Okay, great. Thanks, everyone, for continuing to join us here at Guggenheim's second annual Healthcare Innovation Conference. My name is Brad Canino, Senior Analyst here. Very happy to kick off the morning fireside chats with Cullinan Therapeutics. I've got Nadim Ahmed, CEO; Jeff Jones, CMO. Thanks so much for joining us. Great to be here. Thanks. Nadim, maybe you can just kick off and introduce the portfolio and key priorities for the company as you see them today. Sure, yeah, happy to do that, Brad. Thanks for having us. Look, I would say that Cullinan, we're very excited to be here in Q4 with multiple catalysts in the coming weeks and months. From a pipeline strategy perspective, because I think that's important, contextual information, we focus exclusively on those molecules that have the potential to either be first in class or best in class, so that we can bring transformative medicines for patients with cancer and autoimmune diseases. We recently updated our pipeline. And so now we have a pipeline of what we would say relatively de-risked molecules, because every molecule is addressing a clinically validated target. Every molecule has shown monotherapy efficacy in the clinic. And each program is addressing substantial market opportunities. If you look at our updated pipeline, three of the four molecules are T-cell engagers, which has really become a core capability now for the company. Recently, last week, we announced that there were two programs that did not meet our internal rigorous go/no-go criteria, and we discontinued those. Those were CLN-617, which was our IL-2, IL-12 fusion protein, and CLN-619, our MICA/MICB antibody. For us, this sort of disciplined decision-making really allows us to be very efficient in terms of resource allocation to our priority programs, especially CLN-978, our CD19 x CD3 T-cell engager. That is a program that we are super excited about. We believe we have a highly differentiated molecule off the shelf and potential best in class disease-modifying treatment for a range of autoimmune diseases. We now have a dedicated immunology team that is focused exclusively on CLN-978. They're managing a global development program across three indications, again, large market opportunities. We plan to be the first company to put out company-sponsored CD19 T-cell engager data into the marketplace. We have an SLE or lupus study that's ongoing with initial data planned for the first half of 2026. We have, in parallel, an RA study with the Erlangen Group in Germany, who really pioneered the use of T-cell engagers in autoimmune diseases. Initial data for that study is also expected in the second half of 2026. We've just recently activated a study in Sjögren's disease, which is now open for recruitment. The progress there is going really well. I would also say that we're very pleased now with the external validation we've seen on two fronts. One, if you looked at the EULAR data this summer, as well as the very recent ACR meeting, it's clear that the scientific community thinks that CD19 is a high-impact target. It's also clear that T-cell engagers are an important new treatment modality for autoimmune diseases. The second reference point is, if you look at the strategics of large pharma, where they've transacted has exclusively been CD19 T-cell engagers. That's an area they continue to be very interested in. I think we're very pleased with the program. On the oncology side of things, very recently, we released data from our CLN-049 program. That's a potential first in class FLT3 x CD3 T-cell engager. Very promising data. We showed with the initial data a 30% composite complete response rate. Obviously, in the area, you know the whole brand. For us, that's really exciting. The fact that we have an oral presentation at ASH gives us the kind of external validation from the hematology community. The thing I'll say about AML also is that there's a very, very clear development and regulatory path here. It's a disease, unfortunately, for patients with very poor prognosis, but at the same time, it does mean that the development bar and regulatory bar is relatively low. The data that we've generated is from an ongoing dose escalation study. We're still dose escalating. That's a program we're super excited about. Zipalertinib is our potential best in class EGFR tyrosine kinase inhibitor that's addressing the exon 20 insertion mutation in non-small cell lung cancer patients. There, we had a good positive meeting with the FDA last month. Our partner, Taiho, is on track to initiate the NDA submission by the end of this year. That will obviously be an important milestone for the company, our first NDA submission. Our view of zipalertinib is not only is it addressing important unmet patient needs, strategically, it can also be a source of non-dilutive capital for the company as we head to commercialization and outstanding regulatory milestone payments of $130 million, 50/50 profit share in the U.S. I'll just conclude by saying we're very well resourced. We just reported last week that as of the end of September this year, we have approximately $475 million in cash. With the two programs we just discontinued, we now have cash runway into 2029. That gives us the opportunity to continue to advance our programs, continue to generate both near-term and long-term catalysts without the need for raising capital near-term. Having cash and catalysts is a pretty good place to be in this market. We are very pleased to be where we are. Great. Let's spend a few moments on 049 into the ASH data, which are coming in just a few weeks now. When I hear FLT3, I think a decade plus of oral small molecule inhibitors going after patients with the alterations. Talk a little bit about the design of 049 and who you think this construct can address in terms of a patient population. Sure. So Brad, I'll take that one. FLT3, therapies directed at FLT3 have largely addressed mutated FLT3 mutations in the kinase domain activating mutations. Those occur in about a third of patients with AML. FLT3 is actually expressed in greater than 80% of patients with AML. As a target for immunotherapy, it opens up the potential to treat a broad swath of AML patients, the majority. By targeting the extracellular domain of FLT3, the activity of a molecule like 049 is indifferent to internal kinase on-domain mutations. It can address, again, at least 80%, probably higher, percent of AML. This program has been percolating on stealth at Cullinan now for several years. As you said, we will have an oral presentation at ASH this year. I think it's really an exciting opportunity to develop a therapy that has broad applicability in AML, whereas many of the recent approvals have been for small molecules, as you say, that target molecularly defined subsets in AML, like FLT3, like NPM1, and other mutations. What we've seen so far is that not only does 049 open up the broad potential of AML, it appears to be active without respect to underlying genetic mutations. FLT3 mutated, not mutated, p53, we've seen activity. As anyone who's familiar with AML knows, in patients with p53 mutations, the overall survival is only six months beyond diagnosis, so a dire prognosis. We're very gratified to just double-click on the complete response rate. A composite complete response rate of 30% in the middle of a dose escalation trial is really remarkable, and we're excited about the potential for the program. Yeah, maybe let's contextualize that response rate a little bit more. How would you describe the patient population that you enrolled, and what could you typically expect from some of the available salvage therapies for those patients? It's a good question. There is a lot of heterogeneity in the AML population. In relapse refractory trials, you tend to enroll higher-risk cytogenetics, so complex abnormal karyotype, TP53 mutations. Our data set also includes patients who would have already failed targeted small molecules, like the recently approved menin inhibitors, FLT3 inhibitors. A relatively treatment-experienced population, again, enriched for the kind of genetic abnormalities that typically characterize fatal AML. Not a cherry-picked population at all. When you look at those small molecules that have been approved, while they have great clinical benefit, that benefit only extends to a minority of patients, and the response rates are still not what you'd like. Composite complete response rates in the 20%-30% range, no more than 35% in the best situations, with durable responses of four to six months, depending on the patient subgroup. Lots of room for improvement, lots of potential for a therapy that can cross across these genetic populations and potentially be added to existing standards of care down the line. Yeah. I know it's early in the dose escalation, but you brought up the disappointment in the durability responses for some other therapies. Have you been able to learn anything about the durability of 049 yet in this study? That's an important question, because clinical benefit that's fleeting is not clinically meaningful to patients and their docs. We have seen, even within the dose escalation, some complete responses that are out to six months. As you alluded, it's a dose escalation study, so it's ongoing. Much of the durability data was immature at the time of the abstract. That's a key piece of information that we'll update at the presentation in December. Great. In terms of go-forward development strategy, how are you pitching this to investors now about how much additional work is needed to potentially think about putting this into a registrational study? Yeah. I think, again, the thing with AML is that the development and regulatory pathway is very, very clear, including accelerated approval based on a single-arm study. If you look at the most recently approved agents as a reference benchmark, Jeff just spoke to the 20%-30% CRc rate, the response duration of four to six months, but also the size of those studies, 80-100 patients. This is an opportunity to bring a drug to approval with a very clean pathway in a very capital-efficient way. What would we think about, your question? One, obviously, we would think about, OK, from this phase one dose escalation, what are the doses we are going to take into expansion? We have all been project optimized in our careers along the way, so we would want to do a little bit of dose optimization. It is a very efficient path to approval here. To what Jeff was referring to, we also, of course, would want to look at the combinatorial approaches with an expansion/confirmation study around it as well. Yeah. Maybe just because you mentioned Project Optimus, I think I skipped over safety. FLT3 wild-type expression, what types of tissues should we think about that being relevant for? What have you seen in terms of the safety profile of the initial dose escalation? Thank you for asking the question, because we think part of the reason why we're successful here where other T-cell engagers have failed is that FLT3's expression on cells other than AML blasts is fairly restricted. On normal myeloid precursors, it's a minority of cells. There's some limited subsets of dendritic cells that will express FLT3. The distinction between abnormal and normal is much greater, leading to a greater therapeutic index, particularly for things like myelosuppression that are particularly problematic with CD33 and CD123 targeted therapies, which have had activity in AML but often can't be treated to maximal benefit, either because of myelosuppression, prolonged recovery of counts, or unacceptably high rates of CRS, ICANS. I think that target really does provide a lot of the benefit. There's always some degree of myelosuppression that's observed with therapies in AML. I think the FLT3 target really helps us establish a balance. To the further discussion of modality-specific adverse events, CRS and ICANS have been mild in the cases that we have seen to date, mostly on the initial dose or a step-up dose, and do not recur as therapy continues, grade 1, grade 2, primarily. OK, I'd also like to emphasize Jeff's point. In our current study, it's an all-comer population. We didn't screen based on FLT3 expression. If you look at where relapse refractory AML today is, it's a very fragmented patient population. You've got 10% IDH1, 15% IDH2, you've got the NPM1. It's very fragmented. The opportunity to bring a broadly applicable treatment across a generalizable population, I think for us is very exciting. Got it. I look forward to seeing the data down in Orlando at ASH soon. Come to our investor event in the evening too, 8th December, for anyone who's listening. Great. Maybe we'll switch over to CLN-978. I mean, Nadim, you mentioned you'll be the first company to report autoimmune data first half of next year with a CD19 TCE. What gives you confidence that 978 is the right bispecific to really be the pioneer of that field? What properties does it possess? Yeah, Jeff, do you want to say that? Sure. 978 was purpose-built to be a better CD19 T-cell engager. That was the first one, blinatumomab, that was approved. Understanding that experience, we created 978 with specific design features that would be useful in situations where CD19 expression is relatively low. While that was initially purposed for oncologic applications, when you think about the intention of B-cell depletion in autoimmune disease, high affinity, picomolar in the case of 978, is potentially able to reach further into the B-cell maturation continuum, extending all the way from pre-B cells to subsets of plasma cells, the antibody-producing cells that will still express CD19, albeit at very low levels. We also did not dial down CD3 affinity in creating 978. We established a broad cytokine window with the distinction between CD19 binding of picomolar range to CD3 in the nanomolar range. That created a broad cytokine window that is the dose that's B-cell depleting but not productive of untoward levels of cytokine production. The molecule is small. It has half-life extension through binding to human serum albumin. Despite the fact that it's bite-like in construction, it has an antibody-like half-life amenable to intermittent administration. Administration from the beginning has always been subcutaneous. We saw in our preclinical studies that subcutaneous administration significantly decreased the risk of cytokine release. That was our observation among the first three patients we treated with the drug in a now discontinued non-Hodgkin's lymphoma study, where at the starting dose of 30 micrograms, one of three patients achieved a complete response to therapy. We saw no higher than grade 1 CRS. I think our initial clinical observations gave us greater confidence that what we had seen preclinically could be replicated in the clinic. OK. Yeah, I would also add to what Jeff Jones. I think our view is, again, being the first company in the space to put sponsored data out there gives us kind of an executional competitive edge. We also have a highly differentiated molecule, as Jeff went through. Great. In that first half update, what will be the key focus of the data for 978? How do you think that will help advance the treatment hypothesis of B-cell depletion with the TCE for autoimmune diseases? Sure. Yeah, if you remember, if you look at all three of our studies in the space across the diseases, we have a Part A and a Part B. Part A is the dose escalation phase of the study. For the initial data cuts, we are focusing on Part A, especially in terms of safety and B-cell depletion. To be more specific to your question, Brad, on safety, we want to see a manageable CRS profile, for example, grade 1, minimal grade 2, but not more than that. We want to see a dose-dependent depletion of B-cells as well. I think, of course, any clinical outcomes we have at the time, we will report out. Any impact on autoantibodies, we will report out at the time. I think together with the PK/PD data from Part A, that will give us an idea of the dose or doses to then take into Part B, where we can do the multi-dose experiments. Got it. With that CRS profile, do you think these types of therapies could eventually be given in the outpatient setting? Yeah, I absolutely do. I think if you look at what's happening with the commercially approved CD20 T-cell engagers in lymphoma, certainly epcoritamab and mosunetuzumab routinely given in the outpatient setting, I think if we deliver on the profile that we describe for CLN-978 with the addition of subcutaneous dosing, the appropriate prophylactic medication, I think absolutely we have an opportunity to bring this ultimately to the outpatient setting, which I think will be a very large commercial advantage compared to other modalities. Yeah. And then when it comes to B-cell depletion, seeing the dose dependency, I think one of the questions I get from investors is around the way we read that. Traditionally, in the periphery, it has some limitations in terms of how much you can actually quantify. And are you really getting it to the low enough level? And there seems to be a debate around, can TCEs match the depth of B-cell depletion of CAR-Ts? Where do you stand on this debate today in terms of the ability for TCEs to match? Yeah, I think, Brad, the data that's been published to date is kind of unfairly stacked against T-cell engagers, to be frank. In the case of some of the data that's been shown for blinatumomab, for instance, that drug, which has to be administered by continuous IV administration because of fleeting half-life, has been dosed primarily at nine micrograms. That's the starting dose in patients with ALL. In only a limited number of situations has it been escalated to the full therapeutic dose in ALL of 28 micrograms. Because it's cumbersome to administer, the administration schedules have also been quite brief, five to seven days, as compared to 28 days of coverage in oncologic situations. I think when you look at B-cell depletion there, it appears attenuated versus CAR-T. I think that if blinatumomab had been dosed more closely to its approved dose in ALL, the outcome would have been different. It's going to be challenging to do that in autoimmune patients because it's just a clunky molecule. We think that a better TCE, one that is more antibody-like in its drug properties, has the potential to achieve things that, unfortunately, blinatumomab has not been as successful. Makes sense. Then down the road, as you've selected a dose schedule, as you talk to rheumatologists, what do they think success looks like for TCE in a lupus population? Yeah, I think I would maybe also pick up on your last question, Brad, is the first thing I would say is that CAR-T therapies have blazed a trail here. I mean, without CAR-T therapies, we wouldn't be here. I think that was really important. I would say it was really important proof of concept data. I think, as you see with most technologies, there's always an iteration of that technology, right? We believe that T-cell engagers represent that iteration, that next-generation technology. With T-cell engagers, we see that we have the potency of T-cell redirecting therapies in the form of a potential disease-modifying treatment, but with the convenience and accessibility of antibody treatment. Certainly, when we speak to rheumatologists, what they tell us is they want to have treatments that are off the shelf, that they can treat their patients where they are in the community. That is very hard to do with a more complex modality. That is one thing. Secondly, I think as we think about where this space goes in the future, since you are asking, I think ultimately the clinical commercial landscape of treatment will necessarily show that CAR-T cell therapies will likely be a post-T-cell engager treatment sequence as you think about treatment sequences. I think where we see T-cell engagers being used first is pre-CAR-T across autoimmune diseases. We also see an opportunity to displace antibodies. The reason I say that is antibodies clearly are very safe, but the efficacy is very marginal, right? With the antibodies we see to date, they're always added on top of chronic background immunosuppressive therapy. With a T-cell-directed approach like T-cell engagers, and in our studies, patients have to come off their background therapy to even enter our studies. I think you have a much more potent approach here. Ultimately, I think we'd start ahead of CAR-T, but then we'd want to displace monoclonal antibodies based on the potency that you can get with T-cell engagers. I think the other advantage that T-cell engagers have over, for example, CAR-T is that if you need to redose, you can do that. Obviously, that would be very difficult to do with CAR-T administration. To put patients through multiple rounds of lymphodepletion would be a tough ask. Right. Right. Unfortunately, I think we're running out of time. But Nadim, Jeff, thank you so much for joining us. And thank you, everyone, for listening in. Appreciate it. Thanks, everyone.