Okay, great. Thanks everyone for continuing to join us here. My name is Bradley Canino, Senior Analyst here at Guggenheim. I'm happy to do the next fireside with Cullinan Therapeutics. I've got Nadim Ahmed, CEO, Jeffrey Jones, CMO. Thank you so much for joining us.
Great to be here, Brad. Thanks.
Maybe if we can just kick off and introduce the portfolio and key priorities for Cullinan in 2026.
Sure. Good morning, everyone. This is a super exciting year for the company, 2026. It's the first year in the company where we're having catalysts across our entire portfolio. So we're super excited about that, but especially for our two high-priority T cell engager programs, which are CLN-978, which is our CD19 x CD3 bispecific T cell engager for autoimmune diseases, and following the great data at ASH, CLN-049, our FLT3 x CD3 T cell engager for AML. So, you know, we laid out our milestones ahead of JP Morgan, and so we've got catalysts in every quarter starting from Q2.
So with CLN-978, look, we believe we have a potential best-in-class molecule to be a potential disease-modifying treatment for a range of autoimmune diseases. We have a global development program across very large market indications. Within the CD19 T cell engager class itself, we believe we have a molecule that's very well differentiated from the others in that space, particularly as it relates to things like very high binding affinity for CD19, small molecular size, which could be important for tissue penetration, combined with the convenience of subcutaneous administration. And so that program is in development across three high-value indications: lupus, RA, and Sjögren's disease, and we plan data readouts from all three studies throughout 2026.
The other area I think that we feel we have a differentiated product is, you know, there are a lot of monoclonal antibodies in the space of autoimmune diseases, and I think the challenge of monoclonal antibodies really is the potency. So they're certainly safe, but we're not seeing the kind of efficacy that you see with these T cell redirecting therapies. So excited about that opportunity. And then the last thing I would say is, look, B cell depletion remains a very hot area of interest, as you probably saw in terms of strategic interest. You know, Lilly just acquired Orna Therapeutics this week, so it remains a very hot area from an acquisition perspective.
The switching to oncology with CLN-049, our FLT3xCD3 molecule, that it has first-in-class potential to address a broad group of AML patients, and really unlock significant commercial potential. So we presented compelling monotherapy efficacy data for that molecule at ASH, where we saw CR/CRh rates that meet the bar for regulatory approval, potentially. And we were also very pleased to receive Fast Track designation from the FDA a week ahead of ASH. That was really good timing for us. And so in 2026, we're planning to really identify the recommended Phase II dose for a pivotal single-arm study that could lead to full or accelerated approval. In parallel, we're also developing the molecule in the frontline therapy setting with a combination study planned later this year.
And then the final thing I would say is, you know, from a cash position perspective, at the end of 2025, we reported over $430 million in cash, which gives us runway into 2029, which allows us to continue to advance our programs, but especially CLN-978 and CLN-049 in AML, autoimmune diseases, without the near-term need to raise capital. So this is a year that I think could be a really defining year for the company, and we're super excited about the multiple catalysts we have reading out this year.
Okay, great overview. So first catalyst coming up, 2Q, single dose of CLN-978. What have you said about the progress of enrollment in the studies that you'll be reporting from, which is the lupus and RA, that will encompass that first data in 2Q?
Yeah, sure. So what we said ahead of JPM is that we had completed the first two dose cohorts, so the 10 microgram, 20 microgram for both lupus and RA, and we were accruing into the 30 microgram dose level cohort for both studies. So for Q2, at the very least, we'll have those three dose level cohorts reported, and in terms of patients, that translates to at least nine patients in the lupus study and at least seven patients in the RA study. So I say at least because we think at least three cohorts. Obviously, the study is designed to go into a fourth cohort, 45 micrograms, so let's see how recruitment goes.
Okay. In the 10 and the 20 micrograms, how do those doses relate to the dose you used in oncology, where you saw that great clinical activity in NHL patients?
Yeah. So, Brad, they're not too far off. So in the oncology study, we did conduct a very brief first-in-human study with a starting dose of 30 micrograms, and we administered that subcutaneously on a Q-weekly schedule. And as Brad alludes, we saw a complete response in one of three patients treated at the starting dose of a T cell engager study, which is pretty remarkable when you think about it. So when we brought the molecule over into autoimmune development, despite the fact that we saw no higher than Grade 1 CRS at that dose, we thought in the interest of patient safety, we would start two dose levels below.
So, we expected and modeled that the 10 microgram dose, where we started our dose exploration in autoimmune disease, is physiologically active and could effectively limit the risk for higher grade CRS on the subsequent higher, potentially therapeutic dose delivered on day eight. So not too far off. Fortunately, in our discussions with FDA, we were successful. This was probably the greatest success, in our discussion, that we weren't pushed to delivering homeopathic doses in our study, which has been problematic for some other T cell engagers in development, both for autoimmune disease and oncology, actually.
Okay, so knowing that you're using some lower doses, but potentially still active, what does good look like in this first update in 2Q?
Yeah, so understanding that this is still essentially, kind of a modified single ascending dose study, most importantly, we will hope to show a dose response effect for B cell depletion. In the case of the SLE study, that's only peripheral blood B cell depletion. In the RA study, that data set is enriched with tissue-level B cell depletion obtained from paired biopsies of both the affected joint linings as well as lymph nodes. And so we think that we can show a dose response for B cell depletion, again, both peripherally and in tissue, with a retained therapeutic index. And that really sets up the potential for a more robust efficacy assessment when we move into repeat dosing.
In addition, this year, beyond the single ascending dose experience that we'll share in Q2, we have guided to that initial repeat dosing data in Q3, and that's really the place where we expect to be able to demonstrate more robust efficacy. But that first experience with the single dose gives you reason to believe that it is achievable.
Okay. Maybe we can dive into that a little bit more. When you, when you talk about the 3Q multi-target dose, what is the additional data unlock in terms of efficacy that you think can be demonstrated in that specific study, which is still part of the dose escalation, still small sample size?
Sure. So, understanding that the data for T cell engagers and various indications is still largely confined to academic experiences with case reports and case series, one clear signal emerges, and that is an exposure-response relationship for efficacy. So in the initial experience with blinatumomab, patients were given what now the docs at Erlangen would say is a subtherapeutic dose, or suboptimal dose, I should say. They saw efficacy at a low dose of only 9 micrograms administered for 5 days and then repeated again two weeks later. But in subsequent experiences, when blinatumomab has been administered at the full ALL dose and given for 10 or 14 days, there have been disease-modifying responses observed in hard-to-treat diseases like scleroderma. This was data that was shared last summer at EULAR from a number of academic groups.
So teclistamab, another series, different target, of course, BCMA, but there, when patients were treated with the dose ramp-up to the myeloma dose and then received a second dose about a month later, they saw robust efficacy, but also saw the characteristic features of immune reset. So I think this exposure is what's improved with the repeat dosing. So you, you know, you'll give. You achieve the requisite exposure by repeating a dose that is very well-tolerated, but is itself potent with respect to B-cell depletion.
Yeah, I would also add, as it pertains to the data that Jeff outlined, and the case series, you know, format, IITs, et cetera, we've seen in the external environment, our plan is to present the first company-sponsored data for a CD19 T-cell engager, which I think is, is very, very important because you're under much more controlled conditions. You're able to reproduce the results as well. So we're excited to be able to be the first ones, especially from a competitive perspective.
Mm-hmm. And then, as we think about later on down the road, when you're at these finalized doses and schedules, the safety component is going to be a big aspect of this, and I think ideally, there's an aspect of bringing this to an outpatient setting. So what are your thresholds for what you need to limit in terms of Grade 1, Grade 2 CRS and ICANS to be able to potentially match that profile later on?
Yeah. So, it's a good question, and we have had those conversations within with KOLs. We've, you know, put in front of them some, still at this point, relatively rudimentary target product profiles. And one thing is clear, that if you can achieve robust remissions, that is treatment-free remissions in about a quarter of patients with no higher than Grade 1 CRS in the majority of cases, maybe single-digit rates of Grade 2 CRS and no ICANS, you have something that would be very amenable to adoption in the community setting. And so again, meaningful efficacy in a significant subset, but really modest rates of Grade 2 CRS. Grade 3 CRS, of course, is out of the question. But-
Mm-hmm.
... and ICANS, I think, is something that our rheumatologists are a little less familiar with, but when it's explained to them, I think it's not something they would like to manage.
Makes sense. Maybe if we could double-click on that, when you talked about the efficacy potential and what physicians and patients are really looking for in this for it to be attractive, you know, what is a... How would you actually better define a treatment-free remission for these patients relative to something they could get on a conventional therapy?
Yeah, I think, if you ask most patients, they would prefer not to be. So, and patient-free time, that is time where you don't have to go in for infusions, where you don't have to plan your life around visits to the doc, where you don't have to remember medications, where you can pack your suitcase for vacation without having to think about whether you've got your pill box, all of those things matter to patients. So a duration of time where patients are truly treatment-free, even if they're free from a relatively well-tolerated maintenance medication is very valuable and, and differentiating.
And I think that is the potential that has emerged for T cell engagers, where, you know, in the most recent series from Erlangen, patients could go six months, and ongoing without having to take any medication for a variety of, autoimmune diseases. That included IIM, RA, scleroderma, and lupus. So, I mean, that's really transformative for patients who,
Mm-hmm.
... who, at a very minimum, would like to not have to take steroids, but, in the optimal situation, not have to take anything. Like, patient free time.
Yeah, I think that's, as Jeff said, we certainly hear that from rheumatologists. Today, what they tell us is, "We're not able to give patients that sort of treatment-free remission because they're on this chronic immunosuppressive therapy." And even with the monoclonal antibodies, for example, they're always added on top of..., whereas with the promise of T cell engagers is that you're giving a monotherapy treatment, an acute period of time, that then allows you to enjoy a treatment-free remission. And I think that the way we're thinking about CLN-978 is that, you know, we have the opportunity to deliver the potency of a T cell redirecting therapy, but with the convenience and accessibility of a antibody, so being able to deliver in the community setting where patients both live and work.
Got it. And everything we've been talking about has been for the CD19 TCE, which you propose to be the best and, you know, widest covering target for most of these B-cell driven diseases. You also did in-license a BCMA TCE. So how do you think about the strategy for that relative-
Sure
... to what seems to be you suggesting a focus on CD19 as being the best?
Yeah, so I think our view is that, with a CD19 and a BCMA, you're able to reach more autoimmune diseases and more patients than either target alone, and that was really a strategy behind, you know, doing that acquisition. I think our view is that if you think about, for example, diseases in rheumatology, they mainly tend to be driven by B-cell dysfunction. So having a potent B-cell depleter makes a lot of sense there, and that's why our development plan, so far with CLN-978, has been focused on rheumatological indications. It's pretty clear that there are diseases where the pathogenic autoantibodies, they're being produced by long-lived plasma cells, and so there you really need a plasma cell depleter. In those diseases, it makes much more sense to direct, you know, a BCMA type of therapy.
So, for example, things like myasthenia gravis, some of these immune-driven hematological indications, some of these thyroid-driven indications, it's clear that the culprit is a pathogenic antibody that is produced by long-lived plasma cells. So we have a very clear and differentiated development plan for CLN-978 versus BCMA. And so I think it gave us an opportunity to expand the reach of our autoimmune diseases by having both. And I think the other thing the acquisition gave us is it allowed us to become the only company with both a clinical stage CD19 and a clinical stage BCMA agent.
Got it. Okay. Well, we'll spend some time on CLN-049, the FLT3 bispecific. You presented data last December at ASH. What was that preliminary patient benefit that you saw in the Phase I, and what is compelling about it to get you to continue to invest into this program?
Yeah. Maybe, Jeff, do you want to address the clinical question? I-
Yeah, sure. I mean, in many respects, AML is a binary disease. You're in remission or you're not. So the most important outcome in any study of a new AML drug is your ability to achieve some form of complete remission. And so these can be complete remissions, where you see eradication of the AML and full recovery of normal blood cancer... pardon me, blood cell formation, hematopoiesis, or in other cases, eradication of the AML and incomplete or partial recovery of hematopoiesis. But all of those are the kinds of robust responses that you want to see in developing an AML drug in order for it to move forward. And we saw those in our Phase I dose escalation.
Once we had reached the dose of 6 micrograms per kilogram in the dose escalation, we began to see these deep responses, and the frequency of these deep responses continued to increase as we increased the target dose that we delivered, to 12 micrograms per kilogram, which was the last dose we had explored at the time of our ASH presentation. So those responses were seen in about just under a third of patients, 31%, at the 12 microgram per kilogram dose, and that compares favorably with drugs that have recently been approved for AML, with response rates, response meaning composite complete response rates of 23%-mid 30% and durability of response in the four to six months, month range.
While the follow-up for durability in our data was still relatively short, we did see that some of those complete responses were durable beyond 16 weeks, and in fact, we had at least one patient who had a durable, complete response with ongoing therapy out to six months. The other remarkable aspect of this, and why this is still an area where we think we have potential, is that in AML, genetics are kind of the destiny of the disease. So underlying genetic features are really both prognostic and predictive of response, and we saw responses in patients that typically don't respond to anything. Patients with P53 mutations, patients with complex abnormal karyotype, who typically die from their AML, and in the case of P53, have a median life expectancy of six months beyond the time of diagnosis.
So to see similarly robust responses there really gives us confidence that we have a potential drug, and so we're working to rapidly execute that program, as we can further discuss.
Yeah, I would add from the investment perspective, Brad, it's a very clear development and regulatory pathway. Jeff alluded to kind of recent approvals over the past few years, which have been, you know, single arm studies of about 100 patients to either get accelerated or full approval. And remember, with all of those molecules, they're targeting a very specific biomolecular subset of patients. Our study was an all-comer patient population. So now we potentially have a treatment that can address the broad all-comer patient population of our AML patients. And so with a single Phase II study, there's the opportunity to get approved in the relapsed refractory segment, which is a billion-dollar opportunity on its own. And with a single Phase III study, you can then expand into the frontline setting, larger group of patients, longer treatment duration.
And so one Phase II study, one Phase III study can get you to unlock significant commercial potential with a very clear development and regulatory pathway. And in terms of company expertise, you know, Jeff's treated a lot of AML patients with his hematology expertise. I've developed, launched a lot of drugs in AML, so this is really in our sweet spot, very clear regulatory pathway, and a very significant return on investment if we're able to reproduce these results.
This is the first-in-class FLT3 bispecific. So what was the KOL response at ASH, especially compared to some of the other immunotherapy attempts and different targets that have been presented at meetings for AML in the past?
Yeah, I would say it was. I would, exuberant is not maybe a word I would use to talk about any hematologist, but people were really excited. So our team had meetings with more than 30 different investigators, globally, both U.S., Europe, and beyond, and uniform interest in potentially participating in the study, which was very gratifying. I think the abstract itself was selected for the official highlights of ASH presentation, because I think it really was recognition that this is standout data for an immunotherapy in AML, a place where there's been a lot of whiffs at bat. CAR T has been a big fizzle there. There's been some spark in NK cells, but nothing that's really stuck quite yet. And so I think this is really recognized as a unique opportunity.
When people look across hematology and they say: Well, geez, there's CD20 in lymphoma, there's BCMA in myeloma, and these are potentially transformative drugs, particularly when they're given in combination, I think they see that same potential for 049, where it has robust monotherapy activity, but maybe there's opportunity to unlock even greater therapeutic potential in combination. We have announced our intentions to begin a Phase 1b/2 combination study with AZA in previously untreated patients before the end of this year.
Okay. Now, Nadim, you sketched out the potential pivotal plan. What's the in-between to get there, though? What are the next steps, and how long do you think it will take to get to a position where you're at least ready to get to that first single-arm, second-line pivotal?
Yeah. Certainly something we've been thinking about right now.
Yeah. So at the time of ASH, we stated our intentions to begin dose expansion at two doses as part of the next phase of the study. This would be in an all-comer patient population, designed to satisfy our regulatory expectations for dose optimization under Project Optimus. This will lead to selection of a recommended Phase II dose for further development, which we hope to complete by the end of this year. In a second cohort of patients, we'll actually look specifically at TP53-mutated patients. And there, not only will we look at relapsed refractory patients, but also previously untreated patients. There is no existing standard of care in the frontline. As I mentioned, survival is six months, and so there's equal poise to actually conduct a Phase I trial in that patient population.
We'll get some experience in giving the drug to previously untreated patients as well. Our hope is to initiate, as Nadim shared, a Phase II single-arm Phase II study in 2027, which could lead to approval under the accelerated pathway here in the U.S.
Okay, great. Maybe in the last minute or so, how does the zipalertinib for the EGFR exon 20 TKI wrap into the Cullinan story for this year?
Sure. Yeah, look, I think the very first thing I would say is, getting your first NDA under your belt as a biotech company is pretty important achievement, so we're super excited about that. The other thing I would say is, you know, with the completion of the relapsed study, that was the last piece of Cullinan Therapeutics leading the development work. So now Taiho is leading the rest of the development work. So for us, it's getting that second-line approval, followed by frontline, which Taiho has guided to, completing enrollment first half of this year and completing the NDA submission for relapsed disease this quarter. And then Taiho leads the rest of the effort. The other thing about this program, though, is in addition to the unmet need, it also provides a significant source of near-term, non-dilutive capital to the company also.
$130 million in regulatory milestones still outstanding for frontline and second-line US approvals, and we have a 50/50 profit share in the U.S., so it's become quite a strategic asset for us.
Okay, wonderful. Well, very busy year ahead. I look forward to seeing it all. Thank you so much, Jeff. Thank you, Nadim.
Thanks for having me, Brad.
Thanks, everyone, for tuning in.
Thanks, everybody.