Awesome. Well, great. Thanks so much for joining us today. We have Gritstone bio, and Celia here to join us, who's the CFO for the company. Maybe, Celia, you could just start with, like, a brief overview, particularly focused on what you see as key value drivers for the company... Yeah. for the next 12-24 months. Of course. Well, it's good to be here, Corinne, in such a packed room at the end of the day. Tons and tons of people in here. Thank you for the invitation, first and foremost. Yeah. We're pleased to be here after quite a few years of not really having this conference. Gritstone is in a pretty amazing spot right now. We have a pretty major catalyst that's coming up in Q1 of next year for our lead program, GRANITE, which is a personalized neoantigen-based cancer vaccine. We've been hearing a lot about cancer vaccines lately, especially coming out of ASCO. This has been more or less a graveyard in the field, but that is changing, and there is a lot of promise out there, and we're incredibly excited about that. I would say that's our... That is the near-term value driver for the company, which felt like a long time away when I started at the company, but it is just around the corner. Absolutely. You kind of mentioned it, but cancer vaccines have been something of a graveyard. How do you think about the differentiating features of the GRANITE platform that could overcome some of the traditional challenges we've seen in that field? Yeah, of course. Great question. A couple of the reasons that cancer vaccines haven't really worked in the past is we didn't know what targets to go after, and we also didn't use powerful enough vectors. Those are two things that we think we've been able to address at Gritstone. We believe the neoantigen based approach, which is also something that Moderna and BioNTech are doing, is ultimately the best approach. Neoantigens present specifically on tumor cells, and we also think we have a best-in-class way of identifying which neoantigens to actually go after and put into our vaccines. Separately, on the vector side, we think we're using some of the most powerful vectors that are out there, and we do what's called a heterologous prime boost. This means we're mixing and matching the vaccine vectors. We're using the traditional, I guess, call it old school, vaccine vector, the chimpanzee adenoviral vaccine vector, which we know to be one of the best, well, really, the best primer of CD8 T cell responses. We're boosting with self-amplifying mRNA, which is a next-generation mRNA platform. Great. I mean, you've referenced it, GRANITE's not the only thing to have made progress here, you do have the Moderna and the BioNTech platforms. I guess, how do you view the data we've seen across the modality relative to the Gritstone approach? Yeah, of course. Well, the most exciting thing is that what Moderna and Merck have been able to show is, I mean, this is the first time we've seen efficacy in a phase II randomized study of any cancer vaccine, so in a neoantigen-based cancer vaccine. It is great external validation for the neoantigen-based approach, and we think it also bodes well for what we're doing. They're actually going after a hot tumor, which is, an adjuvant melanoma. With hot tumors, these neoantigen-based vaccines are actually able to boost a pre-existing T cell response. I mentioned that we actually use that ChAd, or chimpanzee adenoviral vaccine, because it's a great primer of CD8 T cell responses. That's partially why we're going after cold tumors, because we know we can actually prime that CD8 T cell response and come in and boost it with our self-amplifying mRNA. We're getting great external validation from what we're seeing from Moderna, what we hope to be seeing from BioNTech later this year. They will have data for their melanoma trial as well. They've also indicated that they will have data for their in colorectal cancer sometime next year, and we'll be slotted in there in Q1 of next year. It's certainly an really exciting time for the space. Absolutely. Obviously, identification of the neoantigens is a key component of this. How does the EDGE platform differentiate versus some of the other algorithms at play? As much as I'm gonna try and channel my inner Andrew Allen here, I'm not gonna be so great at it without a British accent. EDGE, we do believe, is a best-in-class platform, and that has been published. That was published in Nature Communications, sorry, Nature Biotechnology in 2018. It's hard for me to actually compare and contrast because we haven't actually seen how Moderna identifies their Mm-hmm. their neoantigens. Right. With BioNTech, we do know that they use what Neon had used. BioNTech had actually acquired Neon a few years back. Mm-hmm. We know that their antigen prediction platform was quite good. Mm-hmm ... fairly good expectations for their data coming out later this year. What we've shown with our EDGE prediction platform is northwards of a 75% positive predictive value. In terms of the nuances there, I'm probably not the best person to actually answer that question. Understood. You did recently update the EDGE platform to include both CD4 and CD8 T cell proliferation as a goal. As you think about that, what is the advantage of eliciting both populations? More is always better sometimes. Not always. We know we've seen CD4 T cell responses with the other vaccines, and we believe those CD4 T cells actually do help with the CD8 T cell response, so it is helpful to have both. We are still very much focused on inducing a potent and robust CD8 T cell response. Okay. When could we see this particular update be deployed?... in terms of the clinical trials and? Yep. We shared a poster at AACR earlier this year, that is starting to be deployed. Okay. more so in the SLATE program. Okay. it will not be in this upcoming GRANITE readout or? No. GRANITE, you mentioned this, you have the two heterologous prime boost vaccines. How do you think about the distinct clinical activity of the two, you know, why isn't anyone else doing it that way? Why are you when no one else is, I should say? Yeah, it's an approach that we decide upon early on in the process. Our approach is very much rooted in infectious diseases. Again, we believe that priming of the CD8 T cell response is best done with that chimpanzee adenoviral vector. Sorry, that is a tongue twister. Say that 10 times fast. We decided that priming that CD8 T cell response would then allow us to come in and boost the response, and that would actually allow us to go after immunologically cold tumors. We wanted to. What we saw with the advent of checkpoint inhibitors is there are a lot of tumor types where they're not working. What was actually identified early on is that some of these ended up being cold tumors that had very specific neoantigens, which is why we ultimately went after that approach. Both Moderna and BioNTech are going after hot tumors, which makes sense because they already have T cells, and they're able to boost that T cell response that's already there. They basically don't need the prime because. They don't need the prime. They do patient selection. Exactly. Got it. Yeah. As you think about the self-amplifying mRNA, and how does that differentiate in terms of the particular decision to do saRNA? Yeah. Self-amplifying mRNA is a next-generation mRNA platform. We were actually the first to put that into the clinic in our oncology program. It's exactly what it sounds like. It self-replicates, it self-amplifies. That allows us to actually dose lower. Mm. The key differentiating factor with self-amplifying mRNA is durability, potency and durability, and that's something we've been able to see both on the oncology side and on the infectious disease side. Yeah, understood. Maybe switching to the clinical data we've seen to date, you reported some data from a study of GRANITE in metastatic colorectal cancer. Could you just maybe start by level setting us and telling us what we've seen so far? Yes. In a Phase I/II basket study that we administered GRANITE in advanced solid tumors, we administered that to 29 patients. 13 of those patients actually had microsatellite stable colorectal cancer. Of those 13, 11 of those had ctDNA at baseline, we were able to evaluate a molecular response in those patients. By a molecular response, I mean a reduction in ctDNA, as measured by a 30% reduction in ctDNA. In approximately half of those patients, we actually saw a molecular response, and in those subjects, we actually saw their median overall survival have a profound difference than patients who were not molecular responders. In that molecular response group, the median overall survival from our last update was at least 22 months. In this patient population, the expected OS is to be somewhere between six and eight months. That's what we actually saw in the patients that did not have a molecular response. Those patients' OS was about 7.8 months. Okay, understood. maybe in terms of the, like, ongoing studies, you're evaluating GRANITE in earlier stage populations. As you think about that, can you just help us understand the indication selection for first-line maintenance colorectal cancer? Yeah, of course. I mentioned we did a basket study in our Phase I/II. The largest number of patients we had was both in non-small cell lung and microsatellite stable colorectal cancer. MSS-CRC is a cold tumor. Mm-hmm. We think because of our unique MOA, we can have an effect in cold tumors. This is also a cancer which is the second leading cause of death in the U.S. and around the world, this represents a very large unmet medical need. If we can actually show that it's working and because these were later-stage patients, and we were still seeing a response, being able to move upstream, we do expect to see better results. We feel if we do see what we expect to see in this Phase II randomized study, this could theoretically be used in any solid cold tumor or, and even hot tumor, of course. Okay. Could you just refresh us on the trial design, some of the specifics around inclusion criteria, the cadence of the trial, et cetera? Sure. This trial is a phase II randomized open label study. We recently expanded the study from 80 patients up to 100. Either sadly or positively, we had actually very high demand for enrolling in the study, which really speaks to the unmet need for this disease area. We decided to expand the study, which is a great thing to do for patients. We, the control arm is receiving induction therapy. Well, both arms are receiving induction therapy for the first 24 weeks, and then the treatment group well, is going to then get their GRANITE treatment. induction and background therapy is, FOLFOX plus Bev or FOLFOXIRI plus Bev, and then in the treatment group, we add on GRANITE plus Ipi plus Atezo, and the control group will remain on just their, FOLFOX plus Bev or FOLFOXIRI plus Bev. Okay, understood. In terms of the manufacture of the vaccine, when does that take place during the trial? What first happens is we take a patient's tumor, we biopsy, and we send it to our sequencing lab in Cambridge, and we identify which neoantigens we actually want to put into the vaccine, and that takes us about 16 or so weeks to manufacture. During that manufacturing period, they are receiving their induction treatment. Okay, it's ready to go as soon as. Correct. -done with the induction phase. In terms of the induction phase, is there anything else you monitor when they move or the induction to maintenance in terms of ctDNA at baseline, et cetera? We do take ctDNA at various time points. I have to get back to you on exactly what those exact time points are, though. No worries. In terms of the neoantigens that you select, you're doing it before the induction phase. What have you seen to date in terms of, like, the fidelity of them from the beginning of their treatment to post-induction? Do you see them maintained the same neoantigens? We haven't analyzed- Okay. anything at this point. Okay. In terms of the preliminary data, I guess, how do you frame potential success scenarios? We saw in the phase I, approximately 55% molecular response rate. What we're powered to show in the phase II portion of our phase II/III randomized study is a 20% delta between the treatment and control group. The data that we are expecting to show early next year is ctDNA data and any other data we have on our secondary endpoints for patients that have had at least four months of GRANITE treatment. Given the enrollment timelines, what should we anticipate with respect to number of patients and the duration of therapy at the time of the readout? We are expecting to show data on approximately half the number of patients sometime in Q1 of next year. That's in patients who have had at least four months of treatment with GRANITE. The study started enrolling early last year, so patients will be at various time points, and I think we all know enrollment looks pretty much like a hockey stick. You'll get a few patients with much longer timelines and then a whole lot of patients with the shorter timelines. Absolutely. I guess, pending success, how should we think about next steps and what comes after that? This is a operationally seamless phase II/III study. What that means is we can essentially use the same clinical trial sites that we were able to use in Phase II, so we don't have to spend time, energy, and capital on site startup, which- Mm-hmm. I think most people know can be very costly and take quite a bit of time. The data that we intend to show early next year, we would then take to FDA and finalize our phase III endpoint for the study. That has not yet been finalized, and then we would roll more or less straight into the phase III, you know, sometime before the end of next year, would be the hope. Okay. In terms of, like, the regulatory conversation, I guess, what's your wish list as you approach the FDA in terms of potential endpoints, timelines? Yeah. I think our base case is a traditional endpoint like overall survival. Mm-hmm. I mean, that is the gold standard. That is what everyone cares about in cancer, is how long can you actually live? We believe, and I think there's data out there to support this, that there is a great surrogate for overall survival, and that is that reduction in ctDNA. A hopeful, very aspirational wish list is that we could actually have that as an endpoint, and it could even be an Accelerated Approval endpoint. Again, that is a aspirational wish list, not what I necessarily expect to occur, but we've certainly seen the industry shifting. When you look back historically over how much literature has been published on ctDNA, that has increased substantially in recent years. We saw probably, you know, close to 70 abstracts at AACR mentioning ctDNA. We saw 230 or so abstracts at ASCO with something similar. We saw updated KIMMTRAK data from Immunocore last week, again, showing that. Mm-hmm. -support of ctDNA being a better biomarker for OS than radiology. Even Moderna, if you take a look at their appendix from their investor event last week, had a whole section on ctDNA. We've also seen FDA moving this direction. They have proactively drafted guidance for clinical development and using, in oncology clinical trials and using ctDNA as a prognostic biomarker. Friends of Cancer Research is very active in this space. They have been collating data across the industry in their ctMoniTR project, which they are presenting in mid-July at their open public meeting. We've certainly seen this shift in the industry. I mean, it's ultimately better for patients if we can- Mm-hmm. figure out quickly that a drug is actually working for them. Right. Understood. Okay, then in terms of overall survival, I guess, could you also help us understand what current standard of care is in this setting and what you would expect to see versus potentially differences with the vaccine program? Yeah, in this treatment setting, we do expect OS to be around two years. Now, that's essentially what we saw in our molecular responders in late line. Mm-hmm. -treatment. I would expect, obviously, at least that and then more. It really remains to be seen. Okay. In terms of the expansion of the study post initial phase II, remind me how much larger you have to go into the phase III? ... phase III, about double the size, so we'll be at close to 200 patients for the phase III study. Okay. Very good. From there, you'd have to see potentially overall survival mature. It'll be a couple of years out from there. Correct. Okay. Maybe we could switch gears a little bit to SLATE. If you could just provide us an update on where you stand with that program and how you're thinking about funding it? Yeah. SLATE is an exciting program for us as well. We also view it as a personalized cancer vaccine. It's not fully individualized like GRANITE, but it's looking at shared neoantigens across certain patient populations amongst common tumor types. We've shown some promising early data with SLATE, very similar molecular responses in our, in our early studies. We do intend to start a randomized phase II with a KRAS-directed SLATE sometime in 2024. We decided to push that out a little bit in order to be able to expand GRANITE. As you know, capital is tight these days, in order to be able to make that expansion, we had to take a little bit of money from SLATE this year. We are still very committed to it, are excited about that platform. It's obviously easier to deploy because you can just make it all at once. Mm-hmm. We look forward to being able to start that randomized phase II study next year. Great. You've iterated a bit on the cassette there, could you talk to us a little bit about how SLATE's evolved over the years and what's driven the evolution? You learn by doing, and simple as that, is each time we deploy Slate, we learn a little bit something new, and we can optimize the cassette, simple as that. Will you continue to optimize it over the next year before- If it makes sense. Okay. If it makes sense. Maybe switching gears to the infectious disease portfolio. Obviously, it's called CORAL. Could you provide us a quick overview of that program and where you stand? Yep. CORAL is our second-generation COVID vaccine program. This started in early 2021 with a collaboration with the NIH. This is mostly based on our self-amplifying mRNA platform. We have since almost completed two other studies, one that we initiated on our own, which is a boost study in the U.K. with 40 subjects. A second program with CEPI, which is the Coalition for Epidemic Preparedness Innovations, that is a 340 subject study being done in South Africa. You know, we came into the COVID, the COVID landscape later than others, with the intent to focus on essentially the maintenance phase, which is going to last, you know, unfortunately, for the rest of our lives. Our intent was to build a next generation, more durable, more potent vaccine. We know durability is something that the current vaccines are not providing. Mm-hmm. We've even seen that commitment from the administration about continuing to search. Mm-hmm ... more durable vaccine options as we go forward. We have been able to show data in over 100 subjects at this point with at least 6 months durability data, and we're seeing this neutralizing antibody response that almost, well, actually a little bit above Moderna's, but with about a tenth of the dose. We're able to dose much lower. We're getting that high neutralizing antibody response, but that's actually sustaining- Mm-hmm ... for at least six months. We'll be able to share some more of that data later this year. Okay. I guess what are the features, as you thought about designing the second-gen program, that allow it to achieve some of these aims, a better durability in particular? It's all down due to the vector and our ability. Similar to on the cancer side, we use our EDGE platform. We identify the viral antigens, we put those into the cassette, and we also add additional T-cell epitopes into the vaccine as well. That is something additional that the other vaccines do not have. Mm. The jury is still out as to how that actually translates into clinical benefit. Mm-hmm ... and how the FDA may view that going forward. Right now, what the field has been focused on is. Mm-hmm that durability of a neutralizing antibody response, which we are seeing across our vaccines. Great. How do you see the path forward for that program, particularly in COVID at this stage? Yeah. COVID has presented a very good opportunity and use case for us to prove out that self-amplifying mRNA can be a next-generation vaccine option across a number of infectious diseases. We've been able to do this, mostly using other people's money. Mm-hmm. That's an approach we hope to continue to do. Yeah. We've been very open about the fact that this is not something we would intend to take forward on our own. Mm-hmm. We don't necessarily have all the expertise or capital to be able to advance that program. It is something that we would look outside of Gritstone to be able to help move forward if we were going to move forward with it. It has provided us with a lot of data and a lot of knowledge on the infectious disease space and other potential pathogens that we could look at in the future. Right. It's a great point. As you think about that, it obviously provided an opportunity for validation of the platform. How do you think about other infectious disease areas that would be of interest to pursue or where this kind of approach makes a lot of sense? Yeah, I think we can look to other mRNA companies and see the different pathogens that they're going after. There's no reason that we can't use self-amplifying mRNA in any of those pathogens. Of course, we've seen a lot out there on multi-respiratory and RSV, flu. Any of these could be potential options for- Mm-hmm Gritstone self-amplifying mRNA. We do also have a collaboration with the Gates Foundation on an HPV therapeutic vaccine. On the HIV side, we have a partnership with Gilead on an HIV therapeutic vaccine as part of their Kick and Kill program. Great. That brings up kind of my next question. Yeah. which is, like, can you walk us through the existing partnerships? Yep. The cadence of disclosures around those, the cadence of milestones? Yep, of course. The Gilead partnership was established in early 2021. We were in the clinic, or I should say they were in the clinic, by the end of 2021, so moving very rapidly. We have a great working relationship with Gilead. They had the first bit of data at CROI earlier this year, but from a non-human primate study, and we hope to see more data in due course. We hope that they'll be able to release more data in due course. If that they do decide to opt into a phase II, that will trigger a $40 million milestone payment for us. When this partnership was entered into in early 2021, we received an upfront payment of $60 million. This was actually the second largest preclinical ID deal done outside of COVID. Hmm At the time, definitely an exciting partnership for us and looking forward to seeing more coming from that. The full deal value is up to $785 million, which is mostly backloaded. On the, I talked earlier about the NIAID phase I trial. That was the first study that actually started on our CORAL program. They fully run that study. They've been operating, running, funding everything. We've essentially provided the product, we anticipate they'll be able to share some data from that in due course as well. From the CEPI study, that's our other major collaboration. We've already shared some data, we'll be able to share the rest, hopefully later this year. Great. In terms of additional partnerships, I guess, how are you thinking about the appropriate partners, potential structure of deals? Yeah. What could we expect to see? Again, I'll point us to Gilead. Gilead's a great example of the types of partnerships we like to do. HIV was not part of our expertise, and being able to partner with the leader in HIV treatment and prevention was the absolute right thing for us to do. Looking across, you know, we'd love to do more partnerships like that. Great. maybe as we think about just capital allocation, how do you think strategically about the various programs and opportunities set in front of you? This is a great question for you as the CFO. Thank you. Yeah. Our cash runway right now is into the third quarter. Again, we are, I'm sorry, into the third quarter of 2024, not this third quarter. Good clarification. We do have other levers. Like I mentioned, the $40 million milestone payment from Gilead. We do also have a credit facility in place, which gives us up to an additional $50 million that we can essentially draw down. Partnering has always been part of our strategy. This is, you know, partnering, collaborations. We like to use other people's money to help validate our platform, so we continually engage in discussions and educate and look to see what's ultimately best for our programs, for getting our products to patients, and to do what's ultimately best for our shareholders. As you look at the oncology versus infectious disease side of your portfolio, do you have a preference for partnering one versus the other, or are you open across the board? I guess, how do you think about that? I think we are ultimately open-minded. You want to do what's best for the company and what's best for patients and best for shareholders. From the oncology side, I think this represents a huge opportunity. If we are able to see the results that we hope to see in MSS-CRC, we think this can unlock a whole SLATE, pardon the pun there, of opportunities for us. We could theoretically go into any cold tumor, any solid tumor, any hot tumor, it's kind of hard to put a value on that today. I would lean a little bit more towards infectious disease, again, we're open-minded, but we did start off as an oncology company. We started off to cure cancer. That was our main goal. Mm-hmm. I think, you know, again, we're open, but we will do what's best ultimately for the company. In terms of the Gilead additional potential unlocking, when could we expect to see that kind of decision from them? That's entirely up to them. I think, you know, again, I can reiterate the fact that they were in the clinic within less than a year of us signing that agreement. They are known to move quickly. It could be as early as this year, it could be next year. We don't really have a very specific timeline. Great. Maybe in our final minutes here, as you think about the kind of current portfolio and the year ahead, what do you think investors maybe don't understand about what's coming? I think they have yet to understand how valuable the GRANITE platform can be, but also how potentially valuable our infectious disease platform can be. There are potential non-dilutive funding sources available to us, especially on the ID side, government, NGO, which have been evidenced by NIH and CEPI. I think just the immense opportunity that is there, we already feel that it's de-risked. We've already shown we can extend overall survival in a patient population that's more advanced than the patient population that we're already studying, and that this is ultimately the tip of the iceberg for us. There are so many more tumor types that can be opened up if we're able to achieve what we believe we're going to achieve next year. As you think about, I guess, how quickly you could advance or think about additional indications, particularly in cold tumors... Yep. How quickly would you start to move forward in other indications post a positive result from GRANITE next year? I mean, I would like to do it immediately, but capital constraints are always there, so I think it just largely. Yeah. depends on that. Are there any in particular at the company that you think are most appropriate? Yeah, I think the adjuvant setting is obviously exciting. That's something that we had intended to pursue initially. Mm-hmm. We had originally intended to do additionally an adjuvant study in MSS-CRC as well. Funds are tight as they have been in the last couple of years. We decided to prioritize the first-line maintenance CRC. I feel like that could be the next. That would make sense to be the next one. Okay. I guess assuming success, potentially funding, it's a little easier, so maybe you move into that as soon as next year. Is that possible? I think we'd still want to focus on moving into the phase III. That would still be our priority. Okay. not, maybe not necessarily next year, but... Okay. soon after. Okay, great. Any final thoughts? No. This has been fantastic. Thank you for having us here, and we're very excited about the year ahead. Yeah, absolutely. Thanks, everybody.