Hi, welcome back to the fifth Annual Oncology Innovation Summit here from TD Cowen. We're really happy to have with us for the next session, the team from Cullinan, where we have Nadeem Ahmed, the CEO, as well as Jeff Jones, CMO. Where we'll be discussing a number of updates from the program, from their programs, one at ASCO, with the MICA/B antibody, CLN-619, but also, we'll probably get a little bit to CD19 as well, and the transition to autoimmunity at the end. But we will kind of keep this mostly focused on the ASCO update. With that, maybe I have a list of questions that I will end up going through, but I would also like to keep it interactive, if possible. So to the investors on the line, if you want to email me questions at mark.fram@tdsecurities.com, or you can also submit questions via the portal. Either route is fine, and I will add those into my list to ask Nadeem and Jeff. But with that, maybe, Nadeem, you want to just level set people with kind of a state of the company and what you view as kind of the major milestones over the next year or so, that investors should be looking towards? Sure. Happy to do that, Mark, and thanks for hosting us. Well, the first thing I would say is that Cullinan Therapeutics is at a really exciting inflection point for the company. We have multiple clinical data readouts this year from our oncology pipeline, and as many of you are aware, and you alluded to, Mark, we also recently announced our strategic expansion into immunology, which will enable us to fully unlock the value of CLN-978, which is our CD19 by CD3 T cell engager. So starting with oncology, given ASCO coming up, you know, we have a diversified pipeline of what we believe are highly differentiated, either first or best-in-class, agents, across a broad range of cancer indications, both solid tumor oncology, hematology. And in terms of near-term data readouts, which I'm sure we'll dig into during this discussion, Mark, you know, as you know, we have a data presentation for CLN-619 at the upcoming ASCO meeting. As a reminder, CLN-619 is our MICA/MICB antibody targeting a novel pathway, so another first-in-class molecule in the clinic. And we'll be presenting updated monotherapy data following the efficacy signal we saw in monotherapy last year at ASCO. And for the first time, we're going to be presenting combination data of CLN-619 plus pembrolizumab. And then for the back half of this year, we also plan to share additional clinical updates from phase one clinical trials for both CLN-4049, which is our FLT3 x CD3 T cell engager, so another T cell engager, which we're investigating in relapsed refractory AML, as well as high-risk MDS. And at the same time, we also have CLN-418, which is our B7-H4 x 4-1BB bispecific immune activator. We've also guided to data second half of this year for that program, which is in phase 1, dose escalation across a range of solid tumors. And then we also expect to have our zipalertinib pivotal study. This is our EGFR inhibitor targeting exon 20 insertion mutations to be fully enrolled by the end of this year. So we have a lot going on, obviously, in oncology. And then the last thing I'll say about autoimmune disease is, you know, with CLN-978, we have an off-the-shelf, potential disease-modifying treatment, which we think has potential across a range of autoimmune diseases. And as we've guided to, we're starting with lupus, SLE, as our first indication. And at the same time, we are very pleased to see the recent publications for the first time of clinical data validating the CD19 T cell engager approach across autoimmune diseases. And we believe, of course, that the T cell engager approach is differentiated from CAR T cell therapy in many, many ways. And then the last thing I'd say, you know, finally, with our recent financing, we now have cash runway into 2028. And so we have the resources to both continue to advance our oncology pipeline, but also fully unlock the value of CLN-978. As we look ahead, since you asked, Mark, over the next two years, you know, we want to continue to read out expansion cohorts from CLN-619, as well as start to report out data for CLN-978 in autoimmune diseases, pivotal data readout from zipalertinib also, and then, of course, data readouts from other programs as we advance our oncology pipeline also. So in a nutshell, that's kind of a state of the union of the company, but we think 2024 is going to be a super exciting year for the company, and looking forward to a future full of opportunity. Thanks for that, Nadeem. We'll start on 619, since that's the most near-term updates. You know, we, we did get a, a chunk of that already, in the press release, you know, alongside in the abstract and press release. But, Jeff, you want to start out with just kind of reminding people the, the mechanism here? Because this is definitely, as Nadeem said, a novel target that we're not, you know, we're not used to dealing with. And then, you know, maybe is there a biological reason that maybe you're seeing some of these signals? Does it line up with, the understanding of that mechanism? Sure. So, first, you know, MICA and MICB really have a pan-cancer potential as targets for immunotherapy and oncology, both solid tumors and hematologic malignancies. And part of the reason is that this is a really, highly conserved mechanism across cells that undergo some sort of cellular stress, whether that's viral infection, oncologic transformation, or even senescence, where they upregulate MICA and MICB as stress-induced ligands, and it flags them for clearance by cells of the innate and adaptive immune system that express NKG2D. So this would not be not only in NK cells, but also subsets of T cells, like CD8, some subsets of CD8s, gamma delta T cells, and NKT cells. And so in general, this is kind of a background housekeeping mechanism that cancer has figured out how to do an end run. So in the tumor microenvironment, proteases will actually cleave MICA and MICB from the cell surface, allowing the cells to elude immune surveillance. The really interesting thing about CLN-619 is that it binds near the site of proteolytic cleavage, which is close to the membrane in the alpha-3 domain, and it actually, by binding there, precludes access of the proteases to the site where they would typically cleave MICA and MICB. And we've shown in our translational data last year at SITC, that we are effectively upregulating cell surface expression of MICA and MICB in most of the tumor specimens that we assessed. So you're alluding, in terms of a pattern of response to data that we shared last year at ASCO for the monotherapy arm of the trial, where we showed an unusual pattern of response, where a large number of the patients who experienced clinical benefit, including two patients with objective response and partial responses, and a number with stable disease, had endometrial cancer, the two objective responders. As well as a larger subset of patients, including ovarian, cervical, and hormone receptor-positive breast cancer, that had stable disease that was extending for, you know, longer than six months. We'll update those observations this year and show that those responses were actually quite durable in pretty much all cases. So you ask, well, why do we think that is? Well, I think there's still some questions to be answered, but we do know that MICA and MICB are in part under estrogen regulation, and that there are estrogen-sensitive response elements in the promoter region of MICA and MICB. We also know, particularly in endometrial cancer, that there are unique sets of NK cells, uNK cells, that are an important part of both normal physiology as well as malignant pathophysiology. So we think that it's probably a combination of those factors, expression of the target, where there's high expression by looking for mRNA, but also the relevant effector cell populations present in abundance that is in part responsible for what we've observed. Maybe we'll stick with the monotherapy for a minute here. Just, yeah, you are moving forward monotherapy in endometrial, given that signal with expansion. Just the treatment landscape in endometrial has been in flux over the past year or so. You know, some approvals are happening and things are shifting lines. Just in that kind of second-line plus setting, like, what's your latest thoughts on it? Like, what's a good response rate, a good duration of response as we get towards expansion data? Yeah. Maybe it's to talk a little bit about what that space looks like and what a patient might receive and what they might expect as sort of the benchmark. So right now, in the second line, the most effective approved drug is PD-1 in patients who are mismatch repair deficient, or PD-1 plus nivolumab in patients who are MMR proficient. But the major change in the landscape over the last year is that PD-1 is moving to the front line in combination with chemo, and is expected by the end of this year to have a broad label inclusive of both of those subpopulations. So now, as patients enter the second line, they really don't have a highly effective therapy, and they'll typically receive monotherapy with various chemotherapy agents, Doxil, Taxotere, where they can expect no better than about a 15% overall response rate and probably less than six months of durability. As a consequence, I think we tend to view a response rate in the 25% range with, durability in excess of six months, to be a reasonably, good indicator of clinical benefit for a novel therapy in this space, and one that could likely meet with regulatory acceptance. From a clinical standpoint, we didn't talk about the safety profile that we showed last year, but one thing that we've heard very consistently from endometrial investigators is that it's not only effective therapies, but also safe therapies in which they're really interested, and that's another place where CLN-619 could really shine. That's helpful. And then maybe we'll... We, we won't fully leave monotherapy, but, but we'll start to bring in the combo piece. You know, the first data is coming in this ASCO presentation, although, you know, a term that's in the abstract and press release. You wanna just kind of review what you showed there for people who may, may have not seen it? Yeah. First, maybe I'll just mention that we began the combination dose escalation to run in parallel. So this was not something that happened after our initial observations. It was always planned to run in parallel. And once we'd cleared the initial dose levels of monotherapy per plan, we began dose escalation at one milligram per kilogram, extending to 10 milligrams per kilogram, in combination with the standard dose of PD-1 on the every three-week schedule. And so we treated a total of 22 patients in that arm of the study, so about half as many as we treated with monotherapy, and 18 of those patients are response evaluable for response, meaning they had at least one post-baseline imaging assessment. So in that group, I think, we were very gratified to see three objective responses, two in patients with oncogenic driver mutation, non-small cell lung cancer. First, a mutated EGFR and a second with ALK rearrangement, and then a third patient, achieved a response, a patient with gastric carcinoma who was, PD-1 naive. I think the responses in non-small cell lung cancer were particularly interesting because these are patients who are really not expected to achieve much clinical benefit from PD-1 therapy. So it does provide a bit of a cleaner signal, than you might sometimes see in combination with PD-1, understanding that the patient population and sensitivity to PD-1 is often heterogeneous. But here, these patients, you know, there was a presentation last year, one of the Keynote studies showing that adding PD-1 to chemo achieved, no significant additive benefit over chemotherapy alone, and that's just one, of a number of studies showing that. So we think that this is a really interesting finding in our combination arm of the study, so interesting that we are pursuing expansion cohorts in non-small cell lung cancer, not only with the combination, but also in the monotherapy arm of the trial to understand the relative contribution of components. Is there a reason to believe this, you know, given the biology of driver mutation-positive lung cancer, that this would be differentially likely to benefit from, like, AB blockade? Or is it more just you can see the signal a little bit clearer because that PD-1 expectation is so low there? Yeah, I think it's both. But I think the reason that the PD-1 activity is so low there is that in both ALK rearranged and EGFR mutated non-small cell lung cancer, antigen presentation machinery is deficient, so there's usually downregulation of MHC-1, which is necessary for an adaptive immune cell response. And so these are patients that typically don't respond to T cell-directed immunotherapy, but the mechanism of action of CLN-619 is not dependent on an intact MHC-1. In fact, MHC-1, in general, tends to downregulate NK cell activity. It makes sense, but again, as in the endometrial patients, a lot still left to tease out as our translational and biomarker studies proceed. Okay, and you did lay out, again, in a press release and in that abstract, you know, the kind of very high-level efficacy information. You know, what else is there to... that investors might learn in the, in the presentation itself that's coming this weekend versus, you know, what we've already been told? Yeah, I think, there are probably two key things, and, and Nadeem, you should also comment. But I think they're the two, and I'd go back to monotherapy, is that, we saw objective responses, but as we think about broader developments of this agent, there's this larger group of patients who achieved clinical benefit, which in the presentation we defined as objective response or stable disease in excess of 18 weeks. And there, it was a much larger group of, patients, 41% of the evaluable patients, who achieved clinical benefit. And, you know, stable disease, you know, it isn't objective response, but stable disease that lasts nearly a year is really providing clinical benefit to a patient with advanced cancer, and it suggests that as you try to move a drug up in earlier lines of therapy, there's greater likelihood of a progression-free survival benefit. So I think that's an important take, and looking at those patients in greater detail is possible in the poster presentation. I think also the safety profile continues to be quite favorable, particularly as compared to some immunotherapies, both as monotherapy and in combination, where we saw no new safety signals. And we believe it continues to show not only that CLN-619 has a favorable safety profile, but its safety profile is such that it's amenable to other combinations beyond PD-1. Yeah, I agree. The only thing I would add to what Jeff said, Mark, is that, you know, when we define clinical benefit response, we've taken quite a conservative approach. We haven't included all stable disease. We kind of said you have to have stable disease for at least 18 weeks. So if you were doing cross-study comparisons, for example, it might look a bit, a little bit lower, but we think prolonged stable disease is what really provides clinical benefit versus, say, transient stable disease. And then certainly, as Jeff says, the safety profile really lends itself to continued monotherapy development as well as, you know, potential combination therapy partnerships beyond even checkpoint inhibitors. We'll get to those other combinations in a second. But you have expansion cohorts in some of the gynecological cancers that you're doing this—you're going to do this lung cancer—driver mutation-positive lung cancer cohort now. Should we view the kind of signal exploration stage, you know, kind of to choose expansion cohorts is kind of at least over for now, or is there still, you know, more info to be gathered that could trigger some additional kind of monotherapy and PD-1 combo cohorts in the- More the latter, Mark, and you'll hear more about that. ... it, we'll hear more at ASCO or more just, over the course of the rest of the year into next year? Well, come along on Saturday, and you'll hear more about it. Okay. Um- Or you can ask for Ben. It's at 6:30 P.M. in the evening on Saturday. That's Central. That's right, exactly. And then, for the other combinations, I guess, should we think of those as some of these other tumor types, or is that there's more logical combinations kind of within the tumor types we've been discussing, so cervical, endometrial, lung? Yeah. One thing I would add before I actually turn that question over to Jeff, the other interesting thing that Jeff alluded to that we've seen with some of these prolonged stable disease patients, you know, we've seen it across tumor types, including patients who have progressed on prior checkpoint inhibitor therapy. So if you look at our PR, and you'll see it in the poster, you know, we saw a prolonged stable disease in pancreatic cancer, which is pretty unusual. We saw it in breast cancer. There may be some, that estrogen linkage, you know, Jeff alluded to before. So I think in terms of early signal seeking, at least, this is very good as it pertains to, you know, when we compare to other, you know, novel immunotherapy agents in the past that, you know, haven't actually shown responses as monotherapy and have gone on to become, you know, combination play. So I think for us, we're super excited about that. But, Jeff, do you want to speak to the combination approaches? Yeah, I mean, I think there's clear evidence across different immunotherapies, whether it's just naked monoclonal antibodies or checkpoint inhibitors, that many of them perform very well in combination with chemotherapy, and chemotherapy is itself immunogenic. So I think there are plenty of opportunities for combinations with standard of care chemotherapy, which is also expected to put cells under cellular stress and increase MICA and MICB expression. So I think it can work at several purposes in combination with a drug like CLN-619. We also know that radiation can work better in combination with PD-1 in some circumstances, and there's also evidence that radiotherapy can promote the upregulation of MICA and MICB. I think there's also a number of places where people have tried, say, in lung cancer, to combine TKIs with immunotherapies and have found that the toxicities are somewhat overlapping and that the combination potentiates the TKI toxicities. I think, based on what we've observed so far with CLN-619, there may be potential for combinations there. And we'll—as Nadeem said, a lot of potential for combination, and we'll we'll talk more about that on Saturday night. Maybe, as we're starting to run low on time, we'll kind of go to rapid fire for other programs. So there's also zipalertinib that, Nadeem, you mentioned in the lead-in. The exon 20 space, obviously, it's had a number of changes over the past year of, well, of drugs failing trials or succeeding in the confirmatory trials. And we're also gonna get several updates at ASCO from kind of competitor programs that longer follow-up of some of those trials, but also, you know, competitors trying to get onto the market. Just where do you see the exon 20 landscape today, and kind of what's a need for zipalertinib's pivotal trial for it, for how it fits in? Yeah, I would make a couple of quick comments in lieu of the time, Mark. So I would say, look, we've seen a thinning of the herd, maybe that's how I would describe it, over the last year or two, where some companies have actually dropped their exon 20 programs. Our view is that we still have a best-in-class potential profile. The one thing that we've done that nobody has really done in a systematic way in relapsed disease, we understood that amivantamab was likely to get their approval converted to full approval with the frontline study, and so we did two things. One, we enrolled patients with prior approved exon 20 inhibitors, mostly amivantamab. So we think that dataset will be very helpful in terms of, you know, regulatory potential for accelerated approval, which we think is very much still on the table, because we'll have a dataset that not only reflects the current standard of care but the future standard of care with post-amivantamab patients. So I think that's really important. Secondly, in terms of the frontline study, we're repeating the similar approach that J&J did with amivantamab, in the sense of we're taking a combination approach, which we think will maximize patient outcomes. Whereas, you know, as you know, mobocertinib, they tried head-to-head versus chemo. That complementary study failed. The other two competitors in this space, one of which you mentioned this year again at ASCO, both of their frontline studies are going head-to-head against chemotherapy. We don't think that's the optimal way to address this disease, so we feel very good about where we are today. You know, what are investors missing about the market opportunity? I think generally, they're pretty skeptical that this is a meaningful commercial opportunity. I guess, what do you think they're missing? Sure. So again, a couple of things. So I think for a period of time, there were two drugs that were approved for relapsed disease. In clinical reality, there are actually no drugs now available for relapsed disease, 'cause Amivantamab's gone to the frontline setting, Mobocertinib has been taken off the market because they failed their confirmatory study. So I think that opens up a space in relapsed disease. But ultimately, we think the best space for zipalertinib is in that frontline setting, and I think we have a very strong safety profile. I mean, if you look at the Papillon study, you know, over 50% AEs in combination. And so we think that's the place where we have, the optimal opportunity. But obviously, starting with relapsed disease first through accelerated approval is our plan. ... And I will give you one CD19 one, which is just, you know, what, you're opening up the SLE trial over the next quarter or so. And, you know, what we hear concerns from investors we hear is that a number of these kind of next, called next gen B-cell targeting agents in SLE seem to be going very slowly in terms of actually recruiting patients, despite what looks like tremendous efficacy from the IST datasets. I guess, what gives you confidence that your trial's gonna fare a bit better? Jeff? Yeah, so I think, number one, we don't have to go to certified CAR T centers to deliver our drug. You know, we are much more patient-friendly in that we don't require prolonged manufacturing times of cytotoxic chemotherapy, and there's no measurable risk of secondary malignancies associated with a T-cell engager like ours. And lastly, we are targeting a broader patient population than, particularly the lupus nephritis trials, the ones that I think have most been struggling, where they're looking to solve a pretty narrow patient population, sick enough that they have a WHO Grade III/IV lupus nephritis, but well enough that they're fit to participate in a phase one clinical trial that requires cytotoxic chemotherapy. That's a lot. So, I think it's both with more flexible entry criteria and a more versatile site footprint that we can be successful. Okay. And then, Nadim, you also mentioned kind of the proof of concept that's happening, that's happened, for this general approach with some data using Blincyto off-label. When might we expect this program to move beyond SLE? Do you need to kind of get some initial exposure data to open those? Is it just all moving in parallel, and SLE happened to be the first IND? Just how should we think about that? Yeah, Mark, I think the fact that we've now had this financing, that actually allows us to open up multiple indications and open them up more in parallel than sequentially. So the next indications are not contingent on data from the SLE study, so that's the first thing to answer that question. And then secondly, look, the topic of next indications has been the subject of intense discussions within the company, and then blinatumomab data came along, too. So, you know, we feel that there's potential for 9 7 8 to work across a broad range of autoimmune diseases, which we're discussing currently. And then I think once we're ready to announce which of those are, we will be, but there's not a gating factor here. Okay. Unfortunately, we're running over, so we're gonna have to cut it there. But we look forward to the update at ASCO and the rest of the programs later in the year as well. And thank everyone for joining from the investor side, but also Nadim and Jeff from Cullinan. Great. Thanks so much, Mark. Bye.