All right. Welcome back to the 46th Annual TD Cowen Healthcare Conference. Marc Frahm from the Biotech team here at TD Cowen. Really pleased to have with us for the next session here, the team from Cullinan Therapeutics. We've got Nadim Ahmed, President and CEO, as well as Jeff Jones, who is the CMO. We will go through a whole list of questions that me and my colleague, Ellen, have come up with. Also feel free to raise your hand, and we will try to involve the audience if you have your own questions you wanna follow up with or anything.
With that, maybe Nadim to start out with, you wanna kind of give a high-level state of the company, status update, and kinda what you view as the kinda key value-creating milestones over the next 12-24 months or so?
Sure, yeah, happy to. First, thanks for the invitation. Very glad to be here. Look, I would say for us at Cullinan Therapeutics, 2026 is gonna be a really exciting year, could be really transformational for the company. We have catalysts and milestones across all of our programs, but especially the two I'd focus on today are our CLN-978, which is our CD19x CD3 T-cell engager for autoimmune diseases, and CLN-049, which is our FLT3x CD3 T-cell engager. Two high-priority T-cell engager programs. With CLN-978 in autoimmune diseases, I think we believe we have a molecule that has the potential to be best in class, and we have a global development program across multiple large market opportunities.
With CLN-978 within the CD19 TCE landscape, we believe we have a very well-differentiated molecule based on very high affinity to bind for CD19, very small molecular size, which could be important for tissue penetration, together with the convenience of subcutaneous administration. Very well-differentiated molecule. We have ongoing development studies in three high-value indications: RA, lupus, and Sjögren's disease, and we plan to present the first company-sponsored data for a CD19 T-cell engager. We'll have data for both lupus and RA, initial clinical data in Q2 of this year, multi-dose data for RA in Q3 of this year, and Sjögren's disease initial clinical data in Q4 of this year. Very excited about that opportunity. The other thing I'd say, look, B-cell depletion remains a very hot area, so especially when it comes to strategics.
You saw the acquisition of Orna Therapeutics by Lilly just about a week or so ago. We saw a reverse merger yesterday, so clearly an area that remains very, very hot. On the oncology side of things, I mentioned CLN-049, our FLT3x CD3 bispecific T-cell engager. Here we have a first-in-class opportunity to take an immunotherapeutic approach to AML, which we haven't seen yet, and it's a drug that could address the broad group of AML patients, so unlocking significant commercial opportunity. Just a few weeks ago at ASH in December, we presented what we believe to be compelling monotherapy efficacy data, and we would argue, data that is in line with what you would expect for regulatory approval. If we reproduce those datas, I think we'll be in a very exciting place.
This year, we're focused on utilizing our Fast Track designation. In some ways, though, I think it set an expectation that, you know, we were gonna expect 100% cures in every autoimmune disease, which obviously isn't the case. You don't get that with any therapy, and I think that probably impacted subsequent datasets. The thing I will say is that data did really establish proof of concept for T-cell redirecting therapies in autoimmune diseases, so I think that's the first main point. Secondly, I would argue that there still is somewhat of a disconnect between investor expectations and investigator expectations in terms of outcomes. I'll give you an example. You know, last couple of years, we've had the chance to speak to multiple rheumatologists, and what they tell us is, "Look I'm comparing new treatments relative to what I have available to me today.
What they have available today does not give their patients treatment-free remissions that you see with the T-cell redirecting therapies, right? There, I think what they tell us is, look, if we can get treatment-free remissions in a proportion of my patients with an off-the-shelf treatment, you're gonna get widespread adoption, and that's something you can't get with current treatment. If you think about monoclonal antibodies, you can't give them without the background chronic immunosuppressive therapy that patients are reaching. I do think it's several-fold, but I think the promise of CLN-978 to give that potency of T-cell redirecting therapies, but with the convenience and accessibility of monoclonal antibody treatment, I think is gonna help us to shape and pave the way for bringing a truly disruptive treatment for patients with autoimmune diseases.
Okay. You know, if you look kind of across there's a number of datasets of different CD19 CARs, some not necessarily CD19 bispecifics, but bispecifics more broadly, some from corporate, but a lot of academic or IITs type of work. Just what do you think the totality of that data has proven so far, and what do you really need to prove yourself?
Sure.
Sure.
I, you know, I think in general, they've established proof of concept that treating patients this way with a T-cell redirecting approach with a TCE is likely to prove therapeutically beneficial across a wide range of autoimmune diseases. To the earlier point, and perhaps impacting investors, is that the signal-to-noise ratio has been pretty high. It's a smattering of patients in this indication treated with this dose, but then they got retreated with another dose. Part of the challenge is trying to sort of put it together in some sort of systematic explanation that says, "This is how orderly drug development will go for this modality." What you see now are compelling case histories that say, yes, patients can be beneficially treated this way with an appropriate therapeutic index.
I think what's been missing, and we hope to provide in our data updates this year, is a comprehensive view of dose response for pharmacodynamic and ultimately efficacy parameters, and then some clear understanding of how these drugs progress through later stages of development. Right now, it's sort of high concept, but the practical aspects of next steps in drug development, and a clear picture of PK/PD relationships and how this comes from concept to drug is the piece that I think people are waiting for us to fill in.
Okay.
I think we'll begin doing that this year for CLN-978.
Yeah. Maybe that's a good jumping off place to kind of framing up the first data presentations later this half. Just how much of that will have already... you know, will be just told with the data versus is the data will enable you to tell the path to some of these?
I mean, in sort of alluding to the expectations for our data in Q2, we have three parallel studies running in dose escalation. The furthest two along are in SLE and RA. We've guided to providing data from the modified single ascending dose part of those studies in the second quarter of this year. What we expect to show there are dose response relationship for important biomarkers, particularly B-cell depletion, not only in the peripheral blood in the case of both studies, but also at the tissue level in the case of RA, and put that together with important safety and preliminary efficacy observations, understanding that the expectations for efficacy after just a single therapeutic dose is relatively small.
I think that will give you the understanding that, yes, this is potentially therapeutic when delivered in a more robust treatment scheme that increases the exposure to the drug. I think it builds that confidence for the data that we provide in Q3 from repeat dosing in RA, since that study's the furthest along, that sort of shows, not only was that dose safe, but now when employed in a therapeutic regimen, you can achieve a meaningful efficacy in RA patients. In this case, these are difficult to treat RA patients who would have already failed multiple disease-modifying therapies like TNFs and JAK inhibitors in most cases.
When we get this, the single- dose data, I mean, obviously you'll have some information about B-cell killing. I guess, what does good look like? Is it just showing a nice dose response that sees deepening and maybe somewhat more extended periods of suppression as you get there that then provides that hope?
Yeah, I think that's true for the initial peripheral blood data. I mean, there are limitations to what that can show, understanding that that is likely a necessary but insufficient condition to achieve the depth of B-cell depletion necessary for immune reset. I think the more important data is going to be the data from biopsies. There, you know, we have some benchmarks for what has been achieved or seems achievable with blinatumomab, low dose CAR T, and the antibodies that will allow us to, you know, to benchmark. Still understanding that a single dose is probably not going to be adequate to achieve the real level of exposure necessary for true immune reset. Theoretically, that dose is probably possible, but it might flirt with unacceptable toxicity.
Maybe immune re-reset is too much to ask of a single dose. You know, you can have clinical activity and clinical efficacy that is short of immune reset. a durable remission as well. Should we expect some clinical impacts too?
I expect that we'll be able to discern some clinical impact, but there are limitations, not only from the single dose, but through heterogeneity of the patient population in a phase I escalation trial that may make sort of dose response. For instance, if at the lower doses, less heavily treated, less heavily affected patients are enrolled, but at the highest doses, you see only the sickest of the sick, it could confound your ability to see dose response just through the nature of who's enrolled.
Yeah. I think I would add, I think the most important thing about our initial data set is, you know, we're doing this dose escalation in a very systematic and rigorous way. Yeah, until now, as Jeff alluded to, all we've seen is data from IITs, individual patient case reports. T-cell engager development is tricky. You know, we have the experience in oncology now in autoimmune diseases. The best way to do it is through a company-sponsored study, and that's what we're planning to do. Going back to your question, Marc, for this initial data with the single target dose, the two things that you wanna see that are most important are you wanna have an acceptable safety profile critical for this patient population. Ideally, you wanna see dose-dependent B-cell depletion, especially in the peripheral blood.
I think if you get those two, that's check one, check two. As you think about optimizing efficacy, and of course, we'll report out clinical markers, but if you really wanna optimize efficacy, that comes with the multi-dose data, and that's only one quarter behind Q2. We'll have the multi-dose data in RA, which I think is gonna be very informative for the field at large.
You said acceptable safety profile. Can you just remind what is that target profile, both from the safety but also, you know, where are you trying to optimize too?
Sure
efficacy perspective?
Yeah. Why don't you start with safety?
Yeah. I think from a safety standpoint, you know, we know from FDA, for instance, that a Grade 3 CRS event is considered a dose-limiting toxicity. What we're really trying to do is reduce the rate of CRS overall, but really focused on minimizing the rate of Grade 2 CRS. Grade 2 CRS is not too different from some kinds of infusion reactions that rheumatologists and other docs who treat autoimmune patients will have managed as infusion reactions with monoclonal antibodies. That's something that's still within the realm of what's manageable, but even that should be minimized. We think 10% or less rates of Grade 2 CRS would still be acceptable based on all of our interactions with KOLs and other docs in the field. In general, Grade 1 CRS, pretty manageable.
It's a fever, can be managed with Tylenol in most cases. That doesn't seem to present any impediment to adoption, but high rates of Grade 2 CRS would be problematic. When we're thinking about this, we're trying to prevent the development of neurotoxicity, most specifically ICANS, and minimize the rate of Grade 2 CRS.
I would add from an efficacy perspective to your question. Again, I think when we speak with KOLs in the space, especially rheumatologists, and I'll use lupus as an example, right? What they tell us is with what they have currently, for example, the biologics like Benlysta, Saphnelo, they're always adding them on top of the chronic immunosuppressive background therapy that patients have to stay on. The thing with T-cell redirecting therapies is that we're seeing monotherapy efficacy at the same time as patients are able to come off these background therapies. That's what's so compelling about this kind of treatment proposition.
I think when you talk to docs, they say, "Listen, I can't get my patient a treatment-free remission today with what I have. If you give me a treatment that can get, say, 20%-30% of my patients at a minimum into a treatment-free remission, obviously, we'll shoot for higher, but that you're gonna get widespread adoption. I think that's how we think about the target product profile, Marc, coming back to your question.
Okay. Is there any more specific guidance you can provide on just the Q2 update, how to think about how many dose levels are in there?
Sure
patients that to think about?
Sure. Just before JPM and update, we shared that we were enrolling patients to the 30 µg cohort of both the SLE and RA studies. We expect we'll complete those cohorts for both studies. That's a minimum of nine patients for SLE and seven patients for RA. I expect the number will be higher than that since we also have the opportunity for further dose escalation as well as backfill at dose levels of interest to gain more PK/PD experience. Minimum 16 patients, nine and seven.
Okay. Then you know, moving forward to the MAD data, also to one of your earlier responses where you're talking about that something the field needs to show to investors is what is that full development path look like? Is the MAD dosing, obviously it gets you a little bit closer to the immune reset, is that an optimized regimen that you will be able to talk about, or that's enabling you to do the true optimization of the regimen?
Yeah. I think it's probably the latter. I mean, if we by you know, lucked into the first best regimen from the very beginning, that would be great. We know, that's unlikely, since we were working with limited human PK data. There is a possibility that we could come up with a better regimen, maybe one that could potentiate greater efficacy while maintaining safety. Secondarily, we know that there will be regulatory expectation that we do some further dose optimization, which in most cases in autoimmune disease has meant a randomized dose optimization study. That's something that we need to contend with.
We also know based on the CAR T experience that if efficacy is compelling and safety is acceptable, there are in certain subsets of these autoimmune diseases, lupus nephritis, for instance, being a very prominent example, where there is a potential path forward for accelerated development. What that looks like outside of CBER in, you know, the Division of Rheumatology and Transplant Medicine is something that will have to be worked out with further regulatory discussion. It does give us, you know, reason to believe that that pathway could be open, with compelling efficacy, retained safety, and maybe that's something we begin exploring, as we move into phase II. I think again, one of the most important things we'll do over the course of the second half of this year is really help lay that out for our stakeholders.
Yeah. I think the one thing I would add to what Jeff said is, you know, again, because we're taking a monotherapy approach here, the development path could be much more efficient than what we've seen with monoclonal antibodies, for example, that are adding on top of background therapy than having to compare against placebo. I think we have a much clearer, more efficient development pathway here.
Okay. Do you think that optimized regimen is likely the same across kind of the gamut of autoimmune diseases that are potentially addressable with-?
Yeah
... the B-cell reset or?
Yeah. I think probably, but that's not gonna be enough to satisfy regulatory expectations, and that's why, as Nadim said, a systematic dose finding regimen refining approach across three indications, while it's somewhat duplicative, people have asked why we didn't do basket studies, but part of what we're able to do at this very early point of the program is if we can show that PK/PD safety observations are relatively similar, it gets us a lot closer to finding a single regimen across diseases instead of having to solve this problem every time we start a new project.
Okay. I think with that, maybe we'll move to FLT3. Maybe, Jeff, you wanna just kind of put the data that was shown at ASH kind of in the broader context of AML?
Yeah. Maybe just starting with the broader context of AML. Aside from Ven/Aza and some targeted molecules that address no more than about 50% of patients, the standard of care in AML has remained 7+3 induction since the early 1970s. Despite a lot of effort, progress has been pretty slow in AML. One big gap has been immunotherapy, whereas a T-cell engager and other immunotherapies are approved in every other large indication in hematology, AML has lagged.
That's why we're really excited about the potential for CLN-049 since the results that we showed at ASH this year, a composite CR rate of 31% at the highest dose tested, 12 µg per kg is competitive with anything that has been recently approved for AML over the last decade, where drugs have been approved with composite complete response rates of anywhere from 23%-30-some percent, with durability of 4.5 to six, seven months.
While our durability is yet to be fully reported since the observations were still young, that composite complete response rate, really why it's so important, one, it's one of the first times this has been shown for an immunotherapy mechanism of action in AML, and secondarily, if replicated in a larger group of patients, would provide an avenue towards accelerated approval in a broad patient population. We so far haven't seen any biomarker that suggests a patient is more or less likely to respond. An all-comer immunotherapy in AML would be something truly novel.
You know, what. You know, obviously it was exciting data, but it's also not a gigantic data set yet, right? What gives you-
Well, I mean, 45 patients for phase I is pretty big.
What gives you confidence that it truly is an all-comer strategy and that over time you're not gonna figure out that you need to do some sort of you know, expression level cutoffs?
Yeah
...or something like that?
Yeah. I think the expression level cutoffs is actually unlikely based on what we saw. There, Marc speaking about FLT3 expression, you might think for a targeted therapy, the level of expression would perhaps be important in selecting patients more or less likely to respond, and that doesn't appear to be the case in the data to date. That would not be uncommon for a T-cell engager. Many of you are familiar with the drug teclistamab, BCMA T-cell engager, very effective in AML. It works in patients, or pardon me, in multiple myeloma. That drug works in patients who are BCMA negative in some cases. BCMA must certainly be expressed, but it's probably below the limits of conventional detection. I think something like that is true here.
Okay. I think if you're back to where my question truly was, but where you were starting to go, which was my next question, which is the all-comers approach, from the is there a selection strategy and maybe different bars, for different subsets.
Yeah
AML patients if we could do that.
I do think there are different bars for success. The most important group of patients is that 30% or so of patients with P53 mutations who have a really dismal prognosis, whether it's de novo or emerges in relapse therapy. In that group of patients, the benchmark for success is probably a response rate that is complete response rate of 20% with four months of durable response. Why so dismal? Well, because the median life expectancy of a patient newly diagnosed with P53 AML is only six months. Four months and 20% is actually clinically meaningful by every account. That's not too far off the mark for approval of the menin inhibitor recently for NPM1 mutated AML, which is not a dismal prognostic subset of AML.
It's actually one of the more favorable risks when it's occurs, in newly diagnosed patients.
Okay. yeah, I think as of ASH, you know, you had not found a DLT yet, or an MTD, sorry.
MTD.
MTD.
That's right.
Yeah. Yeah.
Yeah. We had not.
You were still potentially exploring some more dose escalation. Just, you know, I guess what's the latest there? How much of a focus is that versus? just running forward with the signal that you have?
Sure. Yeah. I don't think our intention has ever been to dose to an MTD per se, but I do think what we saw, at least through the 12 µg dose level, was that there was still a dose response. We believe that because we had retained therapeutic index, we had an option to continue the dose escalation to see if we could eke out more efficacy. You know, if we saw that the safety fell off or if we saw that we had sort of maxed out on the dose response curve for efficacy, that would be our indication to cut and explore the doses that we've already shown efficacy as part of the expansion. We were not at any place like that as the time of ASH.
Okay. If you wanna walk through some of the planned expansion work that you discussed a bit at ASH.
Yeah. What we laid out as a plan at ASH is pretty much according to regulatory expectations. We've received prior feedback for this and other programs that we should explore at least two doses as part of expansion, and we would elect to do that in a broad patient population, all-comer relapsed AML, except for a group of patients with P53 mutations. There we would explore two different doses in that all-comer population. P53, they've done well with our drug so far, with response rates that are equivalent to non-P53. Given the history and the adverse natural history of that subgroup, we pulled it out to explore as a separate cohort. In addition, because there's no established standard of care in the front line, it's also an opportunity to explore monotherapy in previously untreated patients with P53. Really, a unique opportunity.
are those opening now or waiting for you know, to finish some of that dose escalation?
Yeah
...work you just talked about?
What we sort of laid out is that we'd wrap the dose escalation here early in 2026. We are in 2026. We'll commence the expansion phase of the trial in Q2 of this year.
Okay. Then, you know, how should we think about the next update, and how much backfilling is happening? We might see data from that, you know, late this year, or just more about the follow-up of the patients who are still on trial?
Yeah
Obviously the dose escalation that's still happening.
I can't comment on the total number of patients quite yet. I can tell you, as we did at the time of ASH, we had treated at least 53 patients at that point. If you think about the expected follow-up, considering that we'll be finishing the dose escalation this quarter, that means later in the year, responding patients should, in general, have at least six months of follow-up. That six month for the sort of landmark, for all of the reasons we've talked about, is important. That's what we should have in hand by the end of the year.
Unfortunately, we're running over, so I think we're gonna have to cut it off there. Thanks a lot for joining, Jeff and Nadim , everybody in the room, as well as anybody on.