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spk08: Good afternoon, and welcome to the BOLT Biotherapeutics Strategic Update Conference Call. At this time, all participants are in listen-only mode. After the speaker's presentation, we will conduct a question and answer session. Instructions will be given at that time. As a reminder, this call may be recorded. I would like to hand the call over to Willie Quinn, incoming Chief Executive Officer of BOLT Biotherapeutics. Please go ahead, sir.
spk05: Thank you, and good afternoon, everyone. This afternoon, we issued our first quarter 2024 financial results and business update, which outlines the topics we plan to discuss today. You can access the press release by going to the investors and media section of our website at www.boltbio.com. I am joined today by Randy Schatzman, outgoing chief executive officer, and Edith Perez, outgoing chief medical officer. I am also joined by some newly promoted members of BOLT's senior leadership team, including Michael Alonso, co-founder of BOLT and newly promoted senior vice president of research, and Don Colburn, newly promoted senior vice president of clinical development. Before we begin, I'd like to remind everyone that during this call, we will be making forward-looking statements that are subject to a number of risks and uncertainties. These may cause our actual results to differ materially, and I encourage you to read our SEC filings for more details on these risks and uncertainties. You are cautioned not to place any undue reliance on these forward-looking statements, and BOLT disclaims any obligations to update such statements. To start, I'd like to thank everyone for joining us today. As you all know, we don't normally have earnings calls, but we decided it would be a good idea to have a call today to clearly communicate our new vision for BOLT. On today's call, we will provide details regarding strategic pipeline and leadership changes, as well as reviewing our progress during the first quarter. We believe these strategic changes will enable us to optimize the company's operations, maximize shareholder value, and most importantly, deliver meaningful benefit to the many patients with cancer who could benefit from more effective treatment options. I'd like to start the call by addressing our decision to discontinue development of BDC-1001. And for that, I'd like to call on my colleague, Dr. Edith Perez. As one of the foremost experts on HER2-positive breast cancer, Edith helped us navigate this landscape and recruit a stellar group of investigators. Edith?
spk00: Thank you, Willie. I am proud of the work that we've done to establish that are both body immune stimulating antibody conjugates or both body ISACs can be safely delivered and can produce anti-tumor activity in patients with metastatic solid malignancies. I am grateful for the collaboration with world leading investigators who understood and understand the promise of the ISAC approach. And I want to thank them and their patients for all they have done to help advance the scientific understanding of how this brand-new platform of ISACs may ultimately improve cancer care. We continue to build upon that foundation with our next-generation ISAC programs. We have decided to discontinue all development of BDC-1001 and will work with our investigators to achieve an orderly shutdown of our trials. Deciding to discontinue a program is never easy, especially when one sees signs of activity and evidence supporting our proposed mechanism of action. However, we have limited resources and most focused resources on our product candidates that have the highest potential. We set out to reproduce a 30% overall response rate that we saw in BDC-101's dose escalation trial, and we did not see that in the phase two portion of the program. However, the clinical activity of BDC-1001, along with the significant advances in our next-generation ISAC technology, have encouraged us to shift resources to our Clouding 18.2 targeting next-generation ISAC program, and our ongoing Phase 1 study of our DEC-102 agonist antibody. With these changes, I have decided to transition to an advisory role and hand over the reins to Dawn Colburn, who is being promoted to Senior Vice President of Clinical Development. Dawn joined BOLT in 2023, bringing over two decades of experience in oncology clinical development. Prior to joining BOLT, she was Vice President of Clinical Science at Algenus and Arcus Biosciences, where she built and led the Clinical Science Organization and the National Cell Lung Cancer Development Strategy at both organizations. I am happy that Bolt's clinical programs are in good hands, and I look forward to continuing to work with Don and the team in the advisory role. And with that, I'll now hand over the call to Randy. Randy?
spk04: Thank you, Edith. Bolt will now be shifting away from BDC 1001 and prioritizing BDC 3042 and BDC 4182, our next-gen ISAC targeting Clawdon 18.2, which incorporates five years of advancement in ISAC design parameters. In conjunction with this strategic refocusing, the company will be reducing its workforce by approximately 50%. As a result of these actions, we expect to extend our cash runway into the second half of 2026, which enables us to achieve clinical data on our next generation ISAC and our Dectin-2 program with our existing resources. As part of this refocusing, We've also made leadership changes that will best serve the company's path moving forward. My colleague Willie Quinn, Bolt's longstanding chief financial officer, will be stepping in as chief executive officer. Willie has been a strong leader at Bolt since joining the company four years ago with expertise in executing operational and financial strategies, driving corporate growth and raising capital. He's been an invaluable partner to myself, and to both board of directors in overseeing all aspects of the company. We anticipate a seamless transition, and I look forward to transitioning into a strategic advisory role and continuing to be involved in that capacity. Along with these changes, we're also reducing the size of both boards by two directors. Both founder, Ed Engelman, is stepping down from the board of directors and into a position on our scientific advisory committee. Dr. Engelman founded the company in 2015, to expand on his pioneering work in cancer immunotherapeutics and myeloid biology conducted at Stanford University. We're glad that he will be able to continue to be a resource for us here at Bolts. Dr. Richard Miller has also decided to not stand for reelection when his term expires in June. Dr. Miller has served on our board since 2017, and we are grateful for his drug development perspective over the years. Finally, I want to thank all the dedicated and talented employees who will be leaving as part of this realignment. It's been a true pleasure to work with you for these past five years. With that, I'd like to pass the call back to Bolt's incoming Chief Executive Officer, Willie Quinn, to provide an overview of the company's strategy and platform. Willie?
spk05: Thank you, Randy. Before I start, I want to thank all Bolt employees, and particularly Randy, Edith, Ed, and Richard for their leadership in advancing the company to where we are today. While our priorities are shifting, our mission remains the same, to leverage the power of the immune system to find better ways to treat cancer. This is not an easy path, and drug development is inherently risky, but we are making progress. Our understanding of the relation between the immune system and tumor microenvironment continues to improve. And our ISAC platform is dramatically better than it was only a few years ago. As a reminder, at Bolt, we're developing product candidates with the goal of training a patient's own immune system to recognize and eliminate their cancer. We do this by focusing on the tumor microenvironment, which almost always contains some myeloid cells. Myeloid cells, such as macrophages and dendritic cells, are part of what is called the innate immune system. Their function is to recognize molecular patterns unique to pathogens such as bacteria, fungi, and viruses. Our product candidates find ways to use this system to train the body to mount an immune response targeted at the cancer. We have three clear priorities going forward, BDC3042, BDC4182, and our collaboration. We believe BDC3042, a first-in-class agonist antibody that reawakens myeloid cells so they can attack tumor cells, has broad application across many tumor types, and we are encouraged that BDC3042 seems safe and well-tolerated in the Phase I dose escalation thus far. In today's call, you'll also hear more about BDC4182, the first next-generation bulk body ISAC to advance into IND-enabling studies. BDC4182 targets QUADN18.2 and has very promising preclinical data. Finally, we are committed to supporting our collaboration partners, GENMAB and Toray, and look forward to providing details on some of those exciting programs later this year. With that, I would like to turn the call over to Don Colburn, our Senior Vice President of Clinical Development to discuss BDC3042 in greater detail.
spk07: Thank you, Willie. Turning now to BDC3042. BDC3042 is a first-in-class DECTIN2 agonist monoclonal antibody that reprograms tumor-associated macrophages to attack tumor cells. DECTIN2 gene expression is elevated in tumor-associated macrophages across a broad range of solid tumor types. The ongoing first in human clinical study is currently evaluating BDC3042 in patients with six types of metastatic or unresectable cancer, including triple negative breast cancer, colorectal cancer, clear cell renal cell carcinoma, head and neck cancer, non-small cell lung cancer, and ovarian cancer. The study starts with dose escalation of BDC3042 as a single agent to evaluate the safety and determine the recommended phase two dose. BDC3042 has advanced through the first three dose escalation cohorts without any dose-limiting toxicities, and the fourth dose-level cohort is fully enrolled. BDC3042 has been well-tolerated to date. We anticipate providing an update on enrollment and safety in the latter half of this year. I'd like to now hand it off to Michael Alonso, our Senior Vice President of Research, to provide an overview of BDC4182.
spk06: Thank you, Don. I'm happy to join the call today to explain why we are so excited about our next-generation BoldBody ISAC platform and about our Claudin 18.2 BoldBody ISAC in particular. As a reminder, an ISAC is comprised of a tumor-targeting antibody and an immune-stimulating payload. Over the last several years, we have continued to advance our BoldBody ISAC technology and have come to appreciate the importance of the antibody, the linker, the payload, the combination of the three. We have developed next-generation ISACs with enhanced potency and activity that have the potential to deliver superior efficacy with acceptable safety. We have generated preclinical data showing that our next-generation bold-body ISACs can provide better efficacy than naked antibodies and even better than cytotoxic antibody drug conjugates, or ADCs. We have also generated anti-tumor activity in preclinical models with lower antigen density Tumor models were our first-generation ISACs underperformed. I'll now turn to our exciting new program that we are unveiling today, BDC4182, which targets Claudine 18.2. Claudine 18.2 is a protein that is expressed in the stomach epithelial, and in healthy cells, it is somewhat hidden in the transmembrane-type junction. In cancers, such as gastric and pancreatic cancer, expression of Claudine 18.2 is significantly elevated. Caudin 18.2 in these tumors is also localized to surfaces that are more readily accessible to biologists and effector cells, thereby providing an expression pattern that makes for an excellent target for ISACs. We have incorporated the learnings of BDC-1001 into our next-generation ISACs and designed BDC-4182 with enhanced potency and activity. We are excited by the preclinical data generated to date. indicating that next-generation Claudin 18.2 ISACs have superior anti-tumor activity relative to MMAE-based ADCs and can deliver anti-tumor activity in models with low Claudin 18.2 antigen density. BDC4182 has advanced to IMD-enabling activities supported by preclinical results demonstrating potent anti-tumor activity, induction of immunological memory with epitope spreading, and importantly, and acceptable safety profile. With that, I'll turn the call back over to Willie for closing remarks.
spk05: Willie? Thank you, Michael. While it was a difficult decision to pivot away from our first generation ISAC BDC 1001, we are guided by the strong principle of doing what will ultimately be best for patients. And in this case, that means learning from the data and turning our resources towards our clinical candidate BDC 3042 and our next generation ISAC platform. I'd like to reiterate the excitement we have for our pipeline going forward. We are steadfast in our mission of generating breakthrough immunotherapies for patients with cancer, teaching the innate immune system to recognize and kill multiple tumor types. We have a focused pipeline centered on both proven platform technology as well as improvements that have been further validated by our external collaborations with GenMav and Toray. For our clinical stage program, BDC3042, we will plan to share a safety and enrollment update on the phase one dose escalation trial in the second half of this year, and we are advancing BDC4182 towards initiating a clinical trial in 2025. We have a refreshed and prioritized corporate strategy and are adequately capitalized to achieve our upcoming program milestones into the second half of 2026. Bolt at its core is committed to innovative, groundbreaking science, and I am proud of the progress we have made in advancing such differentiated technology in order to bring positive change to the oncology treatment landscape in the future. We will now open the call up for Q&A, for which we will have available our SVP Clinical Development, Don Colburn, our SVP Research, Michael Alonso, and myself. Operator?
spk08: Thank you. If you would like to ask a question, please press star 1-1. If your question has been answered and you'd like to remove yourself from the queue, please press star 1-1 again. One moment for questions. And our first question comes from Jeffrey La Rosa with Learing Partners. Your line is open.
spk02: Hi. Thanks for taking our question today. I'd like to talk more about this, to ask you more about the Clavin 18.2 ISAC, and do you elaborate more on why and how it is more potent than the first-gen platform? Is it just a matter of it being a more potent TLR78 agonist? Why are you still confident in TLR78 agonism versus other innate stimulants? And, you know, I guess, Part of the HER2 experience with 101 was really a fierce competitive landscape with, you know, high bars with, you know, some of the other HER mechanisms there. It's pretty similar with CLAWDIN 18.2 with ADCs and T-cell engagers there. You know, how do you think, you know, this will play out differently competitively versus the HER2 experience? And sort of just kind of talk more about, you know, target selection in general, how that plays into how you select your new ISAC programs and relative to what else is out there. Thank you.
spk05: Yeah, Jeff, those are great questions. This is Willie. And I would like to turn it over to Michael to address those. I think we have some good answers. Perfect. Thanks.
spk06: I think, first and foremost, BDC-1001 certainly demonstrated that ISACs can be safely delivered to patients, elicit immune activation in the patient tumors, and produce meaningful clinical benefit. We've taken these learnings and made several design improvements with the next-generation ISACs that lead to enhanced activation of the immune system that we expect will increase the anti-tumor activity in patients, including those with tumors expressing lower levels of target antigens, as we have seen in our preclinical models. Now, more specifically, as it relates to the ISAC and the design improvements, we've certainly made improvements to the potency of the TLR7 and 8 agonists. We've also made improvements to the antibodies, such that we are seeing enhanced phagocytosis and activation of the myeloid cells, and we have some optimization of the conjugation chemistry. And I think by optimizing, you know, these features with our common design principles, we've certainly produced ISACs that are much more potent than what we observed with BDC-1001 preclinically and have seen some, you know, compelling anti-tumor activity in our preclinical models. As it relates to, you know, why TLR7 and 8 versus some of the other, you know, immune agonists that are out there, I think from the big picture standpoint, we still prefer TLR7 and 8 as they are endosomally located. and can deliver robust activation of the innate immune system. Their expression profiles in humans nicely covers platinum cytoid dendritic cells, as well as monocytes, macrophages, and dendritic cells, which are all cells that, when activated, can lead to a robust innate immune response that will translate then to the adaptive immune response and get some compelling T cell immunity.
spk05: Not to interrupt, but I think The other component that is interesting from a competitive landscape perspective, which is something that we didn't have in the HER2 landscape, is a look versus cytotoxic ADCs, and maybe you could talk a little bit about that too.
spk06: Yeah, so moving into the competitive landscape, you know, we certainly are paying attention to the landscape, notably with, you know, what's out there or what's about to be out there with the zolotuximab, the naked antibody. and its activity in patients with high Claudine 18.2 expression, but also what's coming next in some of the early phase clinical trials, and that's a lot of what we've been seeing is the antibody drug conjugates with the MMAE payloads. You know, we've taken, you know, we've made the cytotoxic ADCs in-house and have compared them to the ISACs in in genetic tumor models with high expression or with medium expression of clot in 18.2, and we certainly see that the ISACs perform, you know, superior to them, at least in our early models that we've assessed to date. So, you know, we're certainly positioning ourselves to, you know, face the competition, and we expect that our differentiated mechanism will provide clinicians with, you know, some interesting options as it relates to immune stimulation and the potential for durable immune responses. And I think your last question was on target selection for the next generation Isaacs. And I'll spend a little bit of time just for Claudine, right? So why are we interested in Claudine 18.2? I think I've touched on that a bit. It's certainly been validated now with the, you know, with the experience with Zolotuximab. The expression profile of Claudine 18.2 is also quite compelling. And as much in healthy tissues, it's restricted to the, you know, the tight junctions in the gastric epithelial. And then during tumorigenesis or as, you know, the cancer progresses, you see it, you know, losing some of the cell polarity and then being, you know, more readily accessible to biologics. So we're thinking about the next generation ISACs that are significantly more potent than the first generation ISACs while still having safety in mind, you know, very specific expression of the tumor targeting antigen can certainly lead to, you know, a compelling hypothesis to test in the clinic. And that's what we're excited to do.
spk05: And Jeff, I'll just end by pointing out that we also just uploaded a new corporate presentation, which is available on our website. And it does include a few slides on the preclinical data that we've generated for BDC 4182. So I encourage you to take a look at that. And obviously, we're happy to have follow-up conversations. Okay, great.
spk02: Yeah, thanks for taking our questions. Appreciate it.
spk08: Thank you. Our next question comes from Steven Willie with Stiefel. Your line is open.
spk01: Yeah, good afternoon. Thanks for taking the question. I guess maybe just to follow up on the prior question and maybe a little bit more specifically, can you talk about the differentiation of the payload on 4182 relative to 1001, I guess specifically as it pertains to the skew of TLR7 versus 8 agonism. If I remember correctly, I think 1001 was skewed more towards TLR7. Should we assume that in this being more potent, you've driven that skew more towards 8?
spk05: So, again, I'll let Michael jump in on that. And I do think we have some good slides that also speak to that, but I'll let him answer the question.
spk06: Yeah, I think aside from getting into how far is it skewed one way or another, I would say that the payload that we're utilizing for BDC4182 is significantly more potent on both TLR7 and TLR8 relative to what we utilize for BDC1001. And I think what's important and you can reference the corporate deck on slide 20 when you go through these data, is that as you transition from the first-generation linker payload to the second-generation linker payload, our goal is to still activate the innate immune system, which includes the myeloid cells and the platenocytoid dendritic cells. And what we've learned is that as you climb down the antigen ladder, i.e., if you target tumors with lower antigen density, you see significantly enhanced antitumor activity with the next-generation ISACs, not just on Claudine, but also on HER2, TRO2, and CEA relative to the first generation. So, we are delivering significantly more activity via in vitro in our preclinical models, but also in vivo in our tumor models.
spk01: Okay. And then just with respect to 3042, can you just I guess maybe speak to your level of confidence that you'll be able to see monotherapy activity with this agent in dose escalation or even dose expansion. And can you give us any inclination as to kind of what your preclinical data tells you about at what dose level you would expect to maybe see some potential efficacy just based upon the exposures that you're starting to achieve at any given dose level?
spk05: Yeah, thanks, Steve. We are very excited about 3042, and I'll hand it over to Dawn to just talk a little bit about the status of where we are in the clinic there. And then either she can talk a little bit about mechanism or Michael can jump in as needed. Dawn?
spk07: Yeah, thank you. So, you know, for a program like 3042, We don't yet know what we will see in the clinic during our dose escalation experience. We are hopeful that we will start seeing some activity at some of the dose levels coming up. But, you know, it's still very early days and pretty low doses that we're administering to these patients. The preclinical models lead us to believe that we should see monotherapy activity here. And, you know, I think it will just need to be borne out in the clinic as to whether or not we will actually see monotherapy activity with this agent. And I'll hand it over to Michael to speak to sort of dose expectations.
spk06: I think Don said it perfectly. I think we are in the range where we are starting to get very interested in the clinical doses, and we'll know more as we get to those patients.
spk01: Okay. Thanks for taking the question. Thanks, Steve.
spk08: Thank you. Our next question comes from Michael Schmidt with Guggenheim. Your line is open.
spk03: Hey, guys. Thanks for taking my question. I had two questions. The first one on BDC 1001. Yeah, I'm just curious what sort of the trigger was to drop the program. I thought you just had recently initiated the use of expansion cohorts? Was it data from one or more specific cohorts that did not meet the bar? And what are learnings from the BDC-1001 experience?
spk05: Yeah, great question, Michael. We definitely tried to make this decision as early as we could. in light of the other interesting programs we have, because we wanted to make sure that our precious resources were going in the very best place possible. But it's always a difficult decision, especially when you're seeing signs of clinical activity and you think you might have a program, but you're weighing that against the competitive landscape and what else you could do. And maybe I'll just hand it over to Don a little bit, who is a lot closer to the BDC 1001 program and kind of the nitty-gritty. And we're not necessarily going to give patient-by-patient details, but I think she can give you a better sense of where we were and how we came to that decision.
spk07: Certainly. Just to remind folks, when we set out to do the expansion cohorts, what we were trying to do is actually reproduce the data that we saw in our dose escalation portion of the first BDC 1001 clinical trial. And that produced a 29 or 30% overall response rate in a mixed group of heavily pretreated patients. So we opened expansion cohorts with a bar of 30%. And quite frankly, we didn't see that in some of the initial cohorts. And so that's why we took the tough decision to go ahead and discontinue the program at this time to give us the runway to look at these other Assets that we have, we still continue to believe very strongly in our technology and just to remind folks. We do. We have seen interesting biomarker data and clinical activity from the dose escalation. It was very safe and well tolerated and we will be actually publishing the totality of our desk escalation data in combination with a lot of this biomarker data in an upcoming manuscript.
spk03: Okay, and on 3042 targeting TAMs, I guess what is the most compelling argument for targeting Dectin-2, and are there any other examples out there of therapies targeting TAMs that could help to de-risk this mechanism clinically? Thanks.
spk05: Yeah, great question. And we love talking about BDC3042 because we do think we have a unique first-in-class mechanism. I'm going to hand it over to Michael to talk a little bit more about that target and our decision to go there.
spk06: Yeah, perfect. Thanks, Willie. I think for targeting DECD2, it's got a couple of things going for it. One, it's a pattern recognition receptor that, when agonized, can repolarize some of the tumor you know, supportive macrophages and convert them into the tumor-destructive macrophages. From an expression standpoint, DECDN2 is actually quite interesting because it is elevated in tumor-associated myeloid cells, which include macrophages and other cell types, and its expression is, you know, relatively modest in the rest of the body, such that you can get some nice tumor targeting with BDC3042, and that's why we're excited about this program. Certainly from, you know, other TAM targeting agents that are out there, we're certainly aware of the previous strategies geared mostly towards depleting some of these tumor-associated macrophages, and we believe very much in redeeming these cells and reprogramming them such that they can really fight for us rather than against us in the tumor. I would say, you know, some of the interesting ones are certainly CD40 agonists that have had some early compelling clinical activity. that were really hampered or hindered rather by some of the potential toxicity of, you know, targeting CD40 such that it has pretty broad expression in the periphery and across the body. So that's why we think the targeting of Dectin-2, which is more specific to the tumor, is compelling. Thank you.
spk05: Thanks, Michael. Great questions.
spk08: Thank you. There are no further questions. I could turn the call back over to Willie Quint for any further remarks.
spk05: Thank you. So this has been an emotional day for us, as you can imagine, and we thank you all for joining us today. We look forward to keeping you updated on our programs and hope to talk to you again soon. Thank you.
spk08: Thank you for your participation. This does include the program. You may now disconnect.
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