For joining us for our next session. We've got Pyxis Oncology represented by their CEO, Thomas Civik.
Leo.
Thanks for being here. Lot of updates for the company, but maybe by way of introduction for those who may be a little less familiar with the story, MICVO's an ADC, pretty unique mechanism of action. Tell us a little bit about sort of the drug, why it's different, and what makes it unique and maybe well-suited for head and neck?
Yeah. It's That's a big question. It can go in a lot of different places, and I know we'll probably get there a little bit later. It's a novel ADC that targets the EDB-FN, which is a splice variant of fibronectin. It's only found in the extracellular matrix, which makes it unique and novel from an ADC perspective. We think that scientific rationale has given us a lot of excitement about something that's different that should be studied in multiple different cancer types. Preclinically, all the work that we did, we found a half dozen cancers where we thought that there was an opportunity for this molecule, and so we brought it to the clinic.
The first stage, like any good drug development, we did dose escalation, basket study. During that time period, we found two things. One, we knew what the dose range was. It was 3.6 mg- 5.4 mg, and we were able to find multiple cancers that the drug was showing activity with. One of them that stood out more than others was head and neck cancer. We quickly transitioned into a dose escalation study at 5.4 mg, and we shared that data back in December of last year with really extraordinary efficacy results in second line head and neck cancer. We also revealed some safety signals with the dose, specifically peripheral neuropathy, that was leading to some high discontinuation rates.
In December of this year, we kept rolling along with the dose escalation, but we put in place a dose cap for those patients at 5.4 mg. We've been guiding and working towards a disclosure in our monotherapy data to deliver in the second I'm sorry, in the mid part of this year for 5.4 mg in head and neck cancer, with a dose cap that we hope to share in a little bit.
Yeah. No, that's great. Maybe just staying with some of the data you've presented. You know, some competitor molecules out there in head and neck, I think previously the company had talked about 40% response rate as a bar. You guys cleared that. Similarly for monotherapy, I guess on the efficacy side, I mean, how competitive is this as a molecule? Is it applicability across head and neck or will be more of a agent position towards one part of the indication?
Well, I think the great news is there's a lot of exciting advancements going on in head and neck cancer right now. You had asked about competition, and to be frank, I don't really think we have any competition. I think we're trying to serve a patient population that's desperate for new therapies, and I'm excited to be on that journey. We've got an extraordinary team at Pyxis Oncology that's really working hard to see if we can unlock the full potential of MICVO. We see it in second line head and neck cancer, and there's no reason that the first place of interrogation for us is for a patient population that's severely underserved right now.
If we can deliver similar efficacy to what we've shown twice now, back in 2024 and 2025, but with an improved safety profile and improved tolerability, mainly discontinuations, we think that there's a really significant place for MICVO to have a profound impact for a lot of patients in second line head and neck cancer. When we do our planning and look at sort of what the number of patients that will be seeking treatment in second line in 2030, let's say, we think there's 21,000 patients that in the U.S. will be looking for something better than what's available today. For us, that feels like we're focused on an area of significant unmet need with a product that could really potentially change the treatment paradigm for those patients. That excites us a lot.
You mentioned the potential toxicity signal. I guess just to dive in a little deeper on that, I mean, how do we know that's caused by MICVO and not, you know, this was tested in later line patients who may have had chemotherapy, that it's not a signal from prior chemotherapy? I mean, to what extent are you solving something that, you know, may not need to be solved with the dosing approaches? Can you just talk more about the toxicity profile?
I mean, I think, Leo, the way we think about it is the data that we hope to generate for the mid-year should give us confidence that if we were to move into a pivotal trial, that we would have a drug that would be able to beat the standard of care that exists today. The standard of care today isn't very great, right? Like decade-old chemos, EGFR that likely have a place today, when you fast forward to 2030 with the next gen EGFR likely moving into first line, there's this wide open space that we think MICVO could fill.
As it relates to the safety and tolerability, I think the truth will be in the data on how severe and how frequent are the AEs of interest, how manageable are they through either very direct interventions or indirect, and how much does the patient population change because of the new standard of care potentially in frontline. It's a long way of me saying I think what we're looking for is, are the AEs manageable enough where people stay on drug for an extended period of time so that they get the benefit that they deserve as a second-line head and neck cancer patient?
When we look at that data, it's really gonna be against the backdrop If we were fortunate enough to be moving into a pivotal trial, do we believe that we could beat the standard of care?
Yeah. You guys have talked about the dose capping strategy.
Yeah.
Just walk us through that a little more. You know, it's going to change the exposure of the drug, hopefully reduce safety signals without impacting efficacy. What's the data to support that can work?
Well, I mean, the easiest place to start is anybody that's developing an ADC today is using some form of modified weight-based dosing. It has become the standard practice of what's happening in this space today. Just to put some numbers against it, the last four ADCs that have been approved use some version of modified weight-based dose, whether it was a dose cap or something called AIBW or adjusted ideal body weight. The four that we're watching also in development that are in the later stages of development also are all using some form of modified weight-based dosing, either dose cap or adjusted ideal body weight. I guess, let me start by saying that if you're developing an ADC, you're likely gonna end up in a path where you're looking at some sort of modified weight-based dosing.
For us, the signal became really clear last December when we looked at the data that we shared in second-line head and neck. There was a clear distinction that heavyweight patients were driving a significant number of the AEs, the severity of them, and that was leading to discontinuation. We then took that data, went back to our scientists, our extraordinary scientists at Pyxis, and said, "Let's do some PK modeling to see if we can figure out where we should set the cutoff, what sort of expectations we should have." All on our corporate deck if you wanna take a look at it.
What we found was that there was this group of patients that we feel like regardless of the dosing scheme, whether it's adjusted ideal body weight or a dose cap, that we can find this sweet spot where we can hopefully maintain efficacy but significantly improve the safety profile, which we hope leads to better tolerability, less discontinuations. I think those three things, this is a tried and true path for ADC drug developers right now. Our clinical data clearly pointed to it, and then we supported it with PK data. That's sort of the package that we've got in our head is to give us confidence on what the path forward is.
Got it. As you're moving forward now with cap dosing, you're also exploring the ideal body weight or adjusted ideal body weight dosing. I guess why one over the other? Are there simplicity trade-offs or there may be trade-offs on efficacy or the safety side of things? I guess how'd you come to that decision? What's gonna ultimately decide what you move forward with?
Yeah, some of it's super scientific, and some of it's just practical. We came to the decision on where we are today for the practical reasons. We had made this observation of heavyweight patients being overexposed, this nonlinear relationship that happens with ADCs. In an attempt to help patients that are on our trials, we decided to implement a dose cap immediately. You don't need a protocol amendment. You can literally just call up the sites and say, "We're gonna Nobody gets more than this amount of drug." The dose cap was extraordinarily easy to implement, we did so back in December. We also put a protocol amendment in place, and that just takes a couple of months to get squared away, and we've done so and started dosing patients for AIBW.
To be really clear, the data that we're gonna share for our midyear update will be exclusively patients that are dosed at a dose cap or at total body weight. The AIBW cohort that we've just started enrolling is an opportunity for us to have a backup plan if that data does emerge as superior for some reason. Our expectations is that it should produce the same results.
Got it. Are there any other strategies that you can use to manage some of the AEs? I mean, is there some amount of better patient selection that can be done, or is that potentially gonna intrude upon sort of the total market opportunity that you talked about?
Wow. It's a really tough question to answer because I think what's true today and what's true five years from today is likely going to change. The patient population that we're seeing in our trial are people that are heavily pretreated. We've been able to in our expansion trial, we've been able to narrow it down to just second or third-line patients. Before that, we were seeing fourth and fifth-line patients that have been exposed to some pretty toxic treatments before they made their way to us. You would expect that some of the AEs that we're interested in do have a cumulative effect, so we're paying close attention to them.
There's the world today that we'll see in our clinical trial, and I'm sure that we'll be part of the package that we share at the midyear update. Fast-forward to five or six years from now. Let's assume that the next-gen EGFR in combination with the PD-1 have become the standard of care in frontline. You're gonna have patients that haven't seen as much or if any, chemo or taxanes at that point. That opportunity to have even cleaner safety profile than what we're seeing in our trial, I think is a real strong possibility for what the future looks like.
Yeah.
You asked about managing the AEs as well. It's as a drug developer, whenever we see anything that is a red flag that gives us concern, the first thing we do is we go talk to the investigators and say, like, "What, what do you think about what you've seen in this group?" We have standup safety meetings with our investigators pretty much every other week. It's always surprising to me. I get scared when I hear about peripheral neuropathy or some of the other AEs. When we talk to our treating physicians, they are so familiar with the ADCs and how to manage their way through these safety profiles, whether it's dose reductions or dose delays, whether it's other things that they do.
It's less scary for them 'cause I think they see it more often. I think maybe the moral to that whole story is working in concert with our investigators is really important to make sure that we're doing the right things for patients all day long every day.
Yeah. I mean, the reason I keep pushing on this point as well is because in your pembrolizumab combo data.
Yeah
I mean, the drug looked much cleaner, from the safety perspective. I guess, how are you thinking about the safety profile in that frontline setting? Do you need the dose cap in the setting? Is an opportunity to push efficacy even further? Is that something you guys are considering?
First off, thank you for recognizing the extraordinary data that we shared in December. It was a small end, we still have a lot more work to do. A response rate in the 70s, a disease control rate that's extraordinarily high gives us a lot of excitement for what the future could hold for that combination. You're right, we dosed at a lower dose at 3.6 mg and 4.4 mg, and the safety profile looks very clean. We plan to update that data, share more patients, more durability later this year, we've guided to the second half of the year. I look forward to sharing that data at that point. Our hope is that the safety profile maintains, the efficacy stays high.
You can also think about a world where there's bifurcation of what's happening for patients in the frontline setting. The data that we shared in December was all HPV-positive patients. We have been enrolling, we've been focusing on frontline patients regardless of HPV status, for that trial moving forward.
Got it. maybe, you know, building on maybe last thing I'll ask on the safety side of it is, you know, it is a novel payload.
How much do we know about the payload itself, whether there's risk of cumulative toxicity? I guess one of the goals is to keep patients on therapy for longer and, you know, potentially one of the associated risks is as patients stay on longer, peripheral neuropathy might reemerge. I guess, how are you thinking about that? I guess, is that something you're trying to balance?
Yeah. I mean, your question really matters on are we talking about second line plus or third line, or are we talking about frontline? The benefit risk ratio for each one of those patient groups is a bit different. The current standard of care, you'd be lucky if you got three or four months of progression-free survival in that group.
We're planning for success here, right?
What's that?
We're planning for success.
We're planning for success. For us, we think we have to deliver much more than that. When we talk to the investigators about the profile that they would want to see in second-line head and neck cancer, we're talking about at a minimum patients being on drug for six months. Those toxicities that you're talking about are things that we want to make sure that we have a good sense of what you should expect and then a management path in place so that if you do see them, how you can help ensure that your patients continue to get benefit. When you talk about frontline, though, you've gotta be able to have a much cleaner safety profile because the patients are gonna be on drug a much longer, we hope.
I think the data is gonna continue to mature. We've got a lot of patients that have been exposed to MICVO over the years, and we look forward to sharing that database later this year.
Yeah. I mean, as we get into some of what you'll disclose later this year, I mean, you were able to recruit a pretty good number of patients quite quickly.
Since the last update. Can you maybe talk about what's different on the clinical execution front, whether it's, you know, something internally you've changed, whether it's showing the data and building the physician excitement? Just any thoughts?
Yes, it's those two things. You just nailed it. We made a really important hire at Pyxis. Our new head of Clinical Operations is just absolutely fantastic. She has got the organization lined up. She's collaborating with our clinical team to ensure that we have an executable plan that's being implemented. Regardless of how much you tighten up execution, you still need significant investigator interest. I think you sort of hinted at it, in December, we shared this extraordinary efficacy results with MICVO, 46% response rate in the second line setting regardless of HPV status, regardless of prior therapies. That got our investigator community quite excited.
When we put on top of that that we were gonna be implementing a dose cap, an approach that they're quite familiar with with other ADCs, I think those two things, tighten up operations, great leadership, great collaboration inside the Pyxis four walls, combined with global investigator excitement for both an efficacy that is what we so far have seen best in disease, combined with a dosing scheme that's gonna hopefully prevent less AEs and less frequency, less severity of them, but also allow people to stay on drug much longer. Great execution, really engaged investigator community.
Got it. You guys are going to be sharing more data mid-year in the second half. Just walk us through what we should expect from monotherapy, from combination, just how we should think about patient numbers, what to focus on for both.
One of the things I'm really proud of our clinical team in doing was designing, I think, a study that answers the question of today, but also the question for tomorrow. Let me just describe that 'cause it'll help get to the end that you're asking about how many patients. In our dose expansion trial, we have two arms that are enrolling 20 patients each, or that have enrolled 20 patients each. One is a post platinum plus PD-1, and the other one is post EGFR plus PD-1. Why I'm so excited about these two arms of our dose escalation study is post platinum sort of answers the question of today, post EGFR answers the question of tomorrow.
We should have 20 patients roughly in each one of those arms that we'll share at our mid-year update. That combination of that set of patients, I think should create a lot of clarity for what this drug is doing, what MICVO has the potential to do for a second line head neck cancer patient. 40 patients in dose expansion. We have another five or so that were in the dose escalation. Put those together, roughly 45. Just from a numbers standpoint, for those keeping score at home, we revealed 18 patients that were safety evaluable in December and 13 that were efficacy evaluable, so pretty significant jump in a very short period of time. Then we're also guiding to the second half of the year, we'll be updating the combo. We haven't shared numbers yet on that yet.
Got it. Then just to clarify, the 45-ish patients, that's all going to be at the 5.4 dose, all dose cap, and that's what we should be focusing on?
That group will be. You're right, it's 45. It's all at 5.4 mg. It will be total body weight and dose cap. You'll get to see both of those.
Got it. Okay. How are you guys It's probably very early to talk about this, but are you guys thinking about what the regulatory path ultimately might be, you know, perhaps in monotherapy? At one point, the company previously said that there was some FDA sign-off on a design. Is that still the case? I mean, gathering more data and working through that, is this something you'd revisit with the FDA?
You know, my experience in being in this industry for a long time is that having open and honest ongoing dialogue with regulatory agencies is usually a really good path. Our regulatory leadership at Pyxis is doing exactly that. We did have a quite productive meeting with the agency in the fourth quarter of last year. We haven't revealed all the details of that meeting as you would expect, but we feel really confident that we have a path forward to get to pivotal if we pass our own criteria for whether or not this is a go for us.
Just lastly, as we think about the data, I mean, you've talked about the HPV status. I mean, are there any other ways we should be thinking about slicing the data across subgroups? I mean, sounds like you're confident the drug works across HPV status. Are there other things that we should be thinking about?
I hope that we have a robust enough data set that you'll be we'll be able to slice it a lot of different ways. It will always run into the law of small numbers and not getting too far ahead of ourselves to make interpretations on subsets. I think our aim is to be able to show the same sort of efficacy that we've already shown you with a much cleaner safety profile, and then combine that with a profile that works regardless of HPV status. There's no scientific reason that it shouldn't, that works regardless of prior therapy, whether it's an EGFR or a prior taxane. Those would be sort of the things that we would love to be able to get into and cut to the level that we feel comfortable still being informative.
Just going back to the combo for one more question. You guys showed some data at AACR on, you know, some translational work.
Yeah
Suggesting that there could be some immune activation, especially in combination with PD-1. How do we think about translating that to the clinic? I guess, what are you learning about the mechanism of MICVO?
Our translational medicine and research team has just been absolutely crushing it, you know, I get really excited when the scientific rationale lines up exactly with what you're trying to prove in the clinic. This is one of those cases. I've got a lot of friends that have that work on PD-1s and PD-L1s across the industry, the one word that they really get uncomfortable hearing in the combination space is this word of synergy. Not just additive, but synergy. What our translational team showed was that in a mouse model, when you take our mouse MICVO and combine it with a mouse KEYTRUDA, that you actually sow synergy in those two drugs for a mouse who normally wouldn't have responded to a PD-1.
We did that both in combination and in monotherapy, and this was in a specific head and neck cancer type. We've also replicated that exact same science in triple negative breast cancer last year. I'll just say it again. When the scientific rationale matches up with where you're going clinically, it's quite exciting. Whether that plays out in the way we hope in the clinic is you will be the judge of that in the second half of the year with our combination study. I Yeah, the story's quite strong, and I'm quite happy with that AACR abstract that was published.
Got 30 seconds left, maybe just a bigger picture one. I guess, how are you thinking about the company as a whole? I mean, are there places you could take MICVO beyond head and neck? I guess, MICVO's something you ultimately wanna pursue on your own or partner. I guess, how are you thinking about just the strategic vision for the company?
You're asking me that question with 20 seconds to answer it, huh, Leo? Look, I think there's a distinct chance that MICVO has the potential to be a pipeline and a product. I know that term gets thrown around a bit, but there's no scientific rationale that it shouldn't work in other cancer types beyond head and neck. As a good drug developer, we're trying to focus on proving that it works as a monotherapy in a late line, hard to treat cancer. If we can do that in head and neck cancer and the scientific rationale holds, there's no reason this can't be a treatment that's helping a lot more patients across the globe.
Thank you. Yeah.
Thank you, Leo. Thank you.