My name is Kelly Shi, one of the Biotech Analysts here. For this session, please join me and welcome Mr. Jay Short, CEO of BioAtla, for this fireside chat session. Welcome. Maybe to start off, could you give us a brief overview of CAB-ADC technology platform at BioAtla?
Thank you, Kelly, and it's a pleasure to be here and see everyone attending in the audience today. You know, just mention that, BioAtla is headquartered in, San Diego, California, and it's a pleasure to be here in London, with you all. And one of the key technologies is a really a breakthrough technology, referred to as Conditionally Active Biologics or CABs. And, the technology is based on a unique discovery that we made at, in our labs at BioAtla for a set of small molecules that each and every one of us already have, they're natural small molecules. And what they do is they protect or shield inappropriate binding on all of our proteins.
However, when you have an acidic microenvironment, like you have with cancer cells and diseased tissue, the hydrogen ions from that acidity lift off those, and bind to those negatively charged small molecules, which we refer to as PaCS, Protein-a ssociated Chemical Switches. And what that does is it opens up novel epitopes on only cancer, cells. And so that's, very nice because that means we can make antibodies to those novel epitopes on cancer cells, but they won't attack normal cells. And that gives us a way to improve the therapeutic window or therapeutic index to make cancer treatments safer and more potent. So hopefully that's a little help.
Terrific. Maybe, could you also set the stage for the various programs ongoing at BioAtla at this moment?
Yeah. So we have three programs or candidate drugs in phase II clinical trials. Actually, one of them is in a potentially registrational trial. Then we also have one additional CAB antibody in phase I trials, which will be completed next year. In each of those various molecules, we had multiple indications and of course, many indications that we're not currently pursuing, but quite a number of them. The first one is an AXL ADC, referred to as BA3011, and we have a key event coming up in December regarding that.
We'll talk more about that in a few moments, and then the next one would be the ROR2- ADC, then followed by a CAB- CTLA-4, which really addressing a very important unmet need in terms of safety and maintaining or improving efficacy. And then, of course, we have our first CAB T- cell engager, which is a dual CAB, one on the tumor targeting arm and one on the T- cell recruiting arm, the CD3 receptor. So that was kind of a quick overview.
Okay, terrific. Maybe let's first focus on AXL, AXL program.
Yeah.
Can you talk about the potential registration of phase II trial in UPS, one subtype of sarcoma? You are now enrolling at a more frequent and a dose-intensive regimen. What is the study design and why you are planning to discuss with FDA, and when should we expect the data?
Yeah. So we have that potentially registrational trial going on in undifferentiated pleomorphic sarcoma, UPS, for obvious reasons. That trial consisted initially of 20 patients in the three Q4W dosing regimen and 20 patients in the two Q3W. We announced in November 7 at our earnings call that we are focusing across the board on the two Q3W and not the three Q4W. So we're in the process of transitioning that entire trial to two Q3W. At the completion now of those 20 patients in that one arm, it was 20 and 20, now it will be just 20 in the one arm. We will then meet again with the FDA and then also make our final decision between Q2W and two Q3W.
So your question touches on what will be the registrational trial for that accelerated trial that we're running on with UPS. In earlier this quarter, last quarter, we completed our various sarcoma cohorts all the way up and down, and we're very pleased to see a positive results immediately exceeding our internal bar for advancing these within like liposarcoma, synovial sarcoma, osteosarcoma, and so among those. And so we. The reason we did those cohorts wasn't because we wanted to start a new cohort now in sarcoma. It was to help us think about the design for the registrational study. And that's exactly what we're looking at now. We just got that data in. We'll be reporting it out sometime next year in quite a bit of detail at an upcoming medical meeting.
But it will be these other sarcoma subtypes that we want to put together with UPS to see if we can expand the opportunity beyond UPS for the registrational trial. That has not been concluded yet, and anything that we propose would also have to go through the FDA as well. So those are the two kind of things that we're headed toward, but I think the question is very good, and, we're well aware that we need to move that. We'd like to see the market go bigger than UPS as we go forward.
Okay, and what is the bar for the other subtypes to move to the registrational trial stage?
Well, I think the bar's been exceeded, and we've communicated that. For the set of patients we were looking at, which I think I recall correctly, was 10 patients, either one PR or 40% of the patients exceeding X number of months. And Eric, what was the number of months again? Three months or four months. Yeah, four months of stable disease or the PR. And so we have multiple subtypes that have passed that, and which of course exceeds whatever standard of care for those particular indications. So that's why those bars are there. And so we have quite a bit to choose from and ways to design this, so we're working on that.
Terrific. And for the AXL trial in non-small cell lung cancer, you set expectation, data update at, IASLC, the International Association for the Study of Lung Cancer in December. What kind of a data set should we expect there? And what do you think the bar in the PD-1 refractory settings?
Well, I think the... We'll be providing quite a bit of data. There'll be spider plots and waterfall plots and other charts as well. And we will also, at the end of that meeting, the day after, on December 4, have a KOL that has direct experience treating patients with the AXL antibody and non-small cell lung cancer. So we'll be talking about all of that. We reported earlier this month that we achieved a 33.3%, you know, ORR in non-small cell lung cancer patients that were PD-1 failure. Very refractory group, had a median of three prior lines, so we're a fourth line, in addition to that EGFR wild type.
But, I think can't underestimate the fact that, these are AXL-positive patients, so that AXL is a very poor prognostic indicator, very refractory patients, and so we're quite pleased with that result. The other quite interesting thing we saw was that we saw responses at 1% TmPS score, target membrane percent score, meaning maybe one out of 100 patients are expressing detectable AXL by an immunohistochemical assay. And so this suggests that our drug will be active below 1%. So we've now, we are running, an expanded study, where we're looking at target agnostic. And our...
When you combine this with our recent data on ROR2, and you recognize the vast majority of ADCs do not use a biomarker, we actually are now forecasting we won't require a target for AXL going forward. So we're gonna bring data to that point, but I think nonetheless, that's where we think we're headed. And the advantage of that, of course, is you're increasing the patient population opportunity, potentially up to threefold. You don't have to require patients to do a biopsy, which is an advantage, which was slowing down our earlier studies. And of course, the recruitment is just gonna go much more rapid, and so we expect that to be a nice path.
The other thing I should mention, on the fourth of December, we have verbal feedback from the FDA, and once we have the written feedback, which we expect at any time, we'll be updating that so people have a sense of what the FDA has, what our discussions with the FDA on how to go forward. And so the two things kind of want to get out there is, the FDA communication and of course, a relatively near timeframe, close timeframe. We'll also be talking about the target agnostic opportunity and that data.
Terrific. And you mentioned this, 33% ORR at IASLC. Do we expect a meaningful durability of response?
We feel like if you, when you think about durability in either PFS or DOR, I mean, I think, you know, you wanna be above four months and be. But we have patients ongoing, so this is a moving number for us, and so it's still going on. We'll give you a sense of where we're at in December, but I don't think it'll be the last number, so I'm very encouraged so far.
Is this a 33% ORR achieved at all AXL levels or they actually have a threshold?
I think in general, we're not seeing a correlation with AXL expression and ORR response, which is a classic kind of evidence that, you know, there's much... You know, think about AXL, what it really is. It's a way for a tumor to gain resistance and escape, and it's a tumor driver. So, AXL's probably operating at relatively low percentage levels and being quite a bit of a driver. And so, we think this AXL positive group we've looked at is extraordinarily difficult to treat, and we're very pleased with what we've seen. But we think we're gonna see responses at below the 1% level and... But I think in general, that's where we see it headed.
Great. Could you also comment on the tolerability profile in non-small cell lung cancer? What is the Grade three AE, and also, AXL ADC has shown from other programs, actually high on peripheral neuropathy-
Mm-hmm.
What do you see about 3011?
Yeah, I mean, I think it's a great question for our Chief Medical Officer, Eric Sievers, if he could just step in here for a few moments and handle that.
Thank you, Kelly. So, specifically, your question was the grade 3 rate? That we're seeing, we see a 6.8% rate of transient reversible hepatic transaminase elevations. That's the highest of all. All of the remaining grade 3 events are in the one and two range. So it's exceptionally well tolerated, and we think that's consistent with the CAB technology. You also asked a question about the Genmab data, where they reported a 38% rate of peripheral neuropathy, and our rate has been running around 18%, so roughly half of that. So thank you.
Terrific. And, switching the topic to ROR2-targeting 3021 program. And, can you give the investor a brief background on this target, why you chose it, and where you are with the program?
Yeah. So we picked it first off, it was a, it's a novel kind of receptor. At the time we selected it, we were fairly early on in this. It's a non-canonical Wnt5a receptor. It's associated with poor survival in patients across a multitude of different indications. And so that's really kind of the basis. It's a tyrosine kinase receptor as well. And so there are others trying to follow, but they're all preclinical at this point, and us and we're in phase II with that. We're very excited about the early data we're seeing in melanoma, which is very convincing, and we'll see where head and neck goes, relatively quickly. But hopefully, it gives you a snapshot of why we chose it, and it's an ADC as well, of course.
Terrific. And you showed a very deep response in multiply refractory melanoma patients.
Yeah.
Could you provide an update on the current enrollment on the trial after you changed to a new biopsy assay?
Yeah. Well, earlier you may recall, we had about five to, you know, up to 10% positivity rate. I think 7% might have been the last one we reported. And so it was going quite slow. So this certainly incentivized us to say: Well, you know, a lot of ADCs aren't requiring biomarkers. Why don't we open this up so that we can get some patients in here? And because we had two out of two responses in the early on, and so when we did that, we were able to bring in—we just opened it up for independent of the target expression, target agnostic. And from the first eight patients, which we reported out on November 7th, we had four responses then going, including phase I. There was one from phase I.
So we have four out of eight, which is substantial, two additional ones that are stable, and then only two progressors. Two of those responses are ROR2 negative by the immunohistochemical assay, which I already referred to, and why I think AXL may also head the same direction. So in general, that's quite good. Our bar is around 25% ORR. So you could bring in another eight patients without any responses, and you'd still be in the game. So this is significant, and keeping patients on here matters. So, we're quite enthusiastic about what ROR2 can bring across the line, just like AXL and I. But it's off to a very good start, and two out of two responses in head and neck cancer as well. Different dose between those two, but nonetheless, quite interesting, and we'll...
We have fully recruited the targeted 20 patients for melanoma. We will complete the recruitment of the 20 head and neck patients in head and neck before year-end. It's well on its way. That's the advantage of just not having to do biopsies to recruit, and you get there very quickly, and that's already true for our CTLA-4 and also our EpCAM, which is so highly expressed that you don't need to have a biomarker. So across the board, it's a big advantage that we've been fighting early on, that I think just really opens things up to transition quite quickly now.
Great. When do we expect the next data in melanoma and head and neck?
Very soon, but we haven't yet made that determination. But obviously, certainly, we will have opportunity for a first scan for all 20 patients in melanoma before year-end. And we'll have a, you know, a number of additional head and neck patients, as well, so you won't have to wait long.
What do you think about the bar there, given there's a cell therapy, TCR and CAR- T, TCR bispecific all like-
For the which one? The head and neck-
Melanoma.
Oh, melanoma?
Yeah.
No, we think it's still 25% in these refractory patients because you really just don't have anything. I mean, there are some interesting therapies that are working, not at 25% level, but they're kind of complicated, and they're very expensive to operate and time-consuming. So, you know, it's wonderful that they're working, but I think 25% with a drug like a CAB antibody, ADC, is a very straightforward therapy that could really make quite a dent, and I'm hoping we do better than 25%. I'm just saying that's where the line is.
Do you have a ROR2 level screening in that program?
Well, retrospective, we are looking at ROR2 status afterwards, just for our own education, but we don't see it as the way to go forward. We see going forward as a target agnostic. You take all patients that have melanoma, that are refractory. Likewise, and we're hopeful that's what's gonna happen in non-small cell lung cancer with AXL as well.
And a combination with nivo. Curious what kind of toxicity profile have you observed for the combination so far?
We're gonna have a very detailed discussion on this on December 13th at our R&D Day. But we're quite encouraged. I mean, you know, the goal here is to equal and even more interesting, increase efficacy while reducing severe immune-related adverse events like colitis. And if we can solve that, so we can keep people on therapy and potentially keep them on therapy at a higher dose, where we're driving more better outcomes, that's really what we're driving for, and we're very, we're very encouraged about this, this molecule. And of course, this will be the first time we talk about the data in December, and we'll save all of that for then. We have put our first patient in on the phase II study, so we're rolling on that as well. And so...
And that's gonna recruit quickly just for the similar reasons.
What is the longest follow-up time in the combo cohort? So basically, the question is, you know, to comparing the contrast with usual is in combo, I think, it can only go for four doses.
Yeah, they have about four cycles, approximately four months, sometimes three months. When it's at, like, a 3 mg per kilogram dose in combination with PD-1, you just really can't get past that. Obviously, we're past that for some of our work, and we wanna talk about it. And we think that this is one of those molecules that has a huge breadth of application because it revitalizes T- cells. And you know, PD-1 is powerful, but it's incremental in a way because it's just releasing the ones that are there. But if you can bring new T- cells in, and you can drive that, and you can do it safely, I think there's. I mean, you can ask the question, why hasn't anyone ever used a CTLA-4 with an ADC? You know, maybe it's too toxic.
But maybe even if you conquer that, what happens? So these are the kinds of things we want to think about, we want to talk about, and we look forward to doing it in December.
How much you can share results on the upcoming program?
Marching upward and, obviously, a T-cell engager like this has a quite unique and interesting profile because you have—it's a dual CAB. You have a CAB on the EpCAM tumor targeting arm, and you have a CAB on the CD3 T-cell activating arm. And so that gives you the select combined product of those selectivities. So if you have 10-fold on one arm, you got 10-fold on the other arm, you get a 100-fold. So that's really unique out there and, and, and unusual, and we—I have high hopes for that molecule, and it's a little too early to talk much more about it, except to say we're excited and we really love the preclinical data.
Any, probably the indications for EpCAM?
Well, I think colorectal cancer, any adenocarcinoma, this is a really high unmet need, really challenging and, we're there, and there's many others as well, but I think that's a really key one if we can key in on that, would be really beneficial to a lot of patients.
Last question. Since your earnings call, you touched upon the topic of collaboration.
Yep.
Could you actually add more color on what type of a partner you're looking for and which program?
Yeah. No question that we're looking for a partner that can accelerate our clinical trials and can expand where we can go, maybe take us into first line much sooner than we could go by ourselves. And we believe that it will happen in one of our three programs. We're not guiding on which one, but I think that each of them have that capability and excitement to potentially drive a very good collaboration. We could, we would consider a regional deal, but also, as long as we're participating well in North America, we'll keep an eye on that, and we're very hopeful that we can find partners that can help us do that.
We'll wrap up our session here, and thanks again for spending time with us and a great discussion.