Okay, great. Thank you everyone for coming. I'm Max Skor, I'm a Biotech Analyst with Morgan Stanley. 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. Great, I would now like to welcome Grant Yonehiro, the COO of Bolt Biotherapeutics. Thank you very much for joining us today. For those of us in the audience who are not familiar with Bolt, can you introduce your approach to treating solid tumors and how your immune stimulatory antibody conjugate, or ISAC platform, is differentiated?
Thank you, Max. Thank you everybody for being here. I'm excited to tell you about the Bolt story and very happy to tell you about our immune-stimulating antibody conjugate. An immune-stimulating antibody conjugate, or ISAC, as we refer to it for short, is very similar to an ADC, except instead of having a cytotoxic payload, we put an immune-stimulating payload on it. This works very differently than an ADC, however. The ISAC comes in and it binds to the target, but instead of trying to get internalized into the tumor cell to kill it, it attracts myeloid cells that then phagocytose the tumor and the ISAC, and the ISAC activates those myeloid cells. Those myeloid cells eat or phagocytose the tumor, but they also take those tumor neoantigens out and present to T cells and activate the whole T cell system.
So we get a very powerful therapeutic approach, where we can completely eliminate tumors in our preclinical models. And what's exciting is we leave the animals with immunological memory, so they're protected against re-challenge, and we get a re-challenge that's much broader than that single antigen that we originally targeted. So it gives us many things that we think could be promising, like being able to get metastatic disease that doesn't express our target, because you got that broad immune response. And with that immunological memory, we protect, so you have that potential for very durable responses.
Great, that's helpful. So, Bolt recently announced plans to discontinue development of BDC-1001 . Can you provide key takeaways and learnings from this program, and what led to the discontinuation?
Yeah. So I think we actually learned a lot, being the first ISAC that we put in the clinic and one of the first couple to go into the clinic. We learned we could deliver the molecule very safely. We had good PK and, you know, a lot of the things you'd look for initially in your trials. We had activation of the immune system, so we saw in the tumor increased immune cell infiltrate, increased macrophages and dendritic cells, as well as T cells. We did see evidence of anti-tumor activity. We saw one CR and five PRs in our trial, so that was very encouraging. Our mechanism is working, and we're getting anti-tumor effects, but we also learned we didn't have quite enough punch.
We did not have the level of efficacy we felt we needed to be commercially competitive in the HER2 space, and so you know, that, that's one of the big learnings and one of the things that we refer to our next generation ISACs have significant improvements in terms of the amount of punch they can give.
And just going back to that, in regards to the competitive landscape in HER2, could you just talk about what the bar was you were looking to reach? And maybe dive in a bit more on what led to missing that.
Yeah, so in our phase I dose escalation, at our recommended dose in evaluable patients, we saw 30% objective response rate, and that was the threshold that we were looking to see in our phase II component of that trial. It was safe, so it could be combined with other agents, and so we thought we could keep bumping that efficacy level up, but that was kind of the minimum monotherapy efficacy that we wanted to see, that we thought would put us in a relatively competitive position, and we were also looking at post-HER2 patients in that trial as well.
Is this trial winding down, or are we expected to see any additional data?
It's in the wind down phase, but what's exciting is the biomarker data from that trial will be presented at SITC. So we have an upcoming presentation in November of the data, which we think well supports our excitement about our next gen ISAC from a "What did we see clinically? We're on the right track, but we just need a stronger punch," so to speak.
That's helpful. So, based on these learnings, how has it informed future clinical development?
I think, in terms of future clinical development, you know, we would still take a similar approach in terms of looking at maybe a variety of tumors. But with our upcoming 4182 program, we're gonna focus in on tumor types that we think give us the greatest probability of seeing efficacy, which is gastric cancer. I think it drives us to trying to see. I think we're always, you know, everybody's always trying to see efficacy as early as possible. You know, the primary goal of phase I is to see safety. But, you know, I think we'll try and do what we can to get through dose escalation quickly, but also try and look for efficacy as capital efficiently as we can.
So if I understand correctly, there's almost a balance between overdosing and stimulating too large of an immune response, and then underdosing and not quite hitting that efficacy. Is that correct in regards to the ISAC platform?
In regards to the ISAC platform, we haven't really seen this U-shaped curve. We've maybe seen a little bit of that with our dendritic Dectin-2 program, our tumor cell macrophage program, our Dectin-2 agonistic antibody. We've seen maybe a little bit of a U-shaped curve from the immune response, but with ISACs, we have not seen that, but you know, it's still very early days, and we're still learning, but we didn't see that with 1001 , for example.
Okay, that's helpful. And last question on 1001 . Is it because HER2 is such a competitive space, that you didn't want to potentially increase the dose and see if you can hit a higher efficacy?
Well, I think the HER2 market is much more competitive when we initiated that program, so... and HER2 has been now introduced to the market when it was in development when we started, and it's turned out to be a great drug, very good for patients, very high response rate, you know, 60-plus% in breast cancer. So, you know, set a very high bar for us. But we were also at 20 mg/kg , which is a pretty high dose. Maybe you could go a little higher. But I think we felt our preclinical data and support didn't really suggest we needed to go higher. We were hitting the level of receptor occupancy we felt we needed to, or we...
It wasn't receptor occupancy, but the Cmin we were looking for in PK, based on all our preclinical data, was being hit or achieved in our dosing range, so we didn't think we needed to go any higher.
Great. Okay, so moving on to BDC-3042 . Could you briefly introduce this program, the data supporting targeting Dectin-2 in patients with advanced cancers?
Yeah. So this is a first-in-class novel target, and so, you know, we don't have a lot of clinical data like you do in the HER2 space that preceded you. But we did a lot of preclinical work to validate the target. We saw very good antitumor efficacy in syngeneic models with a mouse surrogate. Our actual antibody is not cross-reactive between mouse and human. And then we did humanized mouse studies, and we used a positive control Pembro to make sure we were exceeding what Pembro delivered, which also had published data in the same humanized mouse model. So we tried to validate as much as possible preclinically, the efficacy, and we certainly have a lot of biology showing that we can take tumor from actual patients, dissociate the cells, treat them with our drug, and activate them.
So, you know, that also gave us some confidence that this actually works on human tumor cells.
Diving a bit deeper into the preclinical data, can you talk more about which tumor types you're looking at or you've looked at in the preclinical setting?
Yeah. So what's very exciting is Dectin-2 is upregulated on almost all tumors. Tumors secrete factors that upregulate Dectin-2, and then both Merck and BMS have published data on what genes get upregulated with Pembro or Nivo, and those both upregulate Dectin-2. Our mouse models looked at in-depth three different tumor types and I think overall probably five or six different tumor types, both for Dectin-2 expression, but also for taking those, dissociating them, treating them, and seeing if they're upregulated. And those were ones that, based on published data, seemed to have the greatest upregulation of Dectin-2, and those are the tumor types that are in our clinical trial.
Great. So what is the status of the phase I dose-escalation study?
So we're currently in the dose-escalation phase of that study. We're enrolling at the sixth dose cohort, and so far, it's been, you know, well-tolerated, with no dose-limiting toxicities to date. So we're, you know, very pleased with how that's going, and it's progressing pretty well.
How many sites is this currently being run at?
I think approximately four. You know, I think we have, you know, one or two that might be in the process of getting up and running.
How is recruitment going, overall timelines, any insights into that?
Yeah. Our plan is to have data to make a decision based on the dose-escalation data by the first half of next year.
By the first half of next year. Great. And the tumor types that you're enrolling in this dose escalation?
We are enrolling colorectal cancer, head and neck cancer, melanoma, non-small cell lung cancer, clear cell renal cell carcinoma, ovarian, and triple-negative breast.
Okay, and without pressing you too hard, is there any one of those specific tumor types you would say or highlight as being more relevant than the other, based on your learnings from 1001 ?
So, you know, I think we'd be very interested in trying to get a mix of all those tumors. Non-small cell lung cancer seems, by published database, to have maybe higher Dectin-2 expression levels. But, you know, melanoma is very interesting because it's, you know, often treated with PD-1, and it's been more amenable to immune therapies. So, you know, we'd love to get a mix of different tumor types to be able to, you know, make a decision on indication based on it. And because it's a very different mechanism, I don't think we believe any of the 1001 data is particularly helpful for making a decision as to a tumor type.
If you can frame expectations around safety, is there anything we should keep in mind as we see the dose escalation data come out?
You know, I think that we would think this agent could be very well to combine with PD-1 inhibitors, since PD-1 upregulates Dectin-2 expression. And so, you know, we wanna have a good safety profile to be able to do combinations, and I think that's you know, an advantage in kind of how cancer treatment usually goes. You know, it's good to be able to do combinations.
At what stage... I would say probably past dose escalation, maybe in the phase II, you think investors and physicians would feel more comfortable with the platform? Would it be de-risking at that point, in phase II?
Definitely. You know, any sort of clinical data that supports safety and efficacy at a level that, you know, people believe is gonna de-risk that.
So phase II.
I think the dose expansion, I think, is, you know, what we typically refer to it. You know, some people call it, you know, two. Some people call it 1b .
1b, correct. Okay, great. And if we can move on now to the next program, which is BDC-4182. Could you talk a bit about the target and the supporting data, both preclinically and biologically, that's supporting this program?
Absolutely. Yeah. So, we're gonna be presenting at SITC a full preclinical data package on the program, also in November. So, you know, I think investors will certainly be able to see more. But we've taken a validated target, right? So zolbetuximab is, you know, getting approvals and has, you know, two phase III trials that look very good. So we know this target has been validated. We're also seeing other players get early clinical data showing anti-tumor efficacy against this target. So we feel it's, you know, very well validated target. We've done preclinical studies that shows our molecule is not only more efficacious than a naked antibody like zolbetuximab, but also more efficacious than ADCs. And we've tested both, MMAE ADCs with MMAE payloads, as well as, ADCs that have TOP1 payloads, and demonstrated greater efficacy against both those.
You know, we're very encouraged about that. We also have very good safety data and NHP, non-GLP tox study, which gives us comfort that we're probably differentiated over ADCs in terms of safety, based on that data. Again, having that safety could give us the ability to combine well with other agents.
That's helpful, and maybe if we can talk a bit more about the competitive landscape, what the benchmark looks like there, what tumor types are being investigated with these drugs?
Yeah. So I think the current benchmark in terms of drugs towards approval is zolbetuximab, and it's used in combination with chemo and first-line therapy. As monotherapy, it has a relatively low efficacy. I think it's, you know, single-digit efficacy in terms of objective response rate as monotherapy, but in combination, it definitely delivered improvement. There's a couple of ADCs that are moving through the clinic that have some initial data, and they've done two things. One of the things we're excited about on our program is we've been able to show efficacy in very low antigen-expressing models, so IHC 1+ or about 20,000 molecules per cell. And zolbetuximab is approved only for high expressers. 75% of the tumor has to be IHC 2+ or 3+.
And so if you can move to that low expressers, you can double or more than double the size of the patient population. And so, that is what others are also looking at, the ability to go to lower antigen expression. And so, you know, we're, we're hoping to do that. The main two cancers of expressed claudin are, gastric, gastroesophageal, and pancreatic. There's some in ovarian and some in non-small cell lung cancer, and I think there are agents targeting all four of those indications, although most agents primarily target gastric as the first indication.
And if we can dive a bit deeper into what you said, in regards to expression level and why you think potentially your drug could be efficacious in a lower-expressing tumor. I remember other ADCs, initially, they were hoping to go after all tumor types, I think mirvetuximab being an example of that, and then it basically gets selected for higher tumor expressers. Any insights into why specifically you think you'll be able to see efficacy in lower-expressing tumors?
So we do, because with 1001 , or our surrogate of 1001 , we weren't able to get to lower antigen or lower density antigen expression tumors. And, you know, since six years ago or whatever, we've been trying to climb down the ladder in terms of being able to get to these lower density antigen tumors, and that's where we've worked on what we call next gen ISACs, where we've improved both the antibody we select and better understanding what we want out of the antibody, the bioconjugation methods that we use to to improve that, you know, level of punch, as well as the linker payload and the activity and potency of the linker payload.
And when you combine all three of those together, we've been able to drive a very asymmetric increase in activity or efficacy, with still retaining acceptable safety. And so, you know, we see it preclinically that we can move down the antigen ladder, and since, you know, we've kind of translated some of 1001 into the clinic, we expect to be able to see this in the clinic as well.
That's helpful. And then just a question, off the top of my head in regards to preclinical data and your platform in general. After treating, have you looked at potentially the xenografts and whether you're enriching for a specific tumor subtype? Or based on stimulating the immune system, you're actually able to hit different tumor types, basically without leaving anything behind or selecting for a resistant phenotype?
Yeah, I think in our models, we're able to effectively treat many different tumor types as long as they have the target to start with, so I'm not sure that we've been selecting for any different tumor types. Our mechanism does rely on myeloid cells, so you know, there's been programs that we've selected, so we have a third program that's you know in lead optimization that targets CEA, and one of the reasons is that particular antigen internalizes slowly, and we think that could be an advantage, and it's also highly expressed on... or has a high level of macrophages and myeloid cells in the tumor microenvironment, where it's highly expressed, so you know, there's things like that that we think could be a better indication.
But, you know, from the data we have to date, you know, we have seen efficacy in a variety of different tumor types, and pre-clinically, you know, we've seen efficacy in various different models.
Great.
Obviously, syngeneic models for us work much better because when we're working in a xenograft model, we don't get the benefit of T cells and other immune cells.
That's helpful. So before moving on to the financials, could you just walk us through what the milestone calendar looks like for the next six to twelve months?
Sure. So we have, as I mentioned, the 3042 , which is our most advanced program, reading out the dose escalation data for a decision in the first half of next year. We also have, 4182 , or the Claudin 18.2 program, ISAC, going into the clinic next year. And then, we'll also have some presentations. I mentioned two presentations we expect to make at SITC, one on the 1001 , clinical data that gives us, comfort that we're on the right track with our next generation ISAC, and one on our 4182 program, going through the preclinical data that supports advancement into the clinic. We also have a couple of collaborations that are very important to the company, and, you never know what data we might be able to, talk about there.
But you know, I think there's potentially upside surprises from that. You know, as time goes on, they're fully funded, so you know, we have people funding those programs through clinical proof of concept, and then we have certain commercial value we could get, including an option for co-development on one of three programs with our Genmab collaboration.
Yes. Would you like to just give a high-level overview of the collaborations you have currently and maybe a sense of idea on partnering in the future?
Sure. So we have two collaborations, one with Genmab. They're supplying the monoclonal antibody technology or contributing their monoclonal antibody technology to the collaboration, and then they're funding those programs through to clinical proof of concept. This can include their bispecific antibody technology or their DuoBody technology, as well as all the work they've done on various different tumor antigen targets. And so, we've been working with them on moving up to three programs. The goal is to bring three programs to clinical proof of concept, and then Bolt has an option for co-development and certain geographic commercial rights to one of those programs. And that's again, with our next gen technology. They've seen kind of some of the evolution at Bolt of the ISAC. And then we have a collaboration with Toray Industries.
They have a really interesting novel tumor antigen target that they've identified that seems to be fairly broadly expressed in a large range of tumors, and we're collaborating with them, using their proprietary antibody technology for that target, along with our ISAC technology. They fund everything through, you know, early clinical, you know, validation, and then we have the option to co-develop and co-commercialize with them.
Great. And ideas on future partnerships or exploring any of those options?
Yeah. So, you know, we have the ability to generate more products than we can afford to move forward, so we're very interested in partnering, whether it's, you know, our own internal programs that are beyond the two I mentioned, or even the two I mentioned, or whether it's, you know, programs where somebody has an antibody and they want to use our technology for that. And so we're, you know, obviously, in this financial environment, we're always in active discussions and open for business.
Great. I think that's a good segue into financials. If you could talk about your current cash position and runway, what the next twelve to eighteen months looks like in that regard?
Yeah. So we have just under $100 million in cash, and, you know, we did make a very significant reduction in force, approximately 50% reduction in force, recently, completed in July. And that, we project would give us runway to get, to the clinical, readouts on both 3042 and 4182 , which, you know, we think was really the important metric to be able to achieve. And so that's about approximately mid-2026, based on our projections.
Okay, that's helpful. And then final question from me, just in regards to investor sentiment. What do you think overall is investor sentiment, or what are they looking for to basically revisit the story or double down on the story or change the narrative, basically?
You know, I think they want to see clinical data, clinical efficacy data, with, you know, acceptable safety. I think that's, you know, currently kind of the requirement. And hopefully, that's not necessarily the requirement for partners, but I think that's, you know, currently the sense I've seen.
And is there anything else you'd like to highlight?
No, I think we're in a good place to deliver on that. We're very excited about 4182 . We've got really good preclinical data on that, and we think the preclinical data on 1001 largely translated into the clinic, and we'll be presenting that data at SITC.
Okay. Great, Grant. Thank you very much.
Thank you. Thanks.