Bolt Biotherapeutics, Inc. (BOLT) Earnings Call Transcript & Summary

Great. Thanks for joining us for the next session. I think it's time to say good afternoon. I have to figure out if it's still morning or afternoon yet, but good afternoon, everybody, and thanks for joining us for the next session. I'm Matthew Harrison, one of the biotech analysts here at Morgan Stanley. Really pleased to have the team from Bolt with me. Briefly before we get started, I just need to read a disclosure statement. Please note that all important disclosures, including personal holdings disclosures are available on the Morgan Stanley public website at morganstanley.com/researchdisclosures. So with that, I think we can kick it off. Randy, maybe a good place to start is just -- I don't think people are that familiar with ISAC. I think they're familiar with payload conjugation but ISAC as a technique. So maybe just outline what you're doing, why you think ISACs are interesting and what the platform looks like.

Yes. Thank you, Matthew. And it's a pleasure to be here. Thanks for having us. I wanted to introduce my colleague, Eda Perez, who's our Chief Medical Officer, who will pipe in periodically as well. So just a bit of background at Bolt. We're pioneering a new approach to cancer immunotherapy, wherein we quite literally bring the patient's own immune system to their tumor. And we train it to recognize the key neoantigens on the surface of that tumor so that the patient's own immune system can eliminate the tumor. And interestingly, it leaves the host with an immune memory of that cancer. So if the cancer returns, the immune system will continue to recognize it and eliminate it. But coming back to your question, the way we do this is we target myeloid cells that are within the tumor microenvironment, and people will probably remember from your biology that a myeloid cell is key component of the innate part of the immune system. And as such, what they normally do is surveil for foreign invadors, such as bacteria and viruses and eliminate those. Well, what we do at Bolt is we hijack that system, and we target our agents to the myeloid cell. And in particular, our lead agent is one where we take a targeting antibody which targets key antigen on the surface of a patient's tumor. In this case, it's HER2. And to that, we stably conjugate an immune stimulator. In this case, it's a small molecule agonist of toll-like receptors, which are in myeloid cells. So we target this agent to the tumor, and then the tumor cell and the agent, in this case, BDC 1001, which is our lead are engulf to [ by that ] myeloid cell. The payload activates the toll-like receptors, which then kicks off the innate immune system, ultimately brings in the adaptive immune system for tumor kill.

Okay. Great. And so can you talk about how -- I guess, how that's done. I mean, I think people are familiar with some of the other conjugation technologies, but what are the key components to making that work well? Obviously, people have seen ADCs were getting the linker right and getting some of the other components is right. to make that platform work. So what have you done in terms of specialization?

No, that's exactly right. So similar to an ADC, it's a targeting antibody with a payload on it. But dissimilar to an ADC. In this case, we use stable linkers because we don't want the payload to come off. With an ADC, you want the payload to come off and distribute a toxin through the tumor to kill it. In this case, we wanted to remain on the antibody so that it's engulf [ to by ] the myeloid cell. So what's key is to have that stable conjugation. The history of toll-like receptors has been one of systemic administration tends to result in very high toxicities with this. And the idea was to avoid those toxicities by the stable conjugation. So it's not released in systemic circulation. It's only accessing the myeloid cell when it gets into the tumor microenvironment itself. And then the payload is a small molecule that specifically targets the toll-like receptors in this case, TLR 7 and TLR 8 in a very specific manner for stimulation of the myeloid cell and the biology.

And the choice of TLR7 and TLR8 as opposed to some of the other TLRs that you may have chosen. Is that an important choice in terms of the glide?

Well, we think it is. I mean we believe in what we call the 7/8 hypothesis. These are the -- they are expressed in the 2 types of dendritic cells that are -- we think are key the solving solid tumor formation and metastasis in this case.

Okay. Great. So now you have the technology, you have the platform, as you said, the first agent you might have or as BDC-1001 HER2 targeting. Maybe just talk a little bit about that agent and what is specific -- and I guess what I mean is choice of the antibody right because some antibodies are internalized and some aren't. So is there a specific choice you needed to make there and then just remind people development that.

Yes. So what I'll do is I'll just introduce the agent, and I'll let Eda tell you a little bit about where we are in the clinic with that. So BDC-1001, which is our lead agent in a Phase I/II clinical trial currently targets tumors that express HER2. So in this case, the targeting antibody is a biosimilar of trastuzumab, which targets the, in this case, the payload to HER2-expressing cancers. And as such, what it allows us to do is to get into the tumor. And these tumors over -- actually have a high density of myeloid cells in them. So happens is it will bind to the tumor cell and then it's actually the Fc domain of the antibody that activates Fc receptors on the myeloid cell so that both the tumor cell and BDC-1001 are engulfed which ultimately then stimulates the toll like receptor and activates the biology. So we felt that this would be a really good way to prove that the technology work by using a known antibody with very known characteristics to it and how it behaved on cancers, but with the novel linker payload combination. And I'll turn that over to Eda to update a little bit on where that study is.

Yes. I was trying to allude to the beauty of these technologies is that for our first compound, we're using a target has been well validated in the setting of oncology, but bringing the activation of the innate immune system to the site of the tumor to then obviously stimulate the adaptive immune response. So we are conducting, as Randy said, a Phase I/II clinical trial and BDC-1001 or lead companies administered intravenously. And then the patients are being enrolled based on HER2 expression by either immunohistochemistry for the protein or gene amplification. We started the trial with a schedule of once every 3 weeks. As we've continued with enrollment of subjects, we've demonstrated already a variety of facts that are very relevant today. Number one, we've learned about the pharmacokinetic behavior of our compound. We have learned that increasing the frequency of administration allows us to achieve higher levels of patients. Number two, we've demonstrated the safety of this strategy consistent with what we thought would occur, which is we can administer this compound with safety for the subjects enrolled. And we were already seeing changes in plasma as well as tissue consistent with our mechanism of action aligned with early signs of clinical activity. So the trial is enrolling subjects very well with a lot of engagements from physicians, investigated teams and patients, and it's progressing, so we can complete it as per our strategy.

Okay. And can you talk a little bit about -- I know you touched on this a little bit, but you had your data update last year now where you described sort of the overall response that you had and the dose levels that you were in. And at that point, that's when you said you need better trough coverage, right, and change the strategies. So can you just describe in a little bit more detail how you came to that decision about needing better trough coverage, what that level is that you need and why you think the new strategy will achieve that?

Yes, very good. Our decision to report early data, which were really interim data a year ago were based on first of all, showing that at least the strategy of the molecular structure was making sense because we demonstrated safety. And we had, at that time, subjects that have been treated at the lowest doses compared to what we've been able to accomplish over the last previous 8 months since we reported data back in December 2021. So what we continue to do at Bolt is -- let's look at science to help inform our strategy for clinical development, so we continue performing laboratory experiments, exploring the appropriate dose levels in mice to correlate with antitumor activity. So we're using that as a guide related to where we're trying to get in the clinic for our ongoing clinical study. And again, we then moved from a once every 2-week schedule to once every other week schedule continuing to show safety and changes co-system with mechanism of action. And now we're evaluating patients in a 1 per week regimen, not only as monotherapy but also in combination with nivolumab. So it's very good that at this time. In a towards we get into the fall of 2022. We continue showing what we anticipated we would see up to this point, and we look forward to completing the study and releasing additional data.

So if I could emphasize the point, one of the things that -- to build off of whether Edith was explaining in our preclinical data, what we demonstrated clearly was we needed something like 50% to 60% of target receptor occupancy to really activate the mechanism of action. In our early pharmacokinetic data in humans was showing that we weren't achieving the levels that would be able to do that. And so hence, the proposal to go more frequent and get a better exposure in these patients to achieve that 50% to 60% occupancy.

Okay. Great. And so then can you remind us what you said about when we could expect to see the next update? And then what will be included in that update?

Yes. We expect to complete the enrollment to the Phase I portion of the trial this year, assessing the data and reporting the information based on safety, early signs of clinical activity as well as pharmacodynamic changes evaluated both in plasma and in tissue.

And I guess what does success look like from that update? And how are you going to make a decision based on that update, whether to move this forward or not?

With a combination of all of the business together, the main goal certainly of dose escalation trial is identification of the recommended Phase II dose to move forward. And that is our plan at this moment to find that those with the optimal exposure safe for patients and then outline our detailed plans for what we call the dose expansion or Phase II portion of the study.

So it's really about, obviously, ensuring the safety for patients optimizing the clinical outcomes, but also our readouts with biomarkers that will parallel with that and give us an assurance that we've both activated the biology and the clinical outcomes we're seeing as a result of that.

And is there a -- and not to make this so specific, but I mean, do you need -- I guess what I'm asking is, how much weight are you going to put on biomarkers versus the ability to see clinical responses?

Well, clinical response always wins the day. So that will be the most important thing. But we would like to see the biology being activated as we expect, okay, to assure us that everything is coming together the way we expect it to.

Okay. And as you think about the mechanism, I think one of the questions investors probably asked a lot is, you had a competitor who at least was trying to interrogate the similar biology, obviously, different construct, and they've decided to stop. So how does that make you feel about your prospects and where do you think you're different?

Well, we're still bullish on this. We made different choices than they made. The challenges that they had was that the toxicities that they had were pronounced in a way that they weren't able to get enough drug on board to actually drive the mechanism of action. And the beauty here is with the different choices that we have made, we're already demonstrating a very safe profile, which allows us to pretty much explore a complete regimen of dose escalation and exposure in our patients without running into toxicity so that we can make sure that we're driving the mechanism as we expect.

Okay. Okay. So it's more about -- from your view, it's about therapeutic window and the difference in therapeutic window?

Exactly right.

Okay. Okay. Great. I guess last question, I don't know if this is premature at this point, but any thoughts on expansion cohorts and what people should expect in terms of either specific tumor types or other factors that you might consider?

Well, again, we'll build off the data that we have. The dose escalation right now is how many tumor types, it's...

16.

16 tumor types. Obviously, our early data has shown responses in colorectal it. Obviously, when we started this HER2 in breast cancer, I think, is a key place where we'd like to demonstrate activity. So -- but we'll let the -- essentially the data drive where we go with this. But at the time we give update to investors on what the data is looking like, what our recommended Phase II dose is, we'll also have that plan in hand as well

Okay. Great. Great. Maybe we can talk about the rest of the pipeline. Maybe just a quick update on CEA, right? You ran into some what I think are drug-specific problems there? So what's the path forward there? How are you thinking about CEA.

Yes. So we see the technology is broadly applicable to many different types of tumor targeting antibodies and tumor antigens. And so the second entity in our pipeline has been an agent that we call BDC-2034. And there, the targeting antibody was targeting a tumor antigen known as CEA for carcinoembryonic antigen. Well, CEA is actually a family of receptors on the surface of cells. In this case, we wanted to specifically target what we call CCAM5 or CA5. And what we found was that the antibody also targeted 2 other members of the family, CCAM 6 and 8, which are expressed in granular sites in the blood. And so when we did our toxicology studies, we found that, that cross reaction to those other antigens because what we felt was going to be an unacceptable level of toxicity. And so we've deprioritized the program in that sense. What that program now needs, and we've actually demonstrated this, if you take a highly specific CCAM5-directed antibody with the same linker payload -- we don't get any of that toxicity. So it really is about the targeting antibody in this case.

And are you going to do work, and you're going to go back on that? Or just given where you are right now, you're going to come back to that later.

So what we're going to do is we're going to develop what we call a nectegeneration ISAC, okay? CEA is one of the candidates for that. we will obviously use a more specific targeting antibody when we do that. And in addition, it's an opportunity for us to bring what we call our next generation of linker payloads to bear that's actually even better than what we had on 2034. So we'll be baking that off with another program that we have in-house and make a choice as to which one to take forward.

And as you think about -- I want to make sure we get the DECTIN-2. But maybe just talk about what are some of the next-generation features that you have in this.

Well, we have -- one of the beauties that we have at Bolt is a chemistry group that can really dial in specificities, affinities, potency for different TLRs, et cetera, and we can dial that in for the specific biology that we see in the tumor types that we want to solve. And so what we've been able to do, I think, is more refined what those payloads look like. As you know, I think from the -- our competitors' data, it's not always about more potents, okay? It's going to be about the selection of the potency for the actual TLRs themselves at a right potency level. And then it's about the linkers that we use. So there will be a next generation of linker as well as

Great. Great. So decking to a little bit of a different program. So talk to us about how you got into that and what's the biology of that in DECTIN-2?

So DECTIN-2 is really a similar approach to what we're taking with the ISAC DECTIN-2 is a surface receptor, again, on tumor resident macrophages, overexpressed in tumors relative to normal tissues. And what we know is that, again, it is a what we call a pattern recognition receptor and his job is to look for foreign invadors, okay? And it specifically acts on the glyco sugars on these foreign invadors, which can bind to and activate , DECTIN-2 which then again stimulates the innate immune system. It's a very similar response to like activating a toll-like receptor. The beauty here is that we could use a naked antibody. The Bolt team has discovered a high affinity, high specific antibody that activates decent to tick off the [ inmate ] immune response. And it complements what we're doing with the ISAC. There are 2 different biologies, but acting on similar cell types that we think can enhance each other in parallel, but it's a much more simplified system, in this case, for approaching solid cancers.

And for that program, what's the path towards IND submission? What work do you need to do? And I guess let's start there and I have couple of there.

So we've had early interactions with what we call pre-IND interactions with the FDA. We've agreed with them on what our toxicology plan should be, what manufacturing will look like as we head toward the clinic in the first half of next year and to agree on what that transition from our preclinical dosing strategy to what our first into human dosing strategy will look like. So that's all agreed. And right now, everything is on track for 2023.

Okay. And just in terms of the landscape, anybody else that you know of going after DECTIN-2? Like how did you come about this start?

So this is actually technology that came over from Ed Engleman's lab. The team over there was looking at myeloid cell antigens that could be stimulated to reprogram myeloid cells within the tumor microenvironment. And activation of DECTIN-2 in this case, takes what we call a tumor supportive macrophage and reprograms it to a tumor destructive macrophage in this case. And what they found was a small natural ligand that they could activate this receptor with. It's not something that I think would be appropriate as a drug or that you would use to manufacture. And so what we did is we took that on and said, "Well, let's see if we can find an actual specific agonist antibody to mimic this agent, and we are able to do that.

Okay. Okay. And just in terms of safety or tolerability. I mean any -- as you think about potential risks when you start to dose this, what might they be?

Well, again, I think that this is going to be about therapeutic window between the over expression of this that we see in tumors versus the much lower expression that we may see in normal tissues and in inflammatory events. But again, that's what the toxicology strategy that we've laid out with the FDA is about is to ensure a safe transition into people.

Okay. Okay. Great. We touched a little bit on what else you're working on. Maybe before we get to that, just remind people, as with a lot of other companies, you've taken a look at your cost structure and try to extend your cash runway. So what are some of the choices that you made there? And how are you thinking about cash runway and some of the prioritization?

Yes, I think that it's actually a great question. So I think the biggest thing that we were thinking about was because this technology is so broadly enabling. It's a platform, okay? And so for us, what we wanted to do is make some choices set some priorities of what we felt would prove the technology that bring along the next generation of the technology and narrow the number of programs that we were trying to tackle in-house. So what that did was it freed us up from multiple manufacturing campaigns and it freed us up from a lot of pressure to dramatically increase the size of the company that to support this large number of programs. And so we're now focused on a fewer set of programs; and two, we're focused on programs that are supported by our 3 partners completely funded through research and proof-of-concept in the clinic at their cost with opportunities to add things to our pipeline without dipping into our own war chest to do that.

And how do you think about partnerships? Obviously, you've had some early stage ones, is that a potential funding mechanism for the...

Yes. So we think that, obviously, revenues from partnering is going to be an important component to how we finance the company. Right now, we've got 3 partnerships, Genmab, Innovent and [ Torre ]. As I said, they had strong upfront payments for us that helps fund the pipeline programs. We will continue to do more partnerships like that. But in addition, I think as our own pipeline programs begin to move along, there's a lot of corporate interest in those as well. And I think in the future, investors can -- we'll see us partner one or more of those.

Okay. And sorry, you just -- when you talked about your cash profile -- sorry, Eda, do you want to say something?

Yes, perhaps related to our partnerships, we also have a collaboration with Bristol-Myers Squibb because their supply nose with Opdivo or nivolumab for our ongoing trial.

Yes. Great. I just wanted to, Randy, just back on cash. Have you said specifically how many years have captured when -- what your current...

Yes, our guidance is that we've extended the cash -- our cash runway by 2 years. with this exercise, and it takes us out through 2025 at this point.

Okay. Great. Good. Maybe just one last question here about -- because if you remind me, we didn't talk about with 1001 monotherapy versus combination and how to think about how you're going to evaluate that data, which is obviously part of the data release?

Yes, very good. Even though the mechanism of action of our ISAC versus the checkpoint inhibitors, such as animolumab, were expected to be different. We wanted to be cautious in our dose-escalation trial. But up to this point, it has also been very successful from the safety standpoint to combine BDC-1001 with nivolumab. So we're doing a parallel enrollment on the weekly regimen, monotherapy and also combination with nivolumab. So we expect to complete that portion of the trial also this year.

Okay. Great. Great. Perfect. I mean, I guess, the only last thing is to ask early-stage development, how you're thinking about some of these other programs and just time line for what kind of pace of new INDs you're prioritizing?

Yes. So well, I think the most important thing is that we prove out 1001 and build investor confidence that this is a technology that can deliver high levels of efficacy. -- with safety alongside of that for our patients. And then alongside of that, we will invest in and advance these earlier programs along the way. We're going to be judicious about how we do that. But again, I think the team has done a fantastic job of improving the technology along the way to both get a better tumor kill, but also deliver safe profiles at the same time. So it won't be the same number that maybe we anticipated. But along with our partners, we're going to be able to, I think, really prove this out in different types of settings. -- different types of antibody structures with Genmab, it's bispecifics with Innovent, it's novel targets and antibodies. And with [ Tore ], it's a novel target as well. And so we're going to have a lot of chance to look at this and have a high number of shots on goal.

Great. Randy, thanks for being here. Appreciate it.

Thanks for having us.

Thank you.