All right, ladies and gentlemen, welcome. Thanks so much for coming this evening. I've got- this morning. It's been a long week. This morning I've got Nadim here from Cullinan Therapeutics. Thank you so much for joining me. Good to see you, Jon. Before we get into some of the nitty-gritty on the programs, I'd like to give you a few minutes to just tell us where you are at the end of 2023, and looking forward into 2024, what are you excited about? What should investors be excited about? Yeah, absolutely. Maybe I'll start out a little bit with a high-level overview of the company strategy. So a couple of points I would make. You know, we have what we feel is quite a differentiated approach to the discovery process relative to our peers, through what we call a modality-agnostic, targeted oncology approach. So what that essentially means is that the start of our discovery process begins with identifying what we feel are high-impact cancer targets. And then we think about what's the best vehicle to address those targets. So in other words, we do target first, modality second, rather than the other way around that you see with some of our peers. And what that means, essentially, is that we're not dependent on a singular platform or even a singular product. So that would be one thing. Secondly, we have a very high bar for go, no-go decisions. What we do is we front-load as much experimentation as possible in the discovery process through what we call thriller or killer experiments. So when we get a killer result, as the name suggests, we kill the program, and we reallocate resources. When we get a thriller result, we think about how can we accelerate and double down investment there. And so that makes sure that we only bring forward the most promising differentiated molecules into the clinic, obviously, where you have the higher cash burn, to make sure that we deliver on our mission as a company to create new standards of care for patients with cancer. So we're seeing that strategy deliver, actually. I'll give you a couple of data points. So one, we now have a very diversified pipeline across targets, modalities, hematologic tumors, solid tumors, with multiple shots on goal. So that's one thing. Secondly, in about 18 months, we've gone from one program in the clinic to six programs in the clinic, which is a remarkable execution by the team, as we've evolved from essentially a research-based company to a development-stage organization. Ultimately, our aspiration to become a commercial-stage biotech company. So that, I think, is all going in the right direction. And yeah, at the end of Q2, we finished with around $480 million of cash, which gives us runway into the second half of 2026, allowing us, to come back to your question, to deliver on the multiple milestones we have coming up in 2024 and beyond. So really comfortable cash runway. So as we think about 2024, we'll talk about one of the most exciting programs in our pipeline, which is CLN-619, an antibody targeting unique MICA/ MICB pathway. We presented the initial monotherapy data at ASCO this year. Next year, we'll present the initial combination therapy data, so that's in the second quarter of 2024. We also have a molecule called CLN-418, which is a bispecific immune activator targeting B7H4 and 4-1BB. A unique approach, and, you know, we saw the ESMO data earlier this, well, just a few weeks ago, I guess, with the B7H4 ADC type of approach- -where we've seen interesting activity. So those initial data will be second half of 2024. Zipalertinib, our ongoing program, our lead, yeah, program that's the furthest ahead with that, we're- You don't want to call it a lead again. Yeah, exactly. So we're completing accrual in the pivotal study by the end of 2024. We gave that guidance also. For CLN-049, which is our FLT3/CD3 bispecific antibody targeting AML, we'll have the initial clinical data from our phase I study, second half of 2024. And then going back to CLN-619, we've already declared some expansion cohorts, so we'll have the expansion cohort data in the first half of 2025. So the coming months are going to be a very data-rich environment. Catalyst rich. Sure. Which we love to see. Let's start with that, not the lead program, but the furthest advanced. I'd love to start with that, EGFR exon 20 program- Sure. Zipalertinib. Can you characterize... Obviously, this is a very active space right now. Sure. We had two approved agents, now down to one. But multiple agents in the clinic seeking to address some of those issues. Can you position your program relative to some of your competitors in the development process? Yeah, absolutely. So there have been a lot of changes in that space recently, as you alluded to, Jon. And so, you know, I'll break it up into maybe the relapsed opportunity and then the front-line opportunity. And so in the front-line space, we did see that, with mobocertinib, unfortunately, confirmatory study failed. And that was, an approach of comparing single-agent monotherapy mobocertinib versus chemotherapy, which we actually don't believe is the right study design. Secondly, our own front-line study, REZILIENT3, similar to the PAPILLON study by Janssen, which I'll come on to, is comparing zipalertinib plus chemotherapy versus chemotherapy, the current standard of care. And we feel that exon 20 plus chemotherapy approach is the best way to maximize patient outcomes. And we fully anticipated the PAPILLON study would be positive. There'll be an approval in the front-line setting. And so actually, those results validate our study design, so we feel even better about our front-line study design. And since you mentioned development compounds, you know, at least two I'll mention, one from Dizal, one from ArriVent. Both of those frontline studies are repeating the mobocertinib study design of single-agent TKI versus chemotherapy, which, again, we don't think is the optimal approach. We feel that we have a molecule that has a very good profile to deliver in that frontline setting. Secondly, in the relapse setting, as you alluded to, so now, you know, mobocertinib has been withdrawn, amivantamab is moving up into the frontline setting. So that reaffirms the unmet need in that relapse setting, second-line plus. And we feel we have a molecule that has a potential best-in-class profile. We're at the upper end of the efficacy that we've seen with the approved agents. We have a differentiated safety profile, and you combine all that with the convenience of an oral regimen. So we think there's a really strong opportunity in that relapse setting. And, you know, we started our pivotal phase IIb study in that relapse setting at the end of 2022. And we mentioned, and we gave guidance that we're going to completely accrue by the end of 2024. And there we feel, you know, two things. One, similar study design, single-arm study, heading to accelerated approval, just like mobocertinib and amivantamab. At the same time, we also opened up a cohort of patients with prior exon 20- Twenty. -treatment. Yes, because we anticipate some of these changes in the marketplace. And so now, between our prior platinum-treated patients, prior exon 20-treated agents, we feel we have the broadest pool of second-line-plus patients that not only reflect the current clinical landscape, but also the future clinical landscape as we think about accelerated approval. So we still feel very good about where we are there. Makes sense. Before we move on to some of the other agents, which I want to make sure we spend the bulk of the time on, there's one other thing that I wanted to make sure we talk about in exon 20, and that's the combination of brain penetrance and patient selection. When we look across agents in development, and the approved agents, frankly, we have to be very careful in comparing datasets because of differences in patient inclusion criteria. Especially surrounding CNS involvement, which is unfortunately very common for- EGFR 20 patients. Can you, can you talk a little bit about what your patient populations are, especially in the second line? Sure. What the appropriate comps are to other- Sure Agents in development? Yeah, absolutely. Look, the patients with CNS metastases represent a significant clinical problem, and you see it accumulate as patients go through their journey from first line, second line, third line, et cetera. So a very real clinical problem. That's the first thing. Secondly, a lot of companies are using preclinical data to theorize what may happen in the clinic. Our view on that is that, you know, a rodent with an intact blood-brain barrier is very different to the clinical situation of a lung cancer patient that probably has an impaired blood-brain barrier. So most of the clinical data we see out there at the moment, most companies, including ours, by the way, is quite anecdotal. So we, in our own phase I/II study, in the clinical situation, we did see regression of lesions in the CNS. The thing I would say to properly address this question, you need a prospective study that accrues patients with active brain mets. Most early-stage development excludes those patients for obvious reasons. They're a much tougher patient population. So in partnership with, with Taiho, who are our development partners, we are actually conducting a phase II study, specifically looking at patients with active brain mets. And so I think we'll, we'll have the answer to that question soon. Okay, well, we look forward to seeing that. Let's move on from exon 20 and talk a little bit about that CLN-619, MICA/MICB- Sure ... a program that you were very excited about. Obviously, the data there is still very early, but there were a couple of very promising signals that you saw. So could you remind us what you presented at ESMO and what made people so interested? Sure, absolutely. I think it's also good to kind of provide the scientific background around this novel pathway. So just to clarify, so MICA/MICB is a ligand or are ligands for the NKG2D receptor we find on immune cells, especially NK cells, certain subsets of T cells. So that's number one. Secondly, on normal cells, we don't see MICA/MICB expression in our bodies. However, what happens when cells undergo stress conditions, whether it's a viral infection, genotoxic insult, malignant transformation, they upregulate MICA and MICB. And when that happens, those cells then, through the NKG2D axis, send a signal to the immune system, which then comes and destroys those cells. Or ought to, in any rate. Ought to. Exactly right. And probably while we're sitting here speaking, you're seeing destruction of MICA/MICB-flagged cells. I'm feeling very stressed. So what happens with the tumor cells is a little bit different. So, in that setting, in the tumor microenvironment, you have proteases that cleave MICA and MICB off those tumor cells, the surface, which then makes those cells once again invisible to the immune system. So that's the way cancer evades the immune system via MICA/MICB. What CLN-619 does is it binds to MICA/MICB on the cell surface, and it stabilizes the MICA/MICB on that cell surface. So that signal then is reintroduced. Is your binding site specific to some protease target site, or is it more of a steric inhibition? Yeah, what we've shown now, we had a poster at AACR, is that we bind to that specific site of proteolytic cleavage. So we prevent that proteolytic cleavage, which is very good for us to show that. And so then what happens is we stabilize MICA/MICB on the cell surface, NK cell subsets of T-cells can then come again and destroy those tumor cells. We also, through the CD16 receptor on those immune cells, invoke ADCC, ADCP. We also enhance the direct interaction between MICA/MICB, NKG2D. So CLN-619 actually evokes both the adaptive and innate immune system, and it's through this multimodal mechanism of action that we believe there's a really strong opportunity to develop both as monotherapy, combination therapy. And then finally, I'll say MICA/MICB is ubiquitously expressed across hematologic and solid tumors. So that portends well for CLN-619, potentially acting across tumor types. So that's kind of the basic mechanism of action, mechanism of disease. And going back to the ASCO data, which of course, we were very excited about, you know, it's not often you see single-agent efficacy in a solid tumor phase I dose-escalation study. And for that, that was really good. It was the first presentation of our monotherapy data, and we saw 3 objective responses at dose of 3 mgs per kg above. So we saw a complete response in a patient with parotid gland cancer. We saw 2 partial responses in patients with endometrial cancer. And 2 of these 3 responses were actually in patients that had progressed on prior checkpoint inhibitor therapy. So that was obviously very interesting. Secondly, all three of these responses on CLN-619 were better than the responses these patients experienced with their prior treatment. So going to that parotid gland cancer patient, that patient, best response was on checkpoint inhibitor treatment prior, experienced a partial response, went on to experience a complete response on CLN-619. With the two endometrial cancer patients, one of them had a best response of stable disease on a prior combination regimen of checkpoint plus nivolumab. The other patient, multiple prior therapies, didn't even experience stable disease. Both of these patients went on to experience partial responses with CLN-619, which again, that's quite unusual to see a better response in a later line of treatment. And then interestingly, we did see with this initial data set, a pattern of activity across gynecological tumors. So in addition to the two endometrial cancer patients, we saw prolonged stable disease in three patients with cervical cancer, two patients with ovarian cancer. And then beyond gynecological tumors, we also saw prolonged stable disease in a patient with breast cancer, prolonged stable disease in a patient with salivary gland cancer. So we saw this pattern of activity with single agent CLN-619 across a broad range of tumors, and that's why we're really excited about that program. Excellent. Let's... Two things I would love to dive into on CLN-619. Maybe first, given the, well, look, it's early data, it's dose escalation, it's phase I, limited numbers, but you do seem to see this signal in GYN cancers. Is there a mechanistic reason to expect that, given MICA/MICB's broad expression, that GYN cancers will be particularly susceptible to inhibition? Sure. Look, I think there are quite a few theories out there. But what we also built into our phase I dose-escalation study is a very rich biomarker panel that we're investigating. And so I think to truly assess the pattern of activity and link it to a biomarker, we need more time to analyze those, those data. But obviously, we're very excited about the signal. Interestingly, recently at SITC, we did show with our preliminary biomarker data, we saw three important things. One, we actually did show in vivo, in patients, upregulation of MICA/MICB expression on tumor cells, which obviously supports the mechanism of action. So that was really good. We also saw in the patients that derived some benefit on the study, whether stable disease or a response, tumor characteristics are typically unresponsive to checkpoint inhibitor therapy, so low tumor mutational burden, low neoantigen presentation index, and also, soluble MICA in the serum emerged as a PD biomarker in a dose-responsive- Presumably inverse? Actually, it's interesting. As the dose of CLN-619 went up, it increased. Two, there are probably two core reasons for that. One, MICA/MICB is produced, as we said earlier, outside of the tumor environment, too. So MICA/MICB comes from a range of different origins. Secondly, you know, you can envisage when CLN-619 binds to that circulating soluble MICA/MICB, it also extends the half-life- ... Stabilizes Stabilizes it. -and stabilizes it as well. Yeah. So we're digging into those data, but at the very least, it seems to be a PD biomarker. Interesting. The other thing I would love to talk about, and don't let me put words in your mouth, but presumably, combination with checkpoints and with other immune agents is the most likely path to extend these initial results into really practice-changing ones. Can you talk about pembrolizumab combination- Sure. When we should expect data there, and where you think the path forward is? Sure. So, our current phase I dose-escalation study has both monotherapy cohort and a combination therapy cohort with pembrolizumab. And so it's that first presentation of the combination therapy data that we're going to have in Q2 2024. So that's the next data presentation following the monotherapy data that we had this year. We also think there are other combination therapies this could be applicable for. We know chemotherapy upregulates MICA/MICB expression, radiotherapy upregulates MICA/MICB expression. So for us, this is just the beginning of the story. Mm-hmm, makes sense. I would love to talk a little. We're running out of time, but I would love to dive in a little bit more into that combination path forward. So you mentioned earlier, having high bars for success, having clear go/no-go. What is your expectation for the pembrolizumab combination? Obviously, it's an escalation cohort. Sure. What are your bars there? What do you want to see out of that initial data set? Sure, yeah. Look, as many of you know, combination therapy is trickier than monotherapy in terms of interpreting the data, right? Which is why it's so important- That's why- that we were able to show monotherapy, right? I'm asking the question. Yes, of course. But I think when you have monotherapy data behind you- ... which again, is pretty uncommon, it puts you in a much better place when it comes to future development. So we have a monotherapy path, we have the combination therapy path. I think in terms of combination therapy, I think we're going to look at all sorts of things. So one, what does it look like in patients who have progressed on prior checkpoint inhibitor therapy? What does it look like in patients who are unresponsive to checkpoint inhibitor therapy? So I think there's a range of things that we're going to want to tease out from the combination therapy data. Again, reminder, it is the first initial presentation. Escalation data. And then we'll dig into it. And look, we've already declared expansion cohorts in endometrial cancer, cervical cancer, monotherapy, and then there's the option in the future to do expansion cohorts in terms of combination therapy. Do you have plans internally for particular tumor types that where the checkpoint combination expansion cohorts might go? Yeah, look, we're going to continue to follow the data and the science, and I think we're going to be driven by that. So we saw signals in some of the gyn cancers, we declared expansion cohorts. We'll do the same with the combination therapy. As we see signals, we'll declare more expansion cohorts. All right. And, in our last few seconds here, you mentioned in your opening remarks a couple of other very interesting targets. Let's run through them just very quickly. FLT3 in AML- ... is obviously a target that has some clinical validation behind it, but has had its own, rocky development path. Sure. What are you looking for in the initial readout next year to differentiate you from the other agents in development? Sure, look- That have been in development. Absolutely. The first thing I would say is CLN-049 binds to the extracellular domain of FLT3, so actually, it's agnostic to mutational status. So now we're able to unlock a pool of patients that are 80% plus that express FLT3, rather than rely on mutant FLT3. So there's a much bigger patient pool available to us. And then, you know, as we dose escalate, we're obviously going to be looking for activity, antitumor activity in those patients with either relapse/refractory AML or high-risk MDS. Yeah. And, the study design there, fairly standard for that, are our AML, high-risk MDS patient population? That's exactly right. Yes. Just lastly, before I turn it over to my colleagues in the next presentation, you mentioned CD- I'm sorry, CDA, B7H4- Sure ... 4-1BB bispecific. Sure. You mentioned the recent data on ADCs there. 4-1BB bispecifics have had a very mixed history and are largely discounted by the investment community. Sure. What's giving you excitement about- Sure ... that sort of bispecific, as opposed to some other B7H4 targeting opportunity? Yeah. I think for us, the fact that we're utilizing B7H4 as a tumor-specific antigen, we believe will overcome some of the tox issues we've seen with 4-1BB approaches. So B7H4 allows us to deliver conditional activation specific to the tumor, avoiding those off-target toxicities. And then the final thing I will say, John, the other exciting program we have is CLN-978, CD19 bispecific, currently in phase I for lymphoma studies. But as you've all seen, CD19 has become a very hot target in immunology. Last couple of days, we saw CAR-T, some issues with cancer, secondary cancers, possibly. And so we think that opens up an opportunity for CLN-978 in autoimmune diseases, and we're continuing to look at the opportunities that that may present.