Welcome back to the 45th Annual TD Cowen Healthcare Conference. Next up, we have the team here from Cullinan Therapeutics. We're really happy to have from that team. We've got Nadim Ahmed, CEO, as well as Jeff Jones, CMO, up here. I'm Marc Frahm from the biotech team here at TD Cowen. We prepared a whole list of questions that we will go through with them, but also we do want to provide the opportunity to be interactive. Anybody in the room that has a question, certainly raise your hand. We'll try to get that answered as well. Maybe to start off with, Nadim, you want to just kind of give a high-level status update on the company to kind of level set everybody?
Sure. Yeah, happy to do that. For us, 2025 is really an inflection point for the company with multiple catalysts ahead. We're a biotech company that's dedicated to creating new standards of care for patients. Strategically, we've built a pipeline of five clinical stage assets that are either focused on targeting key disease drivers or harnessing the immune system to eliminate disease cells across autoimmune diseases and cancer. Last year, we expanded our R&D efforts into immunology by exploring the potential of CLN-978, which is our CD19xCD3 T cell engager, which we're exploring now in autoimmune diseases. While our strategic expansion was driven by the promise of this molecule, I'll also point out that we've been a company who's been focused on immuno-oncology. If you look at our oncology pipeline, we've got assets that all harness the immune system.
At the same time, as you all know, we've seen great convergence scientifically between oncology and immunology. For us, this was a very natural strategic adjacency. If you think about it, cancer is often driven by suppression of the immune system, whereas autoimmune diseases are often driven by an overactive immune system. As a company, we're uniquely differentiated and positioned to, in many ways, restore the natural immune balance. That's the way we think about cancer and autoimmune diseases. With CLN-978, which is our CD19xCD3 T cell engager, we believe as an off-the-shelf regimen, it has the promise to be applied across a range of autoimmune diseases. We have an ongoing study in lupus, where we're currently expanding study sites across EU, Europe and Australia.
It is the first and still only development stage CD19 T cell engager to clear an IND in the U.S. in the autoimmune disease space, giving us some significant competitive advantage there. We are planning to release the initial data from the lupus study in Q4 of this year. At the same time, we are also exploring CLN-978 in rheumatoid arthritis. We plan to work with the investigators who really led the efforts of T cell engagers in autoimmune diseases in both the University of Erlangen in Germany, Georg Schett and his colleagues, as well as the Gemelli University Hospital in Rome. Our RA study is guided to start in Q2 of this year. Q4 for lupus data, Q2 for the initiation of the RA study.
At the same time, in the oncology space, we have a diversified pipeline of what we would argue are first or best-in-class assets. For example, CLN-619, which is a first-in-class antibody targeting the novel MICA/B pathway. We presented data at ASCO last year, where we showed responses in patients that are typically unresponsive to checkpoint inhibitors, specifically non-small cell lung cancer harboring oncogenic driver mutations. At the moment, we have ongoing dose expansion cohorts in endometrial cancer, cervical cancer, and non-small cell lung cancer. We have guided to data in Q2 for the expansion cohorts in endometrial and cervical cancer. I'm so excited about that program. Also, with zipalertinib, which is our EGFR exon 20 inhibitor, just a few weeks ago, we were pleased to announce that we met the primary endpoint of the pivotal study in terms of response rates.
This is in relapsed exon 20 non-small cell lung cancer. We have guided to releasing data mid-year from that pivotal study, as well as in partnership with our partners at Taiho, submitting our first NDA as a company the second half of this year. Lots of progress in terms of the pipeline. At the same time, we have reported we have cash above $600 million at the end of December last year, which gives us plenty of resources to unlock the full value of CLN-978 and advance our oncology pipeline. Obviously, many of you have noticed and have experienced the macroeconomic factors, including yesterday, in the marketplace. That has caused us to be in a situation where we are trading below cash as it pertains to enterprise value. We are getting no credit pipeline. At the same time, as I mentioned, we have plenty of cash in hand.
We've got near-term catalysts in terms of milestones ahead this year. We believe we actually have a very compelling value proposition to invest in the company now ahead of all the catalysts that I outlined. Super excited about the year ahead, which promises to be a transformational year for the company.
Great. Thanks for that overview. Maybe on that last point of evaluation, it's not just Cullinan. Broadly speaking, there was a lot of excitement about kind of next-generation B-cell targeting in autoimmunity, whether it's CARs, TCEs. At least among investors, it seems that a lot of that has soured over the past year, in part, due to some reports of relapses and a couple of cases of ICANS in various academic trials and a little bit of corporate trials as well. What do you think investors are misunderstanding about this opportunity? I mean, that's probably both the Nadim and Jeff's question.
Yeah, let me start out. I think the first data that came from Georg Schett and his colleagues using CD19 CAR-T in autoimmune diseases, they were transformational data. If you look at current standards of care to this point in time with autoimmune diseases, they're mainly treating symptoms, not dealing with the underlying pathophysiology of the disease. This is the first time we've actually seen patients able to come off their background chronic immunosuppressive therapy and experience treatment-free remissions. I do think those data were remarkable. Maybe what you're alluding to, Marc, last year at EULAR, we saw quite a negative reaction from investors. Our viewpoint is that, one, this is the first time we saw industry-sponsored data from cell therapy in the space following Georg Schett's data. Our belief is that investors had unrealistic expectations of 100% cure rates.
I mean, that just was not going to happen. However, the data were actually pretty good. The majority of patients in these studies were able to go into treatment-free remissions. Again, I would make the case that today, with current standards of care, nobody is getting into treatment-free remissions. We saw a couple of safety events, but again, they were probably more like due to patient selection as opposed to the treatment itself. I think that's important context. The data are the data. At the same time, I do think that both clinicians and investors have understood the complexity with giving cell therapy in the autoimmune disease setting, especially not oncology, where it's a different benefit-risk equation, but in the autoimmune disease setting.
For example, having to deal with lymphodepleting regimens, risk of secondary cancer, the manufacturing and logistics associated with patients accessing treatment, where they typically have to travel to a CAR-T certified center to receive treatment. I think, in part, just reaffirmed the very high bar that cell therapy needs to meet for widespread adoption. In contrast, T cell engagers are offering an off-the-shelf potential disease-modifying regimen of favorable safety profile with the convenience and accessibility of antibody treatment. It is a very different way of looking at it. I think certainly with investigators that we've spoken to, what they've told us is, if you can get me a treatment that can get my patients off background therapy and into treatment-free remissions, you're likely to see widespread adoption. I think that's where the paradigm is a little bit different between the two different modalities.
Look, we're very pleased to have a leadership space. As I mentioned, only IND cleared in the autoimmune disease space, so we're very happy about that. The fact that we have the U.S. to ourselves in terms of attracting sites for our ongoing study. The other thing I would mention is that these are very, very large markets. There's plenty of room for multiple assets to be successful here. If you think about lupus, for example, that's 160,000 patients in the U.S., half of which are moderate to severe patients that could be eligible for treatment. Rheumatoid arthritis, you're talking about 1.7 million patients in the U.S., again, half of which are moderate to severe patients. Even the polyrefractory, so-called difficult-to-treat patients represent 60,000 patients in the U.S. These are very, very large market opportunities and very significant commercial opportunities.
If you were to ask one other thing that I think people are missing when you talk about next-generation B-cell depleting therapies, it is that this belief that somehow T cell engagers are not sufficiently potent to differentiate themselves from monoclonal antibodies. There seems to be like they're not CAR-T. That might be true, but they're definitely other order better than monoclonal antibodies regardless of target. There is ample evidence from the oncology setting that continues to be discounted or not be considered relevant. Clearly, in head-to-head comparisons, when there are some now of the CD20 CAR-T versus TCE versus a monoclonal antibody, the TCE wins. I think, as Nadim says, there is this huge opportunity gap between what is currently attainable with any available or investigational monoclonal antibody and what was demonstrated in the initial Georg Schett data series.
There is a lot of room in there to improve upon the existing standard of care and ways of dosing TCEs that are very flexible. As Nadim said, in our conversations with physicians, they see how they could integrate a T cell engager into their practice. They do not see how they could integrate CAR-T into their practice as they currently practice. I think that speaks a lot to the challenges of imagining CAR-T as a really viable product for the masses.
Yeah, I would maybe just add one point to what Jeff just said. Look, just to be clear, we're not saying there isn't a role for CAR-T in autoimmune diseases. What we're saying is it's more likely to be a more narrowly defined population. From a positioning perspective in the treatment sequence, probably a treatment post-T cell engagers when ultimately both of these therapies are available to patients.
As we return to, as we start seeing data out of your program, but also increasingly from the variety of corporate trials that are out there, your latest thoughts on how to assess that initial B-cell suppression and the "immune reset" as to what's meaningful? How long do the B-cells need to be suppressed? How do we ultimately, we do want them to come back so that people have immunity to other things. How do we assess that?
Yeah, so I think that's an open question. The two variables are depth of B-cell depletion and durability of B-cell depletion. Clearly, there's evidence to support that deeper B-cell depletion, that is, eradication of measurable B-cells at the tissue level, is associated with a higher likelihood of durable response. That's clear. Beyond that, it's far less clear how long the patients need to be depleted of B-cells in order to achieve a durable effect. Is it as brief as a day, perhaps? I've heard Georg Schett say it probably doesn't have to be very long, on order of days, not weeks or months. I think that's a question. When you look at the variability within CAR-T data, the B-cells recover as early as 50 days to as long as about four months. Yet patients on both ends of that spectrum achieve durable responses.
I think the question of duration of B-cell depletion is an open question. What you will want to see, however, is that upon return of the B-cell population, it reemerges with a naive phenotype. That has been the hallmark of the immune reset that appears necessary for durability of response. I think for right now, that seems to be more tied to depth versus duration.
Okay. I guess, how does that depth of suppression you want to talk through a little bit about? You were touching on it before of going from a naked antibody to a bispecific versus maybe a CAR-T cell. Looking back to the experience in oncology, where we do have the most data to compare different approaches, how does that profile line up? Where do you put those orders of magnitude?
Yeah. I mean, I think there are a couple of lines of evidence from oncology. The first is that in oncology, we know that eradication of very small volume of tissue-resident disease, minimal residual disease, is tied to the ability to achieve a cure. Blinatumomab, when added to frontline standard of care in ALL, dramatically increases the likelihood of cure of ALL. Monoclonal antibodies, when they were added in that context, were unable to do that. If you look next, there was a recent head-to-head comparison of rituximab plus chemo versus the CD20 TCE, mosunetuzumab plus chemo. The TCE-containing arm resulted in a 50% improvement in survival. Clearly, in a head-to-head comparison, TCE beats CD20.
If you look at TCE versus CAR-T, while there haven't been head-to-head comparisons, if you were to look at just the label data supporting the activity of any of the approved CD20 T cell engagers and CAR-T in follicular lymphoma, you'll see relatively equivalent rates of complete and overall response, as well as a similar durability of response. Those are tissue-based diseases. They're not just blood and bone marrow diseases. I think it really does suggest that when you look at comparable situations, TCE is more potent than monoclonal antibody. In certain clinical settings, it can approach the outcomes achievable with CAR-T.
I think one thing that's become very clear is that the so-called T-cell redirecting therapies, whether it's CAR-T or T-cell engagers, operate in a different quadrant of efficacy in terms of potency compared to the naked monoclonal antibodies.
Very fair.
Do you expect ultimately, with your approach in autoimmunity, that you're going to be able with a bispecific to establish a better safety efficacy profile? Or is the biggest differentiator between your product and a CAR-T cell going to be the convenience factor of an off-the-shelf product?
Sure. Let me start with that first. I think the way I would look at it is that CAR-T has paved the way for T cell engagers as the next natural technology iteration or evolution. That is the kind of the way we see it. Clearly, this opportunity of now having an off-the-shelf potential disease-modifying regimen with a favorable safety profile also gives you the convenience and accessibility of antibody treatment that we just spoke about. When we speak to rheumatologists, what they're looking for, again, going back to what we said earlier, is they're looking for what's better than my current standard of care. In their current standard of care, they are not able to achieve treatment-free remissions. Any treatment-free remission is really important for those clinicians.
When they see CLN-978, they're excited about entering and participating in our clinical study because of that opportunity they have now with potency but as an off-the-shelf regimen. I think, as Jeff said earlier, one of the things we haven't touched on that is a distinguishing factor between CAR-T and T-cell engagers is the ability to redose if you need it. You can't keep administering CAR-T cell therapy for obvious reasons to a patient, whereas with a T-cell engager, you have the flexibility of redosing to kind of enhance efficacy as well.
There are data starting to emerge looking at real-world data for TCEs versus either clinical trial or real-world data of TCEs versus CAR-T with respect to their safety profile. Here, people are looking primarily at the class-related adverse events, cytokine release syndrome, and ICANS. In general, if you compare CD19 CAR-T to CD20 TCEs, you see a lift and shift. It is a lower likelihood of those adverse events, and they tend to be of lower grade. In general, TCEs have a more favorable safety profile for class-related adverse events. The same is true if you look at BCMA CAR-T versus BCMA TCEs. You see the same spectrum of adverse events, but they are less frequent and lower grade. I would expect to see something similar in autoimmune application. I do not have any expectation that it would be different.
Nadim, you were starting to touch on this. What is that minimum kind of sticking at first with just lupus? What is that minimum kind of target product profile in terms of how many patients do you need to get into a treatment-free remission? How many? And how long does that remission need to last?
Yeah, happy. Actually, this is one we can give you feedback based on having spoken with lots of rheumatologists on this specific question. The first thing I would say is when we have spoken to rheumatologists, again, they're comparing the outcomes they desire with what they currently have in their toolbox, right? That's an important grounding place. It's not a 100% five-patient Georg Schett database that was originally out there, or transformative as it was. What rheumatologists tell us is, for something that's off-the-shelf that I can give to my patients, I want to see a minimum of 20%-30% of my patients enter into a treatment-free remission. From a safety perspective, grade 1, grade 2 CRS maximum. That's what I would describe, Marc, as the minimum commercially viable profile.
Of course, our aim is to beat that bar on both efficacy and safety. If you wanted a hard data point, that's certainly something we've heard back from investigators. Whereas their bar for CAR-T is going to be much higher because of all the hurdles you have to go through to kind of get that treatment to patients.
Okay. In terms of treatment-free remission, to your point of the ability potentially to redose, at what point does a redosing become not treatment-free remission because it's every six months, it's every nine months or 12 months? What's that minimum kind of duration between redosing of this?
Let me start, and then Jeff, you can pick it up. I think, again, the thing I do want to emphasize again is, and I know I keep saying, but it is important to point out that current standards of care do not induce treatment-free remissions of any length or duration. Right? That is a very firm anchoring point. I am not sure that we necessarily have a standardized definition of duration. Jeff, you certainly have feedback from people you are spoken to.
Yeah. I mean, I think there are two things to think about. One is treatment-free and also what's the nature of the treatment. One of the biggest concerns in any autoimmune disease is prolonged exposure to even low doses of corticosteroids. I mean, the adverse consequences of even a 5 mg daily dose, which is almost physiologic, are significant when assessed in large groups of patients. Providing patients treatment-free or steroid-free intervals or intervals from other immunosuppressants with something that's well tolerated could be very clinically beneficial. I think the ideal situation, though, is not just treatment-free time, but maybe patient-free time, where you don't have to come into the clinic. You don't have to take pills at home. You don't have to come into the clinic. That, I think, is what we're talking about, treatment-free remission.
Patient-free time of 9-12 months would be very clinically significant for most of these patients.
Commercially very attractive, of course.
Yeah. In terms of that safety profile getting there, it's the key to really transforming how this fits in versus how you're viewing a CAR-T cell that you get to community rheumatologists. Is that the goal? Or is it enough if you just, it's still an academic center. It's just much more into the way academic centers work today. They don't need to bring in teams around a CAR-T cell administration.
Yeah. I would just say most patients live in the wild. They don't live and access academic centers in the U.S., in particular. That's been an impediment to enrollment in clinical trials that require accessing tertiary partner care centers. I think for widespread adoption, it really needs to be applicable to the community. Most patients don't want to leave their homes and their usual sites of care to travel to a university setting. It's time away from their family. It's time away from work. Many patients, depending on the disorder, could be from patient populations where that is an economic hardship. I think those are important factors.
Yeah. I would add another very practical consideration is if you can treat patients in the community, there's all the benefits that Jeff mentioned. Also, community treating physicians do not like referring their patients to academic centers for both clinical and non-clinical reasons. They do not want to lose control of their patients. Sometimes patients go to an MD Anderson and go, "Wow, I want to stay here for my care." Right? From an actual real-world commercialization applicability, those referral networks can be very difficult barriers. Delivering a treatment in the community has a massive advantage from a logistics and wide applicability to the masses of patients with autoimmune diseases too.
The lupus trial is open. You're promising some data by year-end. Just what is the outline of what you hope to be able to provide investors in terms of kind of whether it's patient numbers, amount of follow-up, or just the types of questions you think you will be in position to answer?
Yeah. I would say so if you think about the study, it's a phase I dose escalation study. The primary focus is generating the safety data at the target dose we'd like to take into part B of the study. At the same time, we also build in secondary endpoints like clinical endpoints such as SLEDAI score, B-cell kinetics that Jeff outlined earlier, the PKPD data. All of those things are part of the primary and secondary endpoints of the study. The approach we've always taken when we give guidance on data is to guide to what we think will be meaningful and interpretable by the marketplace.
Obviously, now we've got an ongoing study. We've got to look at the recruitment kinetics. All of those things are built into our thinking as we kind of issue that guidance. As we get closer, we'll be able to give more granularity around it.
Okay. Maybe that same question outside of the we've been talking everything about CLN-978, but there's also the MICA/B dataset in the first half of the year. How should we think about those expansion cohorts data in terms of how much data are we likely to see from them?
Yeah. I mean, without giving specifics on the numbers of patients and such, as Nadim outlined, we've promised that we would share the initial expansion data for cervical and endometrial cancer. We also have ongoing expansion in non-small cell lung cancer, where I think we also saw remarkable results in patients who do not typically respond to immunotherapy. I think we typically say, and in this case, it is also the case that we will present enough data to have a meaningful understanding of the clinical profile in these patient populations that will inform next steps in development.
You think you'll be able to talk to those next steps at the same time?
I think the most important thing in sharing data ever is what are its implications and what are you going to do with it. I think data just without that extra bit is without the appropriate context.
Okay. Can you remind us where there have been a few over the last year, a few updates to other programs in endometrial cancer, I think not so much in cervical, but just where's the latest thinking of what the bar is of the monotherapy?
I think for a broad patient population who will now have been experienced with platinum-based chemotherapy plus PD-1, the broadest group of patients will still be treated with single-agent chemotherapy, where the best reported response rates are 15%. Clinically meaningful outcomes are 25% and above with six months of durability. That is what we are seeing, 25%-30% for some ADCs in the space, HER2, depending on the patient population.
Okay. Unfortunately, that's all the time we're going to have to stop it there.
Okay.
We're out of time. Thanks a lot for joining, Nadim and Jeff, everybody in the room, as well as everybody on the webcast.
Appreciate it. Thanks, everyone.