Hey everyone, welcome to our next session with Cullinan Therapeutics. My name is Leigh Wozek, a biotech analyst here at Kenter, and it's my great pleasure to have the Cullinan team with us today. Nadim and Jeff, welcome, great to have you. Maybe I'll turn it over to you guys to give us a quick overview of the Cullinan story.
Sure, happy to do that. The first thing I'll say is, as a company, we're at an exciting inflection point with multiple catalysts coming up in the months ahead. From a pipeline strategy perspective, we really focus exclusively on molecules that are either going to be first or best in their class, and can be transformative molecules that really do create new standards of care for patients with cancer or autoimmune diseases. Also, given the very high failure rate of early phase clinical development, upwards of 80%, we have taken a multiple shots on goal strategy to maximize asset success. After passing through rigorous stage gates in the discovery phase, we put a series of programs into the clinic over the past couple of years, and the data from these phase one programs will inform really important near-term go/no-go decisions.
I think it's important to make sure you do have rigorous criteria to determine which molecules then go on to later stage development, especially as we want to make sure we prioritize capital allocation to our highest priority program, CLN-978, our CD19 x CD3 bispecific T-cell engager, which we're exploring in a range of autoimmune diseases. With that molecule, we feel good that we have a competitive position, a highly differentiated molecule, and with CLN-978, we really do have a molecule that has the potential to be a best-in-class disease-modifying treatment regimen that can address a range of unmet needs across a broad range of autoimmune diseases.
You know, if you remember, Leigh, it was last year when we expanded our R&D efforts beyond oncology into autoimmune diseases, and as a part of doing that, we, meaning Jeff and his team, he quickly built out an immunology team that's focused exclusively on CLN-978. That team, in the same year, were able to make sure that we were the first and still only company to have cleared an IND with a development stage CD19 T-cell engager in the U.S. Obviously, we're very excited about that program, and they were also able to stand up a global development program now with ongoing studies in three different indications of high unmet need, large market opportunities.
We also added external immunology expertise to our board of directors and our scientific advisory board, and the current state of progress, or status of the programs, is that we have an ongoing global lupus SLE study taking place in Europe, U.S., and Australia. Today, we did update guidance for initial data from that study with a small change in timing, so now the initial data is expected in the first half of 2026 from Q4 2025 originally. At the same time, we also have an RA study that's ongoing in Europe and actively dosing patients, and there we're working with the Erlangen group in Germany who have really pioneered the use of T-cell engagers in autoimmune diseases. We also have a third indication, so we have a Sjogren’s study that's up, active, and ongoing.
I would say we were also very pleased to see the data emerging out of EULAR recently, which really further validates CD19 as a high-impact target and also T-cell engagers as an important treatment modality for the potential treatment of autoimmune diseases. That's the immunology side. We've been busy on the oncology side too, and with our EGFR exon 20 tyrosine kinase inhibitor, zipalertinib, with our partner at Taiho Pharmaceutical, pending FDA discussions, we're planning an NDA submission by the end of this year, so that'll be an important milestone for the company. Just coming up in a few days at the World Congress in Lung Cancer, as well as ESMO next month, we have some important data in important patient segments such as those patients with atypical mutations, patients with active brain mets.
I would say not only is zipalertinib addressing important unmet needs from a strategic perspective, it also provides a future source of non-dilutive capital for the company because as part of our deal with our partners at Taiho Pharmaceutical, we're still owed $130 million in U.S. regulatory milestones. We also have a 50-50 profit share, so that's important to us. I'll conclude by saying, you know, we reported over $500 million of cash at the end of June this year, which gives us cash runway into 2028 based on our current operating plan. That really gives us the resources to continue to execute against our high priority programs, as well as generating multiple near-term and long-term catalysts without the near-term need to raise capital. Hopefully that gave you a snapshot and an overview of where the company is.
Very comprehensive. Maybe just a quick follow-up on the timeline update this morning, that's for 978, and that's in lupus only. What is sort of the background for the timeline shift?
Sure, yeah, I think you raise an important point. This update only applies to the lupus study, and also important to point out that the updated guidance isn't based on any adverse clinical findings from the program, so that's also important to point out. For example, our RA study is still on track per our original guidance for data in the first half of 2026, and our Sjogren's disease study is active and ongoing. I will point out, and I think we're starting to, we've seen it more and more now, lupus studies are difficult to enroll into. Having said that though, we have been encouraged by the very high level of enthusiasm by our treatment sites and investigators, and that's been really manifest by the high level of patient screening activity that we've seen.
Jeff, who's sitting next to me, has, with his team, really engaging these sites, so I'm going to ask him to elaborate on this observation and talk about our action plan moving forward.
Yeah, so maybe Leigh, I'd start by saying that, and just underscoring what Nadim said, that we've had really vigorous investigator interest, and that's manifest in the fact that more than half of the sites that are active in the trial, 11 now listed on clinicaltrials.gov, have submitted patients for screening, some multiple patients for screening. That has at least matched or exceeded expectations for screening. What we have found is that those screenings are not leading to enrolled patients. As we have worked with our sites, site staff, and the investigators, we've come to understand that both in pre-screening and screening, the eligibility criteria for our trial as initiated are too stringent to match the patient population that's available, particularly at community sites. We've honed this down to several key eligibility criteria that are modifiable in an amended protocol that we are implementing.
To be specific, the first is around exposure to prior therapy, where the previous requirement for exposure to a biologic or cyclophosphamide was prohibitive to enroll community patients, many of whom will have received small molecule immune suppressants. In the revised protocol, patients are eligible if they've received a biologic, cyclophosphamide, or a small molecule immune suppressant. Secondarily, we have lowered the disease severity score from a SLEDAI of 8 to 6. This still defines a moderately symptomatic patient with SLE, but it does significantly enlarge the patient pool. We have heard from our investigators that this would enlarge our patient pool. When we've gone back and looked at our actual screening logs, we can see that many of the patients who screened but ultimately did not enroll in the trial could have satisfied the requirements of the amended protocol.
We feel very confident that that, along with an ongoing site activation activity, both here in the U.S., in Europe, and in Australia, position us to continue momentum through the dose escalation. The last thing I'd mention, and this in part to talk about the historic challenges of lupus trials, we are very fortunate to have the partnership of both the Lupus Research Foundation and the Lupus Research Alliance in fostering relationships with academic centers, helping accelerate site activation activities. They are, in the case of the Lupus Research Alliance, a loose network, and then through targeted direct to physician and patient communications that raise awareness of T-cell engagers as a modality of interest in SLE, as well as specifically promote an opportunity to participate in clinical research for CLN-978.
Yeah, I would add, Leigh, just before leaving, this point is firstly, you know, with CLN-978 being our number one program, we're going to make sure we continue to deploy the resources to advance the program expeditiously. I think we have a plan in place for the lupus study that I'm very confident will allow us to deliver initial data in the first half of 2026. At the same time, we also do have an ongoing RA study where we have previously guided to continue to maintain data delivery, initial data delivery in the first half of 2026. We now have an opportunity to maybe give a bit more of a broader update across indications in the first half of 2026. We're certainly looking forward to be able to do that.
Okay, great for that clarification. As you guys mentioned, CLN-978 is probably the first lupus trial for CD19 T-cell engagers in the U.S. We're certainly seeing more competitors trying to enter the space. I understand there's a lot of nuances, at least for investors, when it comes to evaluating different T-cell engagers, when it comes to CD3 affinity formulations and things like that. I guess if you can help us understand, how does CLN-978 stack up against some of the other molecules in the competitive landscape?
Sure, yeah, happy to do that. The first thing I will say is that RT has really established proof of concept in this autoimmune disease space with the ability to be a very potent therapy. I think our view is that with T-cell engagers, you have the opportunity to deliver the potency of T-cell redirecting therapies, but with the convenience and accessibility of antibody treatment. I think that's a really important point. That's certainly something that we hear from rheumatologists, to have the opportunity to take something off the shelf, treat patients where they are in the community, and to be able to give them that potential benefit is important.
Ultimately, we do see that CLN-978, and using lupus as the disease of choice or example here, would be in the treatment sequence used prior to cell therapy for the reasons that I mentioned, and ultimately in the long-term future to potentially be used ahead of monoclonal antibodies. Remember, with monoclonal antibodies, the issue is that patients still have to stay on background chronic immunosuppressive therapy. When you put all of that together, we view our competitive set really as the other CD19 T-cell engagers. CD19, we believe, is the optimal target for autoimmune diseases for a whole host of reasons. I think we feel that we're very competitively placed in that space from both an executional perspective, as I mentioned before, first and only company to have a cleared IND with a CD19 T-cell engager in the U.S.
That certainly gives Jeff and his team lots of opportunity in the U.S. We also have, I would say, quite a differentiated development program with three ongoing studies, very high unmet need populations, but large market opportunities. We're relatively ahead compared to most of the other CD19 T-cell engagers in the space. I think we feel very good about where we are competitively relative to the landscape around us. Our focus really is on the other CD19 T-cell engagers where we feel we not only have a competitive executional position, but also a highly differentiated molecule when it comes to CD19 affinity, wide cytokine window, as well as the small molecule format and size relative to the other CD19 T-cell engagers, which tend to be built on a larger IgG backbone format. Small size may be important for things like tissue penetration.
Yeah, great. As we look forward to the part A update in the first half of next year, my understanding is obviously the safety is going to be the focus. What other metrics should investors focus on? Probably a little too early on the efficacy side, but in terms of some depletion data or marker data, we should pay attention to that.
Sure, yeah, I think, again reiterating that the initial data will be from part A, the dose escalation phase of the study. The two areas we're focusing on are safety data, which is very important for this autoimmune disease setting, but also, as you alluded to, Leigh, B-cell depletion. At the same time, whatever data we have available in terms of, for example, autoantibodies, SLEDAI scores, etc., we will report those data out at the same time. Again, reminding that this is the very first data set from the study, we want to make sure we manage expectations. Obviously, there'll be future reporting of the data from the study where we'll have the opportunity to look at things like durable remissions, etc.
For this first data cut, we're focusing on part A, and we're focusing on safety and B-cell depletion, and we will report out whatever else other data we have, both in terms of clinical and biomarker data.
Maybe, Nadim, just to make one comment to emphasize that doesn't mean we have lack of confidence in the potential for efficacy. It's just as the growing body of data demonstrates, like at EULAR, you alluded to the data this summer. When T-cell engagers are given, the most robust efficacy has been observed when the therapeutic dose is given on a repeat schedule. It's as simple as that. There are a number of examples if you review the EULAR data, and we won't get to that point in our clinical trial until part B. We'll share, as Nadim says, efficacy observations, but in an early phase study with just a single target dose, the expectation should be to see primarily PKPD assessments.
Yeah, that's a great point, Jeff. I think the part B, the multi-dose phase now, as Jeff mentioned, when you look at the ULAR data and you look at T-cell engagers, CD19, BCMA, CD20, the outcome is identical. You optimize efficacy when you give multiple doses.
Okay. I guess we have to wait until, you know, part B to get a really good sense of lead efficacy. In terms of setting lead efficacy benchmark, some rheumatologists may say, okay, 20% remission may be, you know, good enough. That seems like a very low bar. Given some competitors have put out really, you know, very strong data there, I guess internally, what do you think the bar for success is?
Yes, so several points I'll make about that, Leigh. One is, you know, the expectations of investors and investigators aren't always completely aligned. When we speak to rheumatologists, and we've spoken to many of them, what they're looking at is the current treatments that they have available to them. What they tell us is that we are not able to get our patients consistently into a treatment-free remission. Like if you think about, for example, the antibodies, they're always added onto a background of chronic immunosuppressive therapy. I think the difference is with T-cell redirecting therapies, CAR-T or T-cell engagers, for the first time, patients can actually come off that chronic background therapy. What investigators tell us is that, if a minimum, so that's what I want to stress, a minimum of 20% to 30% of my patients can get into a treatment-free remission, you should expect widespread systemic adoption.
Obviously, we're going to push for higher than that, but that's where there's a little bit of difference between investigator expectations and desires versus investor expectations. The second point I would make is that, in those conversations, what has also become clear is that the bar for CAR-T therapy and the bar for T-cell engager adoption is actually very different because of everything you have to go through as a patient and a physician to access CAR-T therapy. For us, that's very encouraging and attractive. That's why I was saying earlier, when clinicians are given the choice, where patients don't have to go to a CAR-T certified center, don't have to go through lympho depletion regimen, they will, in their minds, as they think of treatment sequence, reach for T-cell engagers first before then going on to cell therapy subsequently. All of it actually lines up.
For us, I would say the 20% to 30% is, if you like, the minimum commercial target product profile. Of course, we're pushing for beyond that. It's very clear that the bar for T-cell engager adoption is lower than the bar for CAR-T therapy. I think that's a good thing.
Yeah, and you know, Leigh, you said your competitors. I think Nadim's alluding to the fact that it's really how you define your competitive set. Just in a very doctor-specific kind of way, when we speak to investigators, CAR-T isn't something they will reach for. It's not something that they can give. In the typical place of care for most patients, which is in the community, outside of hospital or tertiary care practice, it's like what is in their tool chest. There's not a time in the foreseeable future where CAR-T will not require referral to a tertiary center that's CAR-T certified. That may be appropriate for some patients, but I wouldn't say that. It's just a totally different expectation based on how care is delivered.
Yeah, and the last one ultimately, even within, for example, the T-cell engager set, these are very, very large markets. It's not like one winner takes all, right? If you look at RA, for example, how many DMARDs do you have to cycle through before you become a difficult-to-treat patient? I think there's plenty of room in that space in these very large markets. Obviously, we're very happy that we're among the front of the pack, but it isn't binary.
Okay. Another question is around the CRS risk, just given autoimmune indication. I think the safety tolerance is perhaps a little lower than oncology. I guess what can you tell us in terms of what you see of the CRS profile so far? In terms of some of the mitigation measures that you guys may be doing in terms of site selection, step dosing, maybe share a little bit about that?
Yeah, so maybe just to talk a little bit about the observations so far for T-cell engagers and autoimmune application, regardless of the target versus oncology. In general, you see a lower incidence of lower-grade CRS, just in general. There does seem to be a higher propensity for high-grade CRS in oncologic use of these molecules. That said, like what's acceptable and how can you mitigate it? Grade 2 CRS is the threshold at which patients have to be monitored and cared for in hospital. We were talking just a moment ago that the majority of autoimmune disease patients are treated in the community. That sort of suggests that's out of the acceptable range. That can happen, but it has to happen at a low frequency. Probably single digits based on our discussions.
Low-grade CRS, fevers, those kinds of things can be managed quite readily and are not too different than infusion-related reactions that docs are used to managing as part of taking care of patients with monoclonal antibodies. I think it really does have to be relatively safe from the CRS perspective, just based on where patients are ideally cared for. The ways of doing that are the same ways that work in oncology. Subcutaneous administration is helpful for its favorable kinetic properties. Step-up dosing is typically essential. Corticosteroid premedication seems not to adversely impair efficacy, but does mitigate CRS risk. All of those features are incorporated into our mode of administration and across our clinical program. We didn't talk about the other class-related side effect for T-cell engagers, neurotoxicity, most particularly immune effector cell nervous system disorder.
In patients with ICANS, we haven't really seen that observable in the T-cell engager experience, at least not yet. That's been true in the data set that's been produced from academic investigators this summer at EULAR. It's very encouraging since that emerged as a significant risk for T-cell engagers in oncology very early on. So far, favorable as they translate from oncology to autoimmune development.
Great. I know you guys are also enrolling, you know, RA patients, obviously huge market potential. What can you say about, you know, CD19 TCEs, I guess, evidence that this is going to work in RA? What kind of, you know, efficacy signal do you want to see, you know, for you guys to move forward with this?
Yeah, I mean, I think the very first experience published for T-cell engagers in RA was the blinatumomab case series that our investigators from the University Hospital in Arlington produced in April, May of last year. In those group of patients who were treated with what was a relatively low dose and limited exposure to blinatumomab, you still saw improvements in symptomatic disease and evidence of B-cell depletion in synovial tissue, reducing B-cell inflammatory changes in the affected joints. I think as the experience with T-cell engagers has grown, it's clear that they were woefully under-dosing patients, both with respect to dose and exposure. I think by pushing the dose and exposure further into the range where they have seen good results with patients with scleroderma and other diseases, you see something far better.
I think the potential for clinical results in RA is significant, where already rituximab is approved and has clinical benefit, but something more potent that does the same thing, but does it through a T-cell redirecting mechanism. I think we have every expectation that it can improve the responses, even in patients who've failed prior B-cell depleting antibody therapy.
Okay, maybe let's move on to your new asset that you brought in, BCMA T-cell engager, from our Chinese partner. I thought that was a pretty, you know, good complementary asset to the CD19. Maybe talk to us about how you want to position these two assets. My understanding is probably going to be in, you know, different disease settings. The second is, can you just comment on the data that's being generated in multiple myeloma already, and how should we think about the translation?
Yeah, so I mean, I think just in terms of our interest in this specific molecule, we looked at a number of others, and we landed on this one because it did demonstrate efficacy that was superior to what had been demonstrated for most of the approved BCMA T-cell engagers, particularly with respect to the propensity to achieve a deep response, CERs with minimal residual disease, where the rates were higher than it's been reported for approved TCEs. The other distinguishing feature was a surprisingly high response rate that we verified through primary diligence in patients with extramedullary disease. This is a particularly hard subset of myeloma patients to treat, where BCMA CAR-T and available TCEs are relatively ineffective as compared to patients without extramedullary disease. This is tissue-based collections of plasma cells, and this is kind of the situation that you encounter in autoimmune patients.
We think that that provides good evidence that this particular molecule can have differential activity in patients with autoimmune disease, where not only antibody reduction, but perhaps plasma cell depletion outside of the marrow and other lymphoid tissues will be necessary to achieve a deep response.
Okay, so you're currently running the, or your partner is running the phase one trial in China. I guess what do you need to see from maybe the PKPD initial safety for you to maybe bring this to the U.S., and just how much data that you generated in, you know, China can you leverage?
Yeah, I think we'll be able to leverage the majority of data from this early phase study. I think the key elements that we hope to carry forward into our ex-China regulatory interactions are these PKPD and safety observations. I don't think it takes 50 patients' worth of data. I think patient numbers similar to what we expect to enroll in our own early phase studies will be sufficient to help make the case for accelerating development outside of China. That we will be able to immediately move to a later phase study is perhaps an expectation too far, but that we will be able to start at higher doses than we might otherwise or limit the amount of dose exploration, I think that is our expectation.
Okay, just looking to 2026, obviously you guys have a lot of things going on in autoimmune, you have oncology. What are the top two or three priorities for you guys internally?
Yeah, I think for 2026, clearly delivering on our guidance for lupus and RA is going to be very, very important. Obviously, we have an ongoing study in Sjogren’s disease, a disease where, by the way, nothing has been approved that’s disease modifying. Obviously, we saw the Novartis data recently, so that’s exciting for the field and good for patients. By then, we would have planned to have submitted our NDA for zipalertinib, we’re excited about that. End of this year, we’ll be presenting our data for CLN-049, our flip through by CD3 bispecific T-cell engager in relapsed refractory AML, still a disease with horrible prognosis. We’re certainly looking forward to that, but you know, I think as you alluded to, 978, continued progression, highest priority.
We’ll see what happens with the study with velinotamig in China, which by the way is a great vehicle for us to do things cost-effectively and very quickly. I’m excited about that opportunity. I think we have some programs in oncology, especially CLN-049, zipalertinib data generation that I think is going to be exciting.
Great, thank you so much, guys.
Appreciate it.