BioAtla, Inc. (BCAB) Earnings Call Transcript & Summary

Good morning, and welcome to the BioAtla Virtual R&D Day. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the BioAtla website following the conclusion of the event. I'd now like to turn the call over to Jay Short, Chairman, Chief Executive Officer and Co-Founder of BioAtla. Please go ahead, Jay.

Thank you, Tara. Welcome to our BA3071 CAB-CTLA-4 R&D event. Before I begin our presentation, I would like to direct your attention to our safe harbor statement on the next slide. This statement outlines important notices and disclaimers related to today's presentation since we are making some forward-looking statements throughout our presentation and Q&A session. This statement and today's presentation are also posted on our website for your reference. So we can go on to the next slide, and I'll start with the agenda. I will start with some opening remarks about the company, and then I would present a bit on our CAB technology and then I will transition into a discussion of some preclinical data highlights before we move on into the clinical session. And we will have speakers on the clinical data that will include Dr. Hamid as well as our Chief Medical Officer, Dr. Eric Sievers. So with that, I'd like to begin on the next slide, describing a bit of the company. Our company has a proprietary technology referred to as conditionally active biologics, which is focused on addressing high unmet needs in solid tumors, which represents over 90% of all tumor types. The technology is designed to widen the therapeutic window by reducing binding to targets on normal cells. We currently have 3 Phase 2 stage assets, 2 of those are ADCs. We also have an immuno-oncology drug, CAB CTLA-4, which we'll be discussing later today. And then in addition, we have a Phase 1 dual CAB bispecific T-cell engager. We are also advancing a potentially registrational trial in UPS. Because of the broad applicability of our CAB platform, we have a diversified portfolio addressing multiple indications, and we have several upcoming readouts, not only today's data, but as well as several other readouts expected in the first half of next year. So given the breadth and the depth of this later-stage clinical portfolio, we are also pursuing some strategic collaboration discussions. The company has a strong cash position with over $141 million at the end of third quarter and is sufficient capital to carry the company into the second half of 2025. So now this shows you on this slide our pipeline. It shows the key indications that we're currently targeting for each of the assets as well as the approximate stage of development for each of these with the CTLA-4 now having kicked off in Phase 2, which we announced in November at our Q3 earnings call. So now I would like to then discuss a bit on our CAB technology. The technology is based on some novel discoveries made by our scientists at BioAtla. What we discovered was a series of naturally occurring negatively charged small molecules in all of us. It's in our bodies. And what these negatively charged small molecules do is that they will attach to the positive charges on essentially all proteins within the body. And these are protecting sites from inappropriate interaction. What was interesting though is that when you look at a cancer cell, they're acidic. And the reason they're acidic is because they're always dividing and duplicating their lipid membrane, the nucleic acids and their enzymes. And that -- those precursor molecules are largely derived from glycolysis. And the last step of that glycolysis is lactic acid generation, which must be secreted from the cell. So the outside environment of a cancer cell is acidic. And so that acidic nature of those cancer cells, you see the release of [ hydrogen ICE ] which neutralize and pull off those negative charge protective molecules that are on proteins. But this -- what this does, though, is it unveils novel epitopes on targets that are only visible in the -- on cancer cells, if those same targets on normal cells are still protected by those small molecules. And so this allows us to make antibodies, which we refer to as CAB antibodies directed at those epitopes, they're reversible antibodies, meaning that when our antibodies are in the cancer or tumor microenvironment, they can attack those particular epitopes. But when those antibodies circulate out of that tumor microenvironment, they no longer have epitopes available to them to attack. And then when they recirculate back into the tumor, they can then once again attack. So this means that our antibodies can be human antibodies or very human like because we're making our changes in these antibodies only in the CDR or hypervariable region of the antibody and they're not projects, there's no requirement for masking of those antibodies. There's no requirement for enzymatic activation. So this makes them exquisitely selective and a very powerful system that allows us to increase the potential efficacy and safety of those molecules. So now with that kind of general background, I'd like to share with you some relevant preclinical data on the CAB-CTLA-4 antibody, but first just give you a comparison to traditional CTLA-4 antibodies. If we look on the left-hand side, these CTLA-4 antibodies are very powerful at blocking or binding to CTLA-4, which allows activation and increase of T-cells and also reduction of Treg cells. The challenge is as though is that traditional CTLA-4 antibodies can't tell or distinguish whether that target is on a tumor cell or whether it's on a normal cell. So what you end up with is a systemic activation of that system. And so that has the risk of leading to severe immune-related adverse events. In contrast, the CAB antibodies show on the right-hand side is only able to attack those -- or bind to those targets in the tumor microenvironment, thereby reducing that systemic activation and thereby minimizing those potential immune-related adverse events. So now let's show a bit of the preclinical data, I mentioned related to the CTLA-4, and I want to start with this on the left-hand side of the panel, where we're looking at the pH, the binding capability of the CAB-CTLA-4 antibody related to the pH. If we look at blood pH, it's essentially always 7.4. But if you -- a lot of normal tissues actually could even be more alkaline than blood pH. So our goal there is to reduce that mining under those mildly alkaline conditions, while maintaining binding of the pH against cancer cells and their pH typically ranges from pH as low as 5.8 up to 6.7. This one other unique aspect of this CAB-CTLA-4 is that different than, let's say, our other CAB antibodies is that, we designed this to have higher activity at pH 7.0 or 6.9 than we typically do because the idea here is to maintain some activity in inflamed lymph nodes, which could have -- which do have some mild acidity when they're inflamed. The idea there being able to assist in recruiting T-cells. So if we then test this CAB antibody for its ability to kill a tumor in a mouse, a very well-characterized mouse knock-in model MC38 tumor, you can see in the pink line there that we get full tumor regression relative to the IgG control in this study. And so despite the fact that we have reduced the binding in these alkaline and normal environments, we have a very strong tumor regression. And this is approximately -- this dose amount is approximately equivalent to about 1 milligram per kilogram of a human dose, just to give you some sense of that. Well, what you can do is then take this animal model, this mouse model, and you can actually look at what's happening with the T-cells, which is outlined on this slide. And if we look in the left-hand set of bars, we're looking under tumor conditions and the right-hand set of bars is looking under normal tissue or blood conditions. The blue bar is an IgG isotype control, whereas the green bar is the Ipilimumab analog and the pink or red bar is the CAB antibody. And so we look at CD8 T-cell -- killer T cells, we're seeing very strong induction of those cells with both Ipi and CAB and we see that the bar is slightly higher on the CAB, but that's not statistically different from Ipi, they both work very effectively there. And you can also look at the CD8 and Treg ratio because we're not only increasing these T-cells, we're also reducing the Tregs. And once again, you see a very strong activity from both the analog and the CAB, not statistically different here either, but both working quite effectively relative to untreated animals shown on the blue bar. Interestingly, and very importantly, if you look at the normal tissues, what you see is, this is an area where you don't want to be activating T-cells because it can contribute to the immune-related adverse events. And you can see Ipi is still working in those areas that you really don't want to be working in, whereas the CAB is much closer, really identical statistically to the IgG controller untreated animals in this normal tissue and blood. So very powerful. So we can actually then -- and actually, this tumor activity, the tumor regression on the prior slide is consistent with this increase in CD8 cells. And also now I want to look a little bit deeper on the adverse events by looking in a well-characterized non-human primate model outlined on the next slide. And this is a relatively large non-human primate model data, going from days 1 to 29 and we're looking at a clinically relevant GI toxicity. And the top group here is a vehicle control and the next group down is the nivo plus Ipi and we're using significant doses here. It's approximately the altimetric scaling if we convert about 14.6 mgs/kg of nivo and about 11 mgs/kg of Ipi, same doses were used with nivo plus our CAB BA3071. And it's very striking the difference. We're seeing a lot of GI-related symptoms with the nivo/Ipi and simply by replacing the Ipi analog with CAB BA3071. We essentially removed the vast majority of those GI symptoms. So very striking difference where -- because of the CAB technology. And while at the same time, we've maintained that tumor killing capability. So this is kind of a background on the preclinical data is something to kind of hopefully inform as we move to the clinical data. But -- so to begin this section, we are honored to have one of the world's leading experts in advancing immuno-oncology into the clinic for patients' benefits, Dr. Omid Hamid. He is the Chief of Translational Research and Immunotherapy and Director of Melanoma Therapeutics at the renowned Angeles Clinic and Research Institute. Without further delay, I would like to hand this presentation over to Dr. Hamid. Dr. Hamid, please.

Thank you very much for that lovely introduction and the ability to present some of the preliminary information on this conditional binding anti-CTLA-4 antibody. In terms of background, we understand that there is this idea of higher dosage of anti-CTLA-4 blockade improving survival, but limiting -- being limited by toxicity. So as you look here to the left, this is a blinded -- double-blinded randomized study of the 10 milligram per kilogram versus 3 milligram per kilogram ipilimumab dosing. And you can see here a tail of the curve and a significant difference between the 10 milligram dose and the 3 milligram per kilogram dose of ipilimumab. We have also understood that in combination, the anti-CTLA-4 dosing is limiting because of toxicity. Here you see to the right, the safety that as you increase, you get greater Grade 3 or 4 adverse events, treatment-related adverse events and AEs leading to treatment discontinuation, but that's been similar in PD-1 CTLA-4 combinations where you get Grade 3, 4 toxicities around 50% and significant discontinuation rates. So our goals and drug development have been to find a drug that can give us similar benefits that can be dosed higher and can give us less toxicity. This is our Phase 1 dose escalation schema with the key objectives of the Phase 2 dose and MTD and PK. You can see the key eligibility criteria being CTLA-4 naive, treatment refractory to standard therapeutics and the subsets of patients that are seen here. These are historically immune active tumors where anti-PD-1 therapy is approved. Here, you see the schema to the right, where we start with 7 milligram dose and are accruing up to 700 milligrams. As you can see, we are now at the 350 milligram dose, which is equivalent to 5 mgs per kilogram, just higher than the approved dose of anti-CTLA-4 therapy with ipilimumab going up to the 700 milligram and even to 1,000 upcoming. All patients were treated Cycle 1 with single-agent drug and then the introduction of nivolumab at 240 milligrams each cycle every 3 weeks going forward. Of note, this 240 milligrams nivolumab dose is higher than the 1 milligram per kilogram dose in the standard anti-CTLA-4 anti-PD-1 with Opdivo -- I'm sorry, with nivolumab and ipilimumab. Here are the patient demographics. And you can see here, the median age, 65, significant ECOG status is 0 and 1 broken about 50-50, but heavily pre-treated patients with the majority of our patients, 3 or more and the highest with 7 lines of therapy. So the median, at least 3 prior lines of therapy here. Here the demographics of the tumor types broken down. We have currently treated 18 patients with 16 evaluable at this point. I bring your attention to the prior number of therapies significant as we'll present some data on our cervical patients who had 3 lines of therapy, gastric patients 4 to 6, our lung cancer patients, 3 or more, and all had seen what is a standard and more chemotherapies, anti-PD-1s, TKIs and ADCs and the urothelial. So these are not trivial patients, these are patients that we see at our Phase 1 clinic all the time without significant options. And these are ones where a drug that can give response with manageable toxicities is important. So as we move on to the discussion of the treatment of -- the treatment-emergent adverse events seen, it's important to note here that as we've gone up to the 700 milligram doses, no Grade 4 or 5 treatment-emergent adverse events have been seen and the MTD has not been reached moving forward. There are only 2 related Grade 3 events observed and 4 related serious adverse events that have happened throughout therapy. Again, no DLT at this point, no AEs leading to death and 1 dose-limiting toxicity so far, and we'll talk a little bit more about that 700 milligram cohort upcoming. Here are the adverse events of special interest as we move forward here. GI, hepato, pulmonary and endocrine toxicity we're seeing. But only 2 cases were noted to be immune related and we have brought them out here in the red. There is a Grade 3 diarrhea, which occurred 4 months while on study on a patient with cervical cancer, which we'll discuss upcoming, of those ipi showed no colitis. The patient was ultimately treated with steroids with resolution. And then a diabetic ketoacidosis that was diagnosed and treated appropriately in our patients with non-small cell lung cancer dosed at the higher dose of 700 milligrams, again, during Cycle 1. And as we take all of these together on our 18 patients that were treated, only 2 patients here are having immune-related adverse events observed amongst the 18 treated patients, and that's a significant benefit of 11% if this falls true. We are hitting what our goals have been to bring a anti-CTLA-4 therapy with a decreased incidence of Grade 3 or 4 immune-related adverse events. Again, along with these -- the benefits in less toxicity, we'd want to see some early evidence of benefit. And here you see the spider plots on our patients who are evaluable and interestingly confirmed responses in 2 patients here, heavily pre-treated gastroesophageal and cervical cancer and stable disease amongst 9 patients of the 16 evaluable. And as you know, this is a hallmark of immunotherapy that benefit can come from stability, partial and complete responses and we are seeing this here. Not only do we see responses, we see responses that bind to our traditional beliefs in how the kinetics should be with immunotherapy, we see rapid responses, we see some deep responses, but the hallmark here of durable responses, which put immunotherapy in a different class from targeted and chemotherapeutics. At our dose where we believe that this is the beginning of efficacy, we're seeing minimal clinical benefit in the 350 milligram combination with PD-1 cohort in patients who are heavily pre-treated. And as you can see here, these are confirmed partial and complete responses in our gastroesophageal and cervical cancer patients. Our gastroesophageal cancer patients of note had FOLFOX with an anti-PD-1 therapy, paclitaxel ramucirumab and anti-CD3 bispecific antibody clinical trial. So going through standard therapies on our cervical cancer patient, again, standard paclitaxel carboplatin, bevacizumab and also an anti-PD-1 pembrolizumab. These are patients that I see clinically that come in that not only require something that has the benefit of a response, but we need durability and we're beginning to see that picture if it's worth a thousand words as they say. So I mean -- and my point, we're just showing you the gastroesophageal and cervical cancer patients. Here's a confirmed partial response in gastroesophageal cancer patient. Of note, this is a HER2 negative patient with limited options going through all standard therapies. And you can see on the left, the baseline scan with pulmonary metastases, and then on treatments in October of this year continuing to benefit. And then the last patient who's a patient that familiar with here. And this is the confirmed complete response cervical cancer patient, young female, HPV positive post-platinum, taxane, anti-PD-1 and anti-VEGF with multiple stations and enlarged lymph nodes, biopsy positive for disease and now continuing to have a complete response while post therapy. And again, another indication of treatment with anti-CTLA-4 CAB here [indiscernible] response and then patients who has come off of therapy, continuing to have response and benefit, again, correlating with what we have seen with anti-CTLA-4 therapy historically.

Thank you, Dr. Hamid. I really appreciate your summary of the clinical experience of BA3071 thus far on trial. I'm Eric Sievers, Chief Medical Officer at BioAtla and I'll summarize the dose titration that's ongoing. As you mentioned earlier, we've treated patients up to the dose of 700 milligrams given every 3 weeks, first as a monotherapy dose and then in combination with nivolumab. And I want to emphasize this is a 10 milligram per kilogram at the equivalent dose. We treated 3 patients at this top dose of 700 milligram, all of these patients had considerable prior treatments as you've summarized previously. And we've observed Grade 1 fevers and chills in each of these patients occurring within the first 24 hours after receipt of the 3071 infusion. And 2 of the 3 patients also developed transient Grade 2 hypoxemia as well. In one of these cases, the patient that developed atrial fibrillation of new onset, this was viewed as a dose-limiting toxicity. And so we will be adding additional patients to the 700 milligram level to further characterize safety and efficacy of the higher doses here and we'll be doing it with prophylactic tocilizumab, notably, the 78-year-old renal cell carcinoma patient who had developed fevers and chills with the first 2 cycles. They received prophylactic tocilizumab with Cycle 4 and have continued that approach now after 6 cycles, tolerating continued therapy quite well with an overall response of stable disease. This is the continuation of the Phase 1 trial. It's a Phase 1/2 trial, where we're looking at both monotherapy as well as combination therapy with a PD-1 blockade. And this is currently underway. So we're enrolling both of these broad cohorts. If we look at the top, it's the monotherapy strategy where we're looking at highly treatment refractory patients with melanoma and advanced carcinomas, where we're taking the first of potentially several Phase 2 doses of 350 milligrams as a monotherapy and evaluating our path to a potential accelerated approval given the high unmet need population. We're also further characterizing the safety and efficacy of this, anticipating about 30 patients in this over the next several months and then ultimately adding in a higher dose of 700 or gram every 3 weeks as tolerated. Moving now to the combination regimen with PD-1, we're planning to enroll patients that are treatment naive, frontline patients with melanoma, non-small cell lung cancer of 350 milligrams of the 3071 with PD-1 and then potentially a higher dose as noted above. And this will inform our path to pivotal randomized controlled study for full approval. So taken together, you've heard Jay's summary of the technology and then Dr. Hamid has nicely provided a clinical summary of the 18 patients. We're seeing a promising efficacy signal with durable responses, confirmed CR, confirmed partial response in multiple patients with prolonged disease control and emerging differentiated safety profile, 2 of 18 patients that have had immune-related adverse events and we're exploring higher dose levels. And as I described in Phase 2 study that's designed to both evaluate the potential for an accelerated approval in the near-term and a confirmatory full approval in patients that have frontline melanoma and potentially lung cancer as well. And I'd like to now turn it over to Tara for a question-and-answer. Thank you.

[Operator Instructions] So our first question comes from Kaveri Pohlman at BTIG.

Thanks for the updates and congrats on the results. Dr. Hamid, can you tell us what was the time to response for these patients? And how would you compare it to ipi monotherapy or ipi/nivo combination?

Yes. So it's a great question about time to response in comparison. I would say that you're seeing that some of those patients who have early response. Remember, we're introducing the anti-CTL -- the anti-PD-1 3 weeks later. So you may see a little bit of a delay in the response. Remember, these are heavily pre-treated patients who have seen anti-PD-1. So the response kinetics that we're seeing here are consistent with what we've seen. Some patients had a quick response, you're seeing a couple of months in on the gastric and the cervical and some are having a stability and moving forward. It's hard to evaluate when you try to put this up against what we've seen with the ipi/nivo in the first line because these are heavily pre-treated patients, and they've already seen anti-PD-1. But when you look at it in comparison to what we've seen in second line ipi/nivo, it's fashion similarly. I mean, these doses are higher than what we've used before. And then second line of ipi/nivo in other solid tumors is rarely utilized. So I'm very pleased with what we're seeing. Clearly, what we want is clinical benefit, which we're seeing in a significant proportion of our patients in the higher dosage, tolerability and the combination moving forward.

And then I guess -- and my second question is kind of along the similar lines. For cervical cancer and gastroesophageal cancer patients, can you tell us what prior treatment option they receive? And what was the duration between them getting off the previous therapy in starting the 3071 also the PD-L1 expression status? And does that PD-L1 expression matters here since all these patients are PD-1 experienced?

Right. So I don't have that. I can tell you the treatments that they've had before. So the cervical cancer patients had platinum taxane, anti-PD-1 and an anti-VEGF therapy. And then the gastric cancer patients had HER2 negative, so had not seen a HER blocking antibody but had FOLFOX PD1, a taxane TKI and anti-VEGF therapy. So -- and also on anti-CD3 bispecific antibody clinical trial. At this point, we do not have and if someone else has that, feel free to share that, the PD-1 status and the duration and time of response to prior therapies. What I will say to you is that what we see in the combination with anti-CTLA-4 and anti-PD-1 is less of a dependence on the PD-1 staining that comes from the data from the melanoma experience, that where we look to treat PD-L1 negative patients with a combination. I'll also tell you that these are tumors that don't have a high response to single agent PD-1. And those are the situations where a combination is indicated. So this is an important combination for our patients that have those tumors that are not very responsive or don't have a durable response to just single agent PD-1.

And then maybe last one. There were some data presented from conditionally activated CTLA-4-targeting antibodies last week. Can you tell us how 3071 could be different here? Are there any supporting data for lymph node activity? And what are your thoughts on antibodies with Fc-enhanced feature?

So I think I've kind of touched on some of this already in terms of the fact that prodrug was what you're referring to. And I know sometimes for people the language of conditionally activated versus our language of conditionally active, because ours don't need to be activated. I think that this strategy where you don't require this activation, the fact that it never once a prodrug is cleaved, they can go circulate out and attack target or bind to target systemically in normal tissue. That's something that the CABs really don't do and that can widen that therapeutic window. So that's, I think, a very important component. I think that given the encouraging data we've seen both on the efficacy side and also on the tox profile, I'm very encouraged that we have a very strong position here. I don't know, Eric, if you would add anything to that further with respect to Kaveri's question.

As we've talked before, there are 2 broad approaches, the Fc modifications and then approaches like Jay has just described where we try to limit the CTLA-4 blockade to the tumor and microenvironment, thus, ideally avoiding normal tissue activation and injury. And so I think that our data that we've released today suggest meaningful clinical benefit and an acceptable toxicity profile is in keeping and certainly highly competitive with the other agents that you've described.

I would add, I don't see how -- even though our agent is active from an ADCC Fc activity standpoint. I don't see how that particular feature in our antibody or anyone else's antibody is going to widen the therapeutic window. The therapeutic window needs something like our CAB technology that differentiates between that normal tissue and tumor tissue.

So our next question comes from Kelly Shi at Jefferies.

Firstly, maybe I missed that information, but have you disclosed what is the average treatment duration of CTLA-4 in the combo? I mean, I understand it's still early, but just curious if you can share more color on that.

Thank you, Kelly, for the question. We don't have a summarized average duration of patients. But from the spider plot on the Slide 20, I think you can get a sense of the duration of treatment of these patients on study. The small cell lung cancer patient is now over 1 year of continued treatment. The 2 cutaneous melanoma patients are out at 35, 40 weeks of treatment. And so these cycles are given every 3 weeks and uveal melanoma patient that's in the range of 25 weeks, in addition to the 2 responding patients that Dr. Hamid summarized.

So can I make an assumption that as long as you saw response, so there are more than 4 cycles of CTLA-4 has been dosed 2 patients in the combo arm -- cohort?

Yes. And I think you raised a really important point. So with ipilimumab that it is often limited to 4 cycles, given every 3 weeks when it's given in the 3 milligram per kilogram dosing and then the alternative regimen of 1 mg per kg can be given ongoing, but we employed a strategy of continuing the dose of the CTLA-4 blockade unless there was unacceptable toxicity or progression. Perhaps I might ask Dr. Hamid to comment a bit about the limitations of ipi dosing in the clinic over time.

Yes. When we start to discuss this idea about the toxicity coming up with anti-CTLA-4/anti-PD-1 combinations, clearly, what's lost is the evidence that we have that despite toxicity and discontinuation that clinical benefit remains. We've seen that in the initial CheckMate 67 studies where patients who had a response and came off with toxicity, a significant proportion continue to benefit without further therapy. So for me, my [indiscernible] on anti-CTLA-4 therapy is higher doses can give benefit. We need to continue to try and refine that approach is what we're doing with this CAB. And then when toxicity occurs, the ability to understand, identify and treat the toxicity so that the patients continue to have benefit is important. Otherwise, the idea of only [ 4 doses ] is one that is -- that has come and become standard from the initial studies with single-agent [indiscernible] which became ipilimumab. And there never has been an identification of a certain number of doses that you clearly need and to discontinue on toxicity is fair. It's an approach that makes sense if you have the belief that you have stimulated the immune system, which creates response and durability of response without the requirement of new dosing.

I also have a follow-up. So for the Phase 2, do you plan to enroll patients with a similar or slightly better patient baseline characteristics? And also given the activities you have seen across different cohorts and also competitive landscape, could you share your thoughts regarding the -- I mean, how to prioritize indication selection moving forward? It could be too early to ask but curious on thoughts.

I'm happy to take that, Kelly. So you asked 2 questions and for I think embedded in that question is the acknowledgment that, as Dr. Hamid showed, this is a heavily pre-treated population of patients that have experienced really most available therapies, and so it's very challenging. And so we will be taking and accepting and enrolling patients that have treatment refractory cancers. We are also now allowing patients to have received prior CTLA-4 blockade as well. And so I think that we would anticipate that for the monotherapy strategy that you see in this slide that we would probably taking a very similar population that has been enrolled on the study to date. And Kelly, can you speak to the second question again in the context of this slide?

Sure. I'm just asking like given the activities have shown from Phase 1 and also competitive landscape, what are your thoughts regarding like how to prioritize indication selection moving forward?

Yes. It's really a matter of a considerable conversation within our company and with investigators acknowledging, as Dr. Hamid has shown us that the CTLA-4 blockade has been around for 1/4 of a century and has clearly established its ability to prolong survival, so we're taking a mechanism that is well established and then moving into indications where there's considerable unmet need. So as this slide illustrates, there's a potential for patients that have had treatment refractory melanoma for a potential accelerated approval among patients that have a variety of carcinomas, it's conceivable that there might be an accelerated approval pathway here as well. It is notable that other sponsors have targeted the MSI colorectal cancer possibility where CTLA-4 blockade is showing to have promise. That is another possibility. I think I really want to emphasize, though, that with a better tolerated CTLA-4, if that's the case, we believe that a treatment-naive frontline melanoma population would be very appropriate in starting a randomized trial there once we've informed that path with roughly 20 to 40 patients treated in combination in the frontline setting. Jay, do you want to add anything to that?

No. I think certainly, the things that I was thinking about is that, I believe we're seeing some early data, but important data suggesting that our tolerability here is high and we have the potential to -- and I think it's coming along with efficacy. So I'm very encouraged by what we're seeing. And I think that's the way I think about the competitive landscape that we can -- we have quite a high potential for a differentiated asset.

If I could just interject here and say one thing, which is just my belief here, if you look at the regimens that are being utilized in other solid tumors, aside from melanoma, they are every 6-week dosages at 1 mg per kilogram of anti-CTLA-4 therapy. And we are way past that year, showing tolerability. If the belief here is that stimulating checkpoint optimally can lead to better response and durability of response and ultimately, hopefully, patient benefit. This is the pathway to take forward, and this is the pathway that you're seeing in drug development, where there are trials that are now looking at triplets and quadruplets and other things, the limitation has been toxicity. And this regimen is showing that we can move higher treats at higher doses and possibly have a better combination, a better CTLA-4 to use in those combinations. So it's early, but this developmental plan is right on the same tracks as where the field is going, specifically in checkpoint inhibitor development in the setting of other checkpoints coming in to the fray, optimizing the benefits you get from CTLA-4 is the tantamount.

Our next question comes from Brian Cheng from JPMorgan.

Congrats on the progress. Maybe our first question is for Dr. Hamid. I'm just curious if you can give us some color on how you think about the efficacy compared to what you see with ipi alone or nivo/ipi combo in the target indication in terms of efficacy? Are there any signs that you see today based on the data set that 3071 maybe differentiating this early on in the clinic, any particular signs within the clinical practice that you are seeing that makes 3071 a differentiator in the space today?

The easy answer to your question is that the lack of significant Grade 3, 4 toxicity is a good sign here. And what you see in the spider plots on the 350 milligram dosage. Those are the indicators for me to continue to support enrollment into the study and move it forward.

Okay. And maybe this is for Jay. Can you give us some color on where you think the bar would be for you to pick either the monotherapy or combination for -- to the pivotal stage melanoma and NSCLC, what will make you decide to proceed [indiscernible] at the monotherapy versus combination?

Well, I think I'm going to allow Eric to touch on this. I mean, I think also we can later have more -- we'll have more comments on this actually at your conference early next year. But I think that we -- I anticipate seeing and certainly what I'm hoping to see -- continue to see something stronger and more efficacious than ipi. We also want to see -- continue to see the differentiated safety profile that we're seeing because I think fundamentally, we believe that keeping patients on longer being able to continue to treat them as a very important component. And -- but I'll stop short of actually giving you a percentage because I think there are a number of accelerated paths and each of those paths have different bars in terms of what would be required. Obviously, first line, you're really expecting to see quite strong results there. But I think this -- this drug candidate has that potential power built into it. Eric, do you want to further add to that?

It's a really great question. And I want to emphasize this is an and strategy, not an or strategy. We have every intention of developing a monotherapy strategy for accelerated approval and the combination strategy for frontline melanoma for sure, as a randomized controlled study. And so just some examples in monotherapy where I think there could be opportunities for accelerated approval. We mentioned that patients with melanoma who have experienced the prior failure of not only PD-1 blockade, but CTLA-4 blockade represent a marked unmet need and it's very reasonable to apply what we believe is a better tolerated CTLA-4 agent in that setting. That could be a potential strategy. There are other strategies. I think it's important to go back to Dr. Hamid's slide that shows the randomized blinded placebo-controlled, excuse me, not placebo-controlled, but 10 versus 3, 10 mgs per kg of ipi versus 3, that provided some very provocative findings with the long-term survival benefits of higher doses. So -- what I'm saying here is that 350 is an active dose, as you've seen today with the CR and the PR in multiple patients with prolonged stable disease. We believe that higher doses might provide the added benefit and we're prioritizing that exploration as well. So taken together, in summary, there are multiple opportunities for accelerated approval for unmet need melanoma and carcinoma populations and then the treatment-naive frontline melanoma is something I want to emphasize.

But I would just say keeping patients on therapy may be an important other aspect of this, and it is important, both higher and longer.

Okay. And last one, if I may. With AXL and ROR2 in your portfolio, can you talk about how this program potentially fit in your near-term strategy to develop this program forward? How should we think of the [ paid ] and the data update also from this CTLA-4 program near term?

I think, obviously, we're running all of 3 of these studies, the ROR2, the AXL and the CTLA-4, but the ROR2 effectively will be completely enrolled by the end of this month and that's on track for that. So we'll have very interesting readouts in the first half of '24. AXL, we are basically completing just a bit of target agnostic data. We're also finishing out the readout of one of the more frequent dosing regimens, but I think we are quite satisfied with our Q2W dose and basically positioning that for a registrational trial in non-small cell lung cancer. So I would say that, as you know, we have a collaboration, strategic discussions going on. We have readouts across all 3 of our assets. We have said that we're -- we expect to form a significant collaboration with one of these Phase 2 assets. We're not guiding on which one at this point. But we'll -- our goal here is to provide more insight and time lines early next year. It is intriguing when you think about a CTLA-4. I think PD-1 has shown how well it can complement many, many different drugs across the board. CTLA-4 has that same theoretical potential that has really not been able to pull it off at the level that PD-1 has simply because -- largely because of the toxicity. If you could resolve a lot of that toxicity, you have the chance of having a potentially even more powerful agent than PD-1 because PD-1 allows the existing T-cells to be activated. CTLA-4 recruits new T-cells into that environment and as well as assisting T-cell increases there. And so we think the CTLA-4 long-term could be a combination, if it's safe enough with ADCs. It also could be a combination with a number of other agents. So all combined together, this is an exciting portfolio that I think encourages more studies and I think moving to target agnostic allows us to do this rapidly.

Our next question comes from Arthur He from H.C. Wainwright.

Hey, congrats on the encouraging data. Just first question, just quickly, just trying to confirm, so for those patients had a response and stable disease, how many of them are still remain on the study? And is there all those highlight in the Slide 19?

Eric is going to probably answer this one.

Sure. So let's look at this slide. And so the patients you see here that are -- on this slide, the uveal, the small cell cutaneous, cutaneous gastroesophageal, the cervical cancer patient has recently discontinued treatment in CR and remains in CR but discontinued treatment.

I see. So there's no other stable disease patient right now remain on the treatment?

I'm sorry, I should be very clear that the other patients here that you see the uveal as of the last data cut, the uveal, the small cell, cutaneous melanoma, melanoma, gastroesophageal all are on treatment as of the last data cut.

And maybe a question -- I have a question for Dr. Hamid. Doctor, could you give us more color on the [indiscernible] Grade 3 AE in the 700-milligram cohort? What's the -- because I didn't see the -- what's the other serious AE you observed in that cohort?

I'll leave that to Eric, who's spoken directly regarding that cohort.

Let's go to that slide. And so the other patient that had an SAE was the patient with renal cell, they were admitted to the hospital. So this is a 78-year-old gentleman who was admitted for the fevers and chills and the transient hypoxia. And they've just spent an night over the -- in the hospital and then were released the next day. The -- I do want to emphasize we characterize the nuance at atrial fibrillation is in the setting of Grade 1 fevers and chills and the Grade 2 transient hypoxia, and that was reversible.

And maybe for both Jay, Eric and Dr. Hamid, based on current safety and efficacy signal you have seen, what's your thought about taking these into some cold tumor?

Yes. I think we talk about that. I think that's on our list of quite interesting possibility and that's something that CTLA-4 could be quite effective at. So under discussion.

Dr. Hamid, what do you think about cold tumors and the role of a drug like this?

Yes. So I would never go into a cold tumor with only single-agent PD-1 if I had the ability to go into combination. And remember, we've gone into very poorly responsive tumors with CTLA-4 combinations that are 1 milligram per kilogram every 6 weeks. So if it were up to me, and again, I am biased because my career has begun with the development of anti-CTLA-4, moved on to anti-PD-1 and other checkpoints and then to bispecifics, TIL therapies, CAR-T, NK, et cetera. My belief is that if you're going to get benefit in checkpoint, you've got to get -- take your best shot, the first shot you take. And there are multiple strategies to do that, that are running parallel. One is multiple checkpoints together, but it's very naive to move on when you still have a tool that has shown significant benefit, the continuation of benefit even post discontinuation and manageable safety and toxicity without optimizing it. At this time, when the anti-CTLA-4 drug that is approved has less focus on it given non-scientific issues. We need to work to find partners that are willing to take this paradigm forward to help us optimize this checkpoint. And yes, I have no doubt that we should take this in cold tumors.

Eric, you want to add on something?

No, I think that Dr. Hamid and Jay nicely characterized those opportunities. I'm very excited for next steps in that regard.

Our final question comes from Reni Benjamin of JMP Securities.

I apologize, I jumped on a little bit late. So if you've answered these, again, I apologize for that. But maybe just starting off, do we have any PK/PD data that might show where you might be in terms of receptor occupancy at these doses? And I guess where I'm getting at is if the responses don't necessarily improve much more from where they are right now, does the program get shelved or do you decide on maybe doing like a non-inferiority study moving the program forward?

I'll remind you this is a dose escalation study. But the PK is at 350 is very similar to ipi and so we don't think there's a significant difference there. Obviously, when we -- when I showed you that non-human primate data, we were certainly driving receptor occupancy there to make sure that we were being able to compare those 2 drugs effectively. I think you can see both safety -- exceptional safety and efficacy was maintained in that. So we think this is a very -- I think we're in very good shape. And you certainly by going to higher doses with the CTLA-4, which is enabled by this CAB technology, I think if you want to drive those kind of outcomes, this is what you need. I don't know you would be insane to shelve this.

And as we think about the preclinical models, and I know you can't directly kind of translate, but what would the predicted kind of maximum dose be in humans for going higher than the 350 and potentially the 700?

Well, I think the -- I think some of the data suggest that you're getting very close around the 10 and certainly by the 14.2 mgs per kg that we would love to -- we're going to see if we can explore here in the near future, 1 gram. I think that you're in great shape up there. I think that's -- and I think at 5 mgs per kg, you've already moved to a very important space, very powerful. So in general, anything above the 1 mg per kg world and the rarely -- the more rarely used 3 mgs per kg, I mean, I think you're really pushing the envelope here in a nice way, what you need to do.

And if you -- just maybe on the AEs, I think you highlighted correct me if I'm wrong, 2 immune-related AEs, right, the diarrhea and diabetic ketoacidosis. I guess, how do you determine if something like diabetic ketoacidosis is immune related? And I guess, the second question, maybe Dr. Hamid can answer this. How serious is that?

Well, let me begin by saying that all immune-related adverse events should be taken seriously. But with the identification and early intervention, they can be managed and a patient can continue being treated. So it's not serious unless you're not identifying these. How do you know that they're immune-related? Number one, any toxicity has got to be thought of is this immune-related. So it's always on the differential until you find a clear indication that it was due to something else, right? So for example, when we were talking about these toxicities, the atrial fibrillation brings upon a concern of whether this was myocarditis, which it wasn't, but it was part of our differential. The diarrhea had no other indication, it is immune-related. DKA in a patient like this in the temporal fashion is related. You do not get DKA if you don't have diabetes. So those are how you figure these things out. Again, for me, any all immune-related adverse events are manageable if you identify them correctly and begin the appropriate management.

Got it. And just one final question maybe for Dr. Hamid. As I -- whenever I'm trying to evaluate, right, and I'm sure you as well, right? We never want a cross-trial compare. But nonetheless, this is what we typically do. If I'm trying to evaluate this drug and in combination with other drugs. In terms of like melanoma, I guess, what would the signal be for you, right, that if you saw, you would give it a thumbs up, like, yes, this is something that we definitely have to move forward. And there are many physicians who might say, if it's equivalent, but just has a better side effect profile, right, a non-inferior type of profile, totally fine to move forward because the side effects are what matter the most. And then there are others who would clearly like to see a win in efficacy. I guess how would you kind of evaluate this?

Right. Great question and one that can't be answered with like a slick to a 2 sentence answer. But I would say that the majority of -- the majority of patients being treated with this combination at this point are being treated with a flip dose regimen due to concerns for toxicity, which is not optimal in major subsets of melanoma. There is a belief amongst those people in melanoma who have experience that if we can optimize anti-CTLA-4, we can benefit a greater number of patients. This combination has shown significant benefits and has changed the landscape of melanoma from a 6- to 8-month median survival to a 6-year median survival. So you can see why we believe that the next step is improving dosing so that we can bring this response to a greater proportion of our population.

This concludes today's Q&A session. I'll now turn it back over to Jay for closing remarks.

I'd like to thank everyone for their attention. I especially like to thank our co-speakers here today for their time and energy that they put into this. And I'm very excited about the potential of this therapy and we look forward to future updates and also look forward to 2024. Thank you for your attention.