have generally what's called a P16 immunohistochemistry, which is a little bit more cumbersome. The test that we're developing is going into an HPV PCR. It's a validated test already with our partner, and it's really about moving that test ideally into the locally advanced setting. By the time it's in the recurrent, it's very similar to a COVID PCR test you're doing.
Okay. Maybe a more direct question on that topic that we do get from time to time. I guess from the clinician's perspective, is there incremental testing that they would be doing beyond what they're doing currently in the commercial setting for Bicara Therapeutics, Tomaso?
I think it will all depend when that test is done. In the first months and years that we're approved, we anticipate that, of course, being done at the time, but we do think it will move earlier into the patient journey. This is the same turnaround time as the CPS testing, which is required for reimbursement of pembrolizumab. What we've been seeing even in the clinic today as we're enrolling patients is that turnaround time for the HPV PCR test comes exactly around the same time as the CPS testing for 22C3.
Got it. Another question we get is, can you just remind us on frequency of dose? Is there potential for that to change over time?
Yeah. The pivotal study, the two doses that we're exploring, 1,600 milligrams and 750, is on a weekly dosing. We will be releasing at a medical meeting early next year a dataset from 2,000 milligrams every two weeks in the 30-patient HPV-negative dataset that we're also quite excited about, which I think will really speak to the ability to move to a less frequent dosing. Our current plan is, once we get to the selected dose on a weekly basis, we do think that there is a possibility and a high probability to be able to bridge on a PK bridging study to an every two-week or more convenient dosing.
Okay. In terms of that timing aligning with potential accelerated approval, how are you thinking about that?
We're very much thinking at the time of launch, so very much aligned.
Okay. That makes sense. Great. You're also studying ficerafusp alfa in other head and neck populations. Can you tell us about some of those cohorts and when we can expect updates on those? I think you have an HPV-positive cohort, if I remember correctly.
Yes. We have an HPV-positive heavy smoker cohort. I would say the one I'm quite excited about is the CPS-zero. These are patients where pembrolizumab has no activity. We've seen some data in dose escalation. The bar is exceedingly low for a non-chemo regimen. We anticipate being able to share early data from that next year as well.
Okay. Excellent. Maybe moving into some of the other solid tumor indications outside of head and neck, you've got SCAC, you know, cutaneous squamous cell carcinoma. You'll also be initiating, you know, a third-line plus.
Yeah. We initiated a third-line plus colorectal cohort earlier this summer, which has been rolling very rapidly. We do plan to have, you know, be able to share data next year on those cohorts as well.
For all three of those indications, you think we'll have some.
Colorectal is the bullet right now. In cutaneous, we shared a dataset earlier this year, the same with anal canal cancer. For cutaneous, we are considering prioritizing moving into the frontline setting in pembrolizumab.
Okay. Great. Maybe just kind of moving back to, you know, commercial potential here, right? Maybe it's worth reminding folks kind of how many centers you have your head and neck trials in. How are those centers thinking about enrolling your trial versus competing trials and kind of maybe level of comfort with Physera in, you know, a commercial landscape where there's more than one?
Yeah. I mean, I think we're getting to a point where there is very strong conviction in what I would say is the EGFR bifunctional specific class as being likely the standard of care in frontline head and neck. I think there will be nuances to what specific patient subsets within head and neck. I think that's baseline in place. Head and neck is a very large indication with a very high unmet medical need. Generally, people are starting to realize that this is a large enough market for multiple players. In all honesty, we've never seen a true winner-take-all category in oncology for such a large indication. I think we are getting the question on sequencing. How do we think about one versus the other?
In all of those scenarios, I think ficerafusp alfa actually comes out on top just based off of our mechanism of action, based off of the datasets we have. We know that, competing tirosimab, for instance, degrades the EGFR receptor. I think the conversation will become more nuanced as investigators have the opportunity to work with both molecules. Today, to your initial question around how sites think about this, head and neck is a large enough indication that in the late 2019 timeframe, there were three large pivotal studies for different PD-1s, and all enrolled in a very similar timeframe. What we're seeing predominantly in the U.S. is very few centers of overlap. I do think it speaks to just what a large indication this is and that there are, unfortunately, a lot of patients.
Okay. In terms of thinking about addressable market in the U.S. versus other countries, there seem to be some nuances in kind of addressable population outside of the U.S. Are there particular geographies that you're thinking about as kind of more toward the top of your list versus the bottom?
For the pivotal studies?
Yeah.
Yes. I mean, I think it really goes down to how we've designed the clinical study as a blinded study. This has to do with subsequent therapy. There are geographies, predominantly, if you think of Brazil, for instance, and South America, we don't use CTOXINLAB in the second-line setting. Typically, in second line, we provide a chemo regimen. That is something we've thought about given, you know, we're looking, we are an EGFR-containing molecule. There are particular geographies, but this is very much going to be a global study and is a global study already.
Okay. That makes sense. Maybe just to kind of wrap up the company-specific conversation, can you remind us of cash runway, what catalysts will that fund the company through? Maybe also just remind us kind of, you know, from IPO, has that changed in any way?
I think we were very lucky to be able to raise a significant amount of capital exactly a year ago, and so our, you know, cash runway takes us, I think we have north of $440 million, which takes us, you know, through the overall survival confirmatory endpoint. It fully funds the pivotal study through the important OS endpoint and allows us to signal if we can use other indications we spoke of today, the CPS-zero, the HPV-positive, the colorectal cohorts. It does not fund, you know, the true commercial layout or another pivotal study in colorectal, but we feel we're very lucky to be in a great cash position.
Okay. Great. Before I move on to the next set of questions, any questions in the room? We do have some mics if anybody is interested. Okay. Don't be shy to raise your hand if they come up. I'm going to move on to a second set of questions that we're asking all biotech companies at the conference. I think there are varying degrees of relevance depending on who we're asking them to. Biotech does seem to be more exposed to external and macro factors of late. We are asking each management team the following three questions. The first is related to China's rise in biotech innovation. How are you thinking about your competitive position here? Will this influence R&D internally or business development strategy? Maybe to sum up that question, does Chinese biotech keep you up at night?
I mean, I would say definitely something that holistically with the biotech industry is important to think about. Specifically to ficerafusp alfa, we don't see an immediate threat from that perspective. I do think as we've thought about building the company, while our focus is really on delivering ficerafusp alfa not only in head and neck, but other tumor types as well, we are at all times really thinking about how we think about solid tumors and developing other targeted tumor modulators. If that's a molecule designed in China, of course, we've entertained the conversation. I do think we will see a rise of EGFR bispecifics coming out of China. It will really be on, I think, if anything, it hopefully will add nuance to what that other part of the bispecific is and what are the areas to really develop.
I think today we feel Bicara Therapeutics is really well set up to at least fend off China for now.
Maybe just on that topic, can you remind us of IP position for?
Yeah. We have a very strong position of matter IP that takes us to a pretty significant amount of time, and we have another process-driven IP as well. We feel from an IP position very strong.
Okay. Great. The next theme is AI. How are you currently leveraging AI, or thinking about AI's future to potentially disrupt your or the broader biotech business models? Is there anything you'd point to in development or clinical activities for ficerafusp alfa or beyond that?
I think there are definitely applications. We're seeing it as we think about just our data management and our clinical execution, where we can incorporate a number of these things from a regulatory standpoint as well. Our focus is on really well-validated targets, so it's not really applying AI to a novel target in any way. I do think there are applications where our teams are really thinking through how best to accelerate clinical development, and that's where our secret sauce will be too.
Okay. That makes sense. The third is, I think, kind of most relevant to most of the companies that we've spoken to. What's been the most impactful to your business on the regulatory side of things? On the list, we have changes to the FDA, pricing debates, tariffs, or anything else you'd highlight. I guess maybe we could take FDA specifically, and then if there's anything else that you highlight.
Yeah. I mean, I think, you know, of course, we continue to monitor our ongoing dialogue with the FDA. To date, I would say we haven't seen any meaningful changes to our interactions. We do continue to believe that the way we've designed our studies, with overall survival being such an important aspect, will continue to speak to the strength of our data and why we continue to believe that this is a very strong molecule. We will adapt accordingly should the world continue to change. I think we've created enough flexibility and adaptability in how we've designed to really be able to continue.
Makes sense. It's early for ficerafusp alfa, but I guess as you think about pricing and the potential commercial launch, has that thought process changed over the last couple of months?
I think it's still too early, but there are definitely geographies that we need to be thoughtful around, especially, you know, I think there are always opportunities to think about geographic-specific potential partnerships. I think our thinking is evolving as, you know, as people really internalize MSN and how to think about it.
Okay. Makes sense. All right. If there are no questions in the room, I think we'll call it there. Thank you.
Thank you very much. Thank you for your participation.
Thank you.
Wonderful. Thank you.