Hey everyone, we're back. Happy to have the CMO of Cullinan Therapeutics here, Jeff Jones, for our next fireside chat. Jeff, maybe start things off with a quick company overview and then we'll get into the Q&A. Sure, thanks for having me this morning, Alex. Cullinan Therapeutics was created with an intention of identifying best-in-class, first-in-class molecules, first only for oncology, but now oncology and autoimmune disease, rapidly prosecuting those through early phase development to identify the most promising therapies with the potential to be transformative for the care of patients. Right now our portfolio is really centered around several high priority programs, both on the autoimmune disease side, which we'll talk about today, as well as oncology. For the autoimmune part of the business, our lead program is CLN-978, the CD19 x CD3 bispecific that we pivoted to development in autoimmune disease a little more than a year ago and now have open phase 1 clinical studies in SLE, RA, and Sjogren’s disease. All three studies are actively enrolling patients at global sites. We've recently shared that we are guiding to initial clinical data for both the SLE and RA programs in the first half of 2026, as we'll discuss later. That's a slight shift on expectations for the SLE data, from the end of this year to the first half of next. The Sjogren’s study came online over the summer, rapidly moving through site activation, and we are actively screening patients there. Earlier this year, we did add a second bispecific T cell engager to our portfolio, this one, belanatamab, targeting BCMA. I would emphasize that this is really meant to be complementary to our CD19 program. We believe that the ability to more specifically target the plasma cell compartment opens up opportunities for development in a distinct area of diseases, apart from the CD19 program, diseases where autoantibodies produced by long-lived plasma cells are more central to the pathophysiology of the disease. We're initiating developments in a somewhat unique arrangement for us with a partner in China, Genrix Bio, the originator of the molecule, who are conducting a pre-planned study in autoimmune disease. We hope to share additional details about that study very shortly. On the oncology side, I just would mention that we do have zipalertinib TKI for EGFR exon 20 non-small cell lung cancer. With our partners at Taiho Oncology, we are planning a filing, our first for Cullinan, by the end of this year, pending regulatory feedback. Great. I think to start things off, many investors in the autoimmune space are used to your normal phase 2 placebo-controlled study, looking at data in that way. From CAR-T to the T cell engager space now, trying to digest IST studies, single patient cohorts, open label studies has been a challenge. I guess to an investor who feels like this is just too early, why should folks pay attention now? What's the evidence that should get you excited about T cell engagers in autoimmune disease? Yeah, and I think it's historically, if you think back, why would there be placebo-controlled studies? It's because in many autoimmune diseases where patient-reported outcomes or physician assessments are an important part of disease response assessment, these are very, very subjective. There are, at baseline, very high placebo rates. The ability to control against placebo is very important for discerning what is often a relatively modest therapeutic benefit over placebo. In the case of a drug like belimumab in SLE, it's 10%- 15% of improvement or percent improvement over placebo. Very subtle in the absence of placebo. What's really different when you say, why should people be excited here? It's that for the first time, both first with CAR-T and more recently with T cell engagers, there appears to be an opportunity to achieve therapeutic benefit in the absence of ongoing immune suppression, where therapies do not require add-on to backgrounds and where durable responses themselves kind of overcome placebo expectations, where you wouldn't expect a placebo to deliver therapeutic benefit six, nine months long in the absence of ongoing immune suppression. It's really the magnitude of the therapeutic benefit that is being observed that's really dramatically different. That will, as I think you'll probably want to talk about, prompt discussion about what's the most appropriate way to demonstrate therapeutic benefit and safety for regulatory purposes, because it may be different based on these kinds of observations. Exactly. Maybe pivoting to CLN-978, your lead CD19 program, obviously a lot of other CD19 T cell engagers out there as well. What are the key elements of differentiation that you think will ultimately be important here moving forward? Yeah, so there's several aspects of the design of the molecule itself that I really think convey distinctions that we saw first in our preclinical studies and then have been borne out in the small but very, very compelling data set we generated in Non-Hodgkin's lymphoma. By binding with high affinity, picomolar affinity to CD19 and nanomolar affinity to CD3, we established a therapeutic window, or cytokine window, between doses that result in deep levels of B cell depletion versus untoward cytokine production associated with clinical cytokine release. Other companies have taken a different approach where they sort of maintain a middling affinity for the target antigen and dial down CD3. We think that may be a less appropriate approach since it really is T cell activation, which is the business end of a T cell engager. That attenuation of CD3 has often required overcoming the attenuated CD3 binding by higher doses. With 978, then, high affinity for binding to CD19, typical affinity, so middle of the pack of approved TCEs for CD3, but still conveying that cytokine window. The molecule is small, it's bite-like in size, only 65 kd, which may potentiate tissue penetration, an important consideration for autoimmune development. The molecule has half-life extension through a clinically validated approach by including an antibody binding domain that gives the molecule antibody-like kinetics, despite its significantly smaller size, less than a half to a third the size of many T cell engager antibody-based formats in clinical development. Maybe we can talk now about SLE, maybe the most competitive indication among the B cell depletion approaches right now. W hat's so compelling about this indication and why are you studying it? Yeah, I'd say if you take a look back, even before the CAR-T data that was first generated in SLE, there was already some evidence to suggest that memory B cells played a central role in the pathophysiology of the disease. Despite the fact that there is a lot of crosstalk in immune system cells that can make identifying a specific target for intervention in this or any other disease quite challenging, there was some understanding of memory B cells' importance. The compelling observation from the CAR-T studies is through deep depletion of the B cell compartment, subtotal B cell depletion, you can achieve an immune reset, interrupt the crosstalk among immune system cells by deeply addressing one compartment somewhat transiently, and that this could convey a deep response, a treatment-free remission that was durable, now in some cases beyond two years. This immune reset phenomenon, the importance of B cells to the central role in their pathophysiology, has really best been demonstrated in SLE to date. As we thought about what indication made the most sense, there were several compelling factors, but one is the science leads you there. The second is because everything that you developed or a T cell redirecting therapy will inevitably be benchmarked against CAR-T data, the failure to generate this data would have always been viewed as a gap in our development program. Makes sense. Maybe we can talk about the design of your proof of concept study, and then I want to get into kind of the recent update as well. Sure, and maybe by way of introduction, I'd say the data from EULAR over the summer, regardless of the molecule, sort of suggested that for T cell engagers, as compared to CAR-T, there would need to be more exploration of dose and schedule in order to identify the most therapeutic regimen for any specific molecule. That's kind of the approach that we always thought we would need to take. In part A of our SLE study, we are conducting a modified single ascending dose study to identify a deeply B cell depleting dose at which we maintain a therapeutic index with respect to class-related adverse events like CRS or ICANNs. We don't have expectation that a single dose of a TCE is likely to achieve the therapeutic benefit necessary to result in immune reset or treatment-free remissions of any durability. In part B of the study, we will carry forward a dose or doses from part A into repeat dosing schedules. This isn't for continuous dosing, still a time-limited or defined duration of treatment, but a repeat dosing schedule that we think can lead to deeper response, ideally responses that are durable in the absence of ongoing immune suppression. I think to that point of dose finding the range that you're studying in SLE now, how does that compare to your oncology doses? Do you think that you need to get to that highest dose to see clinical efficacy? Yeah, that's a great question, Alex. I would say there are two ways of looking at it. The first is the data to date suggests that TCEs are most therapeutic in autoimmune application when they're dosed closer to an oncologic dose. If you look back now to our experience in non-Hodgkin's lymphoma, we identified the 30 microgram dose as a dose where there was threshold activity against lymphoma. One of three patients treated, one with lower burden disease, actually achieved a complete response to therapy after seven doses of treatment. Looking now at our SLE dose escalation, we're starting only two dose levels below the 30 microgram dose, 10 micrograms, and then utilizing that dose as a step up to higher, potentially more therapeutic doses. I do expect, as a direct answer to your question, that we are likely to see the greatest efficacy in the 30, 45 dose range. As long as safety is preserved, I expect we will dose to a dose level beyond that 45 microgram dose level where we stopped before discontinuing the Non-Hodgkin's lymphoma study. You recently updated the protocol. Can you talk about why you did that and what you're seeing at sites currently? Yeah, first, just to emphasize that we didn't update our timelines because of any adverse clinical observations in the ongoing study. I would say that investigator enthusiasm has continued to be high. When I say that, I mean most of the sites that we have active had contributed one or more patients to screening. It's not for lack of investigator interest or engagement from our sites and their site staff, but in discussing the protocol with them, we do understand that relatively stringent eligibility criteria were limiting the number of patients that entered the screening funnel and ultimately the number that converted from screening to enrolled patients. Yeah. Specifically, two eligibility criteria were proving most problematic. The first was a requirement that patients have received prior therapy with a biologic or cyclophosphamide. To speak about that one first, many patients in the U.S., the majority, do not receive either of those medications during their SLE treatment journey. It is far more common that they will have received small molecule immune suppressants. Just because something's approved doesn't mean patients have access either through physician or patient choice or insurance coverage. We have modified that criterion to broaden the eligible patient pool to include patients, particularly those in community-oriented settings, who have received only small molecule immune suppressants but still have refractory disease with moderate severity. To that second point, moderate severity, we've maintained the eligibility at moderate severity but lowered it to the actual cutoff for moderate severity by SLEDAI score from SLEDAI 8 to SLEDAI 6. This is a subtle change, but it also allows some flexibility when symptom scores in this and other autoimmune diseases can sometimes change between the time that a patient begins pre-screening for study and study eligibility. The feedback from our sites is that this will significantly impact the number of patients that they can bring forward to screening. By looking at our screening logs for screen failure reasons, we know that this would convert a substantial number of those from screened to enrolled patients. Have you been able to? We're already implementing this. Yeah, have you been able to dose any patients yet? Yes, we have dosed patients in both the SLE and RA studies. It is still early in the Sjogren’s study. The first site was activated only around the beginning of July, but we are seeing an uptick in screening activity. I guess then with this update from 4Q to first half, what does that look like in terms of the disclosure that you might be able to have now across both SLE and RA? Is a more robust data set possible? Yeah, I'd say there are two ways of thinking about it. I do think that there is a more fulsome data set that's possible when you are looking at observations across two indications. One question will always be, is the dose the same depending on indications? This will begin to start supporting whether that is, as we think, likely to be the case. In terms of the SLE study itself, I would think of this more as a lift and shift rather than, I think it's a delay in delivering what we've always said would be the initial data set, which is patients treated in the phase 1 part A dose escalation, where we're really focused on safety, peripheral blood B cell depletion, and the ability to maintain a therapeutic index at a deeply B cell depleting dose. Yeah, so no news yet or no guidance around whether you might have part B data as part of this update at this point. For SLE, that is not expected at this time. You know, maybe briefly touching on RA and Sjogren's, I guess how strong is the evidence in these indications for CD19 T cell engagers? Yeah, so maybe RA is the most straightforward. I mean, the original data supporting the utility of T cell engagers in autoimmune disease was generated in RA. That from our collaborators at Erlangen, both Dr. Ricardo Briessaber and Georg Schett are helping us conduct that study, our RA study in Europe. Their patient series, published last year and updated at EULAR over the summer, really does show that patients can experience clinical benefit through B cell depletion achieved with the T cell engager. That's with belimotumumab, which is clunky. It's very difficult to maintain the levels of exposure that would really generate the most robust clinical response because of the requirement for continuous infusion and the impracticalities of that in autoimmune disease and rheumatology practice. I think the data is there pre-existing that rituximab and other monoclonal antibodies are capable of achieving a response, but it's suboptimal. We think, as do they, that deeper B cell depletion achieved through a T cell redirecting mechanism can achieve greater benefit. I think the science there is pretty strong, as is the notion that RA is, in many cases, a B cell-driven disease. Yep. For Sjogren’s, no evidence quite yet for T cell engagers in that disease, aside from one case of BCMA-treated patients, again at Erlangen. That is essentially a polyclonal B cell lymphoproliferative disorder. B cell infiltrates are identified in the salivary glands of the majority of patients who have Sjogren’s disease as part of the diagnostic criteria. Patients with Sjogren’s disease have a 40 times greater likelihood than patients without Sjogren’s disease of developing non-Hodgkin’s lymphoma. This is a B cell-centric disease. Therapies that very potently address B cells can be expected to have therapeutic benefit. Off-label prescribing anti-CD20 monoclonal antibodies is already a part of the standard of treatment, albeit not approved specifically for Sjogren’s. Recent data for the anti-BAF receptor antibody at Novartis also suggests that B cell depletion achieves therapeutic benefit in this disease. I think a T cell engager can only do that more effectively than a monoclonal antibody. Makes sense. Maybe in the last few minutes, I want to touch on belantamab. You know, BCMA depletion obviously looks complementary to CD19 depletion. How worried are you about infection risks with this type of a mechanism? Is that a concern or has the field gotten past that at this point? Yeah, so Alex, you're alluding to the fact that with BCMA in depleting long-lived plasma cells, you can interrupt humoral memory immune responses. By leaving patients hypogammaglobulinemic, perhaps impacting immune responses from prior vaccination, it could potentiate a higher risk of infection. I do think compared to CD19, there is inevitably a higher rate of infection from BCMA. In disease areas where there's overlap, where both could potentially be brought to bear, CD19 for that reason would often be the first best choice. In patients where plasma cell depletion has a higher likelihood of achieving the best therapeutic effect, I think that the infection risk is manageable. Much of the management of prophylaxis, risk mitigation has been worked out in multiple myeloma where the extent of duration of treatment is also tied to risk of infection. The underlying risk in the patient population is very high. While higher than CD19, I don't expect that BCMA in autoimmune application will have the same kind of risk profile that we've observed in multiple myeloma. I do think that many of those interventions to reduce risk are pretty well characterized and can help keep patients safe. I guess for belantamab, you alluded to sort of the ongoing work in China. What does the path forward look like for Cullinan to step in and lead development moving forward? Right, so we're working aggressively to prepare for our own Cullinan-sponsored studies. In the meantime, with generating data in autoimmune disease patients specifically in China, we think that will facilitate our regulatory ambitions outside of China. We talked previously about how oncology data doesn't necessarily sway regulators in this therapeutic area where there is different risk-benefit. Having data in autoimmune disease patients, EK and pharmacodynamic data, we do think that it helps smooth the regulatory pathway, but it also provides really important information to guide our own studies with respect to dose and schedule exploration. Yeah, what do the timelines look like for that? We haven't shared a specific timeline for initiating our own studies, but we have stated that Genrex Bio plans to initiate their study before the end of this year, and they are still on track to be treating patients before year-end 2025. Great, maybe in the last minute or two, can you talk about your current cash runway and what the assumptions are with that? Sure, at the end of Q2, the company announced that we had more than $500 million in cash reserves, which gives us runway into 2028. Yeah. We think that this is still our plan that this is based on, continuing to execute our priority programs to key decision points and to initiate next phases of development. It is a relatively conservative plan. This is, as we've talked about earlier, a period where we have significant catalysts, and we're very gratified to know that we have confidence in our runway projections into 2028. Great, Jeff, always a pleasure. Thanks for joining us this morning. Thanks so much, Alex. Appreciate the opportunity to catch up.