All right, great. Thanks, everyone, for continuing to join us here at the Stifel Healthcare Conference. My name is Brad Canino, Senior Biotech Analyst here. Happy to be joined by the next fireside with Cullinan Therapeutics. We've got Nadim Ahmed, CEO; Jeff Jones, CMO. Thanks so much for joining us. Thank you. Thank you. Nadim, maybe if you want to kick off with an introduction to Cullinan Therapeutics and how the portfolio and company has evolved over this past year. Sure. Yeah, obviously, a lot of change. So we're a biotech company that's focused on creating new standards of care for patients with cancer and autoimmune diseases. And we do this with a pipeline of molecules that either address the underlying cause of a disease or harness the immune system. And so if you look at our pipeline, we've strategically collected together a diversified group of assets that have the potential to either be first in class or best in class. And that's the approach we typically take. Earlier this year, we did announce a strategic expansion into autoimmune diseases through our molecule CLN-978, which is our CD19x CD3 bispecific T cell engager. It's an off-the-shelf potential disease-modifying best-in-class regimen that we have recently received clearance from the FDA with the IND in the U.S. to go into autoimmune diseases, as well as Ethics Committee approval in Australia. So we're initiating a global study in SLE in patients with moderate to severe lupus, and we've guided to having initial clinical data from that study in the fourth quarter of next year. At the same time, we've also announced that we are advancing CLN-978 in rheumatoid arthritis as our second indication, and we're really working with the pioneers in the field who have really developed T cell engagers in autoimmune diseases, so that's the Erlangen Group in Germany, as well as the Gemelli University Hospital in Rome, and they were the pioneers of the work through the publication early this year of blinatumomab in rheumatoid arthritis. At the same time, our oncology pipeline continues to move full steam ahead, and there, again, we have a differentiated group of assets, starting with CLN-619, which is our monoclonal antibody targeting the novel MICA/MICB pathway. At ASCO this year, we presented for the first time our combination data with pembrolizumab, where we saw responses in tumor types that you typically wouldn't expect to see checkpoint inhibitors work in, specifically oncogenic driver mutated non-small cell lung cancer, and we also shared an update of the follow-up from the initial monotherapy efficacy that we saw in ASCO last year, where we tend to see long-term durable responses and clinical benefit in patients, so very exciting program. We also just started dosing in a multiple myeloma study for that molecule, and multiple myeloma is a disease that NK cell interactions are very important, so we're excited about that opportunity. Zipalertinib is our Exon 20 EGFR inhibitor. There, we were pleased to complete the pivotal study in relapsed disease ahead of schedule. We also shared the data at ESMO, where we showed very promising clinical activity in patients that had prior exposure to amivantamab, and we've now guided to data from that pivotal study mid-year next year, and then the final thing I'll add is, as of end of September, we have about $640 million in cash, which gives us cash runway into 2028, which will allow us to continue to advance the oncology pipeline, as well as fully unlock the value of CLN-978 in autoimmune diseases. Yeah. So it was great to see 978 become the first CD19 T cell engager with the US IND for autoimmune diseases. How important was it to secure the ability to start at the dose of 10 micrograms? Yeah. So I think, Brad, you've landed on one of the key challenges of regulatory interaction around T cell engagers starting dose. Many times, the agency in the interest of safety, even in oncology, has suggested very low starting doses in the interest of patient safety. So you'll see dose escalation trials where sometimes even 10 dose levels are explored before reaching a biologically active dose. In our case, you'll recall that in our oncology study, we treated patients at a starting dose of 30 micrograms and there saw not only biological activity with respect to peripheral blood B cell depletion, but also a complete response in one of three patients to their cancer. So we were very gratified to receive approval to start our SLE study only two dose levels below at 10 micrograms. Not only is the starting dose a win there, but we think that we likely have to explore the drug over a limited number of dose levels extending from 10 to 45. Four dose levels planned, which should help us hasten to an effective dose and limit the amount of time we spend treating patients at subtherapeutic doses. Okay. Have you commented at all about the peripheral B cell effects you expect to see with the 10 microgram dose? No, we haven't commented yet. It's somewhat challenging to model that completely. We do expect it to be biologically active, but in terms of the degree of B cell depletion, hard to characterize. Now, maybe to Nadim, what is Cullinan's strategy in terms of how to generate the most value for 978 from here? Yeah, I think the way we've been thinking about that, Brad, is so I mentioned SLE as our first indication, rheumatoid arthritis as our next indication, and so our team is really focused on how quickly can we generate clinical data across a range of autoimmune diseases, and so that's what we're really focused on, and I think we believe that's the best way to drive value first for patients, but also our shareholders, and in that context of execution, I would just say that, look, we went from an idea in January of this year at JPMorgan to clearing an IND in October, so from an idea to IND clearance in 10 months, so I think that speaks volumes to the executional capabilities of the team. And to your point earlier, we are the only company that has a development stage CD19 T- cell engager cleared by the FDA to run studies in the U.S. If you look at all the other companies that have CD19- T cell engagers in development stage, all of those studies are being conducted outside the U.S. Okay. Now, Jeff, you mentioned four dose levels planned for the lupus dose escalation. Can you talk more granularly about the different types of escalations and regimens you will test and the thinking behind why to test those? Yeah. So I think the SLE trial will enroll patients with general SLE. So this is not a lupus nephritis trial, just to clarify for some people familiar with the field. When we're starting the dose escalation, the primary intention is to identify a B cell depleting dose to further explore an additional schedule. So the part A or the first part of the trial is essentially a modified single ascending dose study. We'll begin at 10, as Brad stated. And then for dose levels beyond 10, we'll use that dose as a first or step-up dose to higher therapeutic doses as a way of further mitigating the risk for cytokine release syndrome. It's our hope ultimately that by giving this drug subcutaneously, step-up dosing, and steroids for pre-medication, we can abrogate the risk of cytokine release and actually enable, sooner rather than later, all outpatient administration of the drug. Okay. You've guided to first data in 4Q 2025. How are you outlining the broad strokes of what those data will encompass to ensure that it's an interpretable disclosure? Sure. Yeah. I would say, so you alluded on one of the key principles of the company, and we've done that in oncology. So whenever we're presenting or sharing data, we want it to be meaningful and interpretable. So you won't see us releasing patient data sets at a time, for example, on an individual basis. And so as we think about 4Q 2025, Brad, one way to look at it is, what are the kind of endpoints in our study? So it's a phase one study, so primarily safety. But of course, at the same time, we're going to be looking at clinical endpoints. So for example, in lupus, that's things like SLEDAI score reduction, PK/PD, the kinetics of B cells as you deplete them. What are the type of B cells that come back? Ideally, you want the naive B cells to come back, not the pathogenic memory B cells that produce these autoantibodies. We also want to look at impact on autoantibodies. So I think the way to frame it is, we're going to have data that we believe is going to be interpretable, and it will be all of the data we have at the time of data presentation. Now, what type of lupus patients are being recruited? And I'm really asking this question to ask, what should we keep in mind as we interpret disease activity scores in that particular population? Yeah. So as I mentioned, some companies have elected to do trials solely in lupus nephritis. They're, in addition to symptom assessment scores like SLEDAI, that are composite endpoints that involve some subjective assessments of disease activity. There are also opportunities for less subjective physiologic endpoints like proteinuria, creatinine clearance. In our case, we thought that was a bit too narrow to facilitate a rapid dose escalation where we're primarily interested in establishing a safe and potentially therapeutic B cell depleting dose. So we'll enroll general SLE patients. So these will be patients who could have mild cases of lupus nephritis. The only organ system exclusions, in fact, would be patients with severe nephritis that might be spiraling towards need of dialysis or transplant, or patients with cerebritis or other neuropsychiatric manifestations of lupus, which could confound the assessment of neurotoxicity that is sometimes observed with T cell redirecting therapies, both SLEDAI score reduction, PK/PD. In picking the severity, we elected to enroll a patient population closer to the patient population enrolled to CAR-T studies. That's patients with mild to moderate disease, as Nadim said. And that's measured here by a SLEDAI score of eight or higher. Some other companies on the TCE development front have picked a lower score, SLEDAI score as low as four, which is mild disease. But at that low end of the symptom score, there's much less power to discern a meaningful improvement in efficacy, where you need typically to see at least a four-point improvement in the SLEDAI score to say that a patient has had clinical benefit. So essentially, if you're enrolling a patient with four, they either go into a complete remission or they have no measure of clinical benefit. So eight seemed to be a good balance and will also allow us to compare our data to CAR-T patients as well. How will background medications be handled into and through the trial? Yeah, that's an important question. So like the CAR-T trials, there is the potential that some background therapies could interfere with the mechanism of action. So things like mycophenolate, voclosporin, cyclosporin, things that are expected to adversely impair a patient's innate T cell function will have to be washed out for a minimum of two weeks prior to initiating therapy. If a patient were to flare during that time, they could be treated with steroids as bridging therapy, which is pretty typical for CAR-T TCE studies. Okay. Now, as we think about the parallel development in the industry of enhanced CD19 monoclonal antibodies and then TCEs, what is the importance of B cell depletion in the tissues? And why are you confident that you have the right molecule for that? Yeah. So there are a couple of lines of evidence there. So CD19 monoclonal antibodies are primarily dependent on ADCC and/or ADCP, so NK and macrophage-mediated immune responses. We all know that T cell-mediated immune responses are the ones that are the most potent of our immune system. And the way to harness those is either with engineered CAR-T cells or T cell engagers. So I think it's a question of maybe to use a little violent metaphor, conventional versus a nuclear weapon. They can both do the work, one's going to do it a bit more efficiently. And I think the data for that comes from two places. First, on the oncology side, CD20 monoclonal antibodies, CD19 monoclonal antibodies can put patients into a response, but not typically a complete response, not as monotherapy. On the other hand, T cell engagers and CAR-T cells will routinely induce responses and, depending on the disease, complete responses in 50% or more of patients. So I think that demonstrates the potential for those modalities, regardless of the indication, to achieve a greater depth of B cell depletion in tissue-resident B cells. Okay. Now, once you have a starting dose from the lupus phase one, what does the next phase of clinical development look like? What are the critical clinical questions that you need to ask in a phase two type setting? Yeah, so like any other area of medicine, including oncology now, there will be a regulatory and development expectation to explore more than one dose, so dose optimization is an important part of phase II development for a variety of reasons. Secondarily, I think it's going to be very important for us to work out a schedule or duration of therapy. As a first iteration, we're thinking that a defined duration of therapy, maybe even as short as a month or two, could be sufficient to replicate the depth of B cell depletion that's observable with CAR-T. But we're trying to find a balance where we achieve a depth of B cell depletion that is safe for patients and that also doesn't leave them B cell deplete for protracted periods of time, which would be associated with a significantly increased risk for infection, which is something of great concern to many patients as well as treating rheumatologists. Okay. Now, you're also starting a rheumatoid arthritis study expected to initiate in 2Q next year. How similar or different will that be to the dose escalation that you're doing in SLE? Yeah. The first thing I would say there is, one, we're very pleased to be working with the pioneers in the field, both the groups I mentioned, the Erlangen group from Germany, as well as the Gemelli University Hospital from Italy. And so they've done the seminal work in this space. They had the choice of company and molecule to work with. They chose us. So we're very pleased with that. And I think we're kind of in the early planning processes, Brad, for that study. So I think the actual exact study design will be subject to a future update. Okay. Now, what did you see from the blinatumomab work that you referenced that leads you to believe that RA is going to be a real opportunity for CD19 TCEs? Yeah. So I think the role of B cells and the potential for B cell depletion to treat the disease is long established in RA. So rituximab was approved for RA back in 2000, 2001. So it's a long-established therapy. I think the observation is that it hasn't achieved the depth of B cell depletion that's possible. I think that was what led the investigators at Erlangen to explore blinatumomab. There, we saw that patients did achieve objective response. But we also saw in three patients who had synovial tissue assessed that B cells that often accumulate in inflamed joint tissue and actually form germinal center-like structures in some cases, those B cells were fully depleted in two of the three patients who had more durable responses and were not depleted fully in a third patient who actually had progression of the disease relatively rapidly. This kind of gives us two things, two takeaway messages. One, depleting B cells in the tissue is associated with longer response. And then number two, since they only use the starting dose of blinatumomab, nine micrograms versus the approved 28-microgram dose, where it's efficacious in ALL, there probably is a dose-response effect for TCEs to achieve the level of B cell depletion necessary to affect an immune reset and a durable remission. On that, were you concerned at all that the investigators in that study, after, I think, six or so months, decided to put patients on a maintenance of abatacept therapy? And does that, for you, create any risk about the potential durability of TCEs? Just as sort of background, if you talk with Ricardo Grieshaber-Bouyer and the other physicians who were working on this project, they didn't have lofty ambitions to put patients into durable remissions. These very refractory patients, the majority of whom had already failed rituximab multiple times, was to try to reestablish sensitivity to some of the maintenance medications they'd been on before. So in thinking about the best care for these patients, once they had gotten to a point where their disease was again under control, they put them back on maintenance to preserve their response. I think I wouldn't take that as an indicator that a durable response is not feasible. We have limited information about an update for some of those patients that the group reported today at ACR. And there is at least one RA patient who was subsequently treated with teclistamab, a BCMA-directed T cell engager, who has achieved a treatment-free response for the first time after 15 years living with RA. So we'll look forward to getting more details about that presentation as well as a broader set of patients that were treated with blinatumomab. But I think it establishes that T cell engagers are able to achieve durable responses in patients with autoimmune disease, including refractory RA. Yeah. I think, Brad, if you ask that group, to Jeff's point, in hindsight, they feel that it probably was a subtherapeutic dose, even though we saw this very strong proof of concept. And so now they're revisiting the idea at higher doses. And so strong proof of concept, there probably is a dose response. We actually saw that in the systemic sclerosis patient case that they published, where you upped the dose, you saw increased efficacy. So I think it was a start, but I think we can certainly optimize. And that's why we're excited about the opportunity for CLN-978 in rheumatoid arthritis. Yeah. Jeff, you mentioned ACR, which has been going on this past weekend into today, I think. Any real-time learnings for other B cell depleting therapies in autoimmune diseases, T cell engagers specifically, that you would share? Yeah. I think most of the actual robust clinical data that was shared at the meeting was related to CAR-T and continues to demonstrate that what had been reported in an academic series was real and that it's been translatable across other constructs. T cell engager data, other than our initial preclinical presentation, was relatively limited. There was a preclinical presentation from Roche. They have a CD19 by CD3 bispecific. That preclinical data, again, showed relatively comparable potency to CLN-978 in vitro, but would suggest that CLN-978 is about five times as potent in vivo, in doing some rough comparisons. There was also some initial clinical data from a Chinese company, ITabMed, with a drug A-319. This drug is administered by continuous IV infusion. It's somewhat awkward, like blinatumomab, and having a half-life measured in hours. They did show some clinical improvements, reductions in autoantibodies, but I'd say the data were somewhat inconsistently reported in terms of adverse events, and some of the biomarker and clinical data didn't quite correlate. Okay. Now, you mentioned the Roche TCE. There's also a lot of other TCEs that continue to emerge. There's a lot of strategic interest in this space, of course. So we expect new company formation, et cetera. The properties of CLN-978, how do you like to talk about the key attributes relative to what we've seen in some of those competitors? Sure. Yeah. I think the first thing I would say, Brad, is if you look at the strategics of the large pharma companies, either their own molecules that they're developing or ones that they've more recently acquired, like Merck and GSK, they're all focusing in on CD19 as a target of choice. So they're all CD19 T cell engagers. So I think that for us is important external validation of the modality. Secondly, our belief is that in this space of autoimmune diseases, you need the ideal combination of both target and modality. In our view, CLN-978 represents the optimal target with CD19 and also probably the optimal modality in the form of a T cell engager. And I think that's certainly something at the ACR meeting that we experienced both at our poster, which was heavily inundated, and also speaking with investigators at the investigator meeting we had. To Jeff's point, now we're seeing reproducibility of the initial CAR-T data, but they're also seeing a very quick rise in awareness of T cell engagers for rheumatologists. I think that was the other key finding for ACR, so coming back to our specific molecule, so we have a molecule that has very, very high affinity for CD19, and so that's really important as you think about some of the more mature B cells in the breadth of that B cell compartment, whether it's short-lived plasma cells or plasma blasts, having very high affinity in those cells that tend to be a bit dimmer in terms of CD19 expression could be important for autoimmune diseases. The other thing is the size of our molecule, so we're at around 65 kilodalton compared to these other companies that have much more of a traditional IgG backbone, which is 150 kilodalton plus. So to the extent that size may be important for penetration and clearing B cells in tissue, I think that could be another determinant factor. We already mentioned that we're the first ones to clear an IND in this space in the U.S. So having that leading position is really important for us. And we also think speed of execution continues to be important. And so that's why we're moving forward with the program very, very quickly. Okay. Maybe we'll spend a few minutes on CLN-619, the MICA/MICB. We've had two important phase 1 clinical updates from you reported to date. What would you characterize that's established about the drug? And then what learnings do you hope to show next year with the next update? I think first and foremost, we've been able to show that this novel mechanism that is a MICA stabilizing antibody is able to achieve objective responses in patients with relapsed, multiply relapsed solid tumor malignancies. This has included patients who have relapsed after other immunotherapies, including PD-1. Most notable in the monotherapy experience, in fact, was a relatively high number of clinical responses in endometrial cancer. Two of the three objective responses were in endometrial, with a third patient with endometrial with prolonged stable disease. In the combination cohort, a dose escalation in combination with pembrolizumab, we established objective clinical responses could be observed in patients with oncogenic driver mutation, non-small cell lung cancer, ALK and EGFR positive, where PD-1 is actually a relative contraindication or label exclusion. So as we look towards the initial data that we'll share in 2025, we expanded actually in indications where we had observed robust clinical activity to understand whether we have a signal sufficiently strong for additional development. So we have stated our intention to share data from the cervical and endometrial expansion cohorts in the second quarter of this year. And we have. Next year. Next year. Yeah. We're nearly there. Yeah. We're nearly there. And then we have also undertaken additional expansion in non-small cell lung cancer, both as monotherapy and in combination, targeting patients with EGFR and ALK and other oncogenic driver mutations of adenocarcinoma, where PD-1 doesn't have an established role. And this year also announced that after seeing prolonged stable disease in a patient with platinum-resistant ovarian cancer, now extending nearly two years, that we are studying CLN-619 in combination with chemotherapy in platinum-resistant ovarian. So a lot of ways of exploring this in patients where immunotherapy has not been particularly active up until now. Yeah. Maybe you could spend the last minute or two talking about what you see as the unmet need in some of these gynecological cancers where you've got a lot of the focus with the combination. Yeah. Endometrial is pretty straightforward. I think endometrial now, PD-1 has moved up in combination with chemotherapy as part of front line, given in combination with platinum doublet. So among approved therapies, it's pretty much all that had existed in the second line. This leaves a substantial unmet need in patients progressing after PD-1, whether they've received it in the front line or for relapsed disease. I think that's probably the most important unmet need population, where single-agent chemotherapy is the existing standard of care with response rates of no higher than 15%. Yeah. Okay. Well, great to see all the progress this year. Congratulations on all the execution. Thanks so much for joining us. Appreciate it. Thanks, Brad. Thank you, Brad.