Unpredictable. There are a lot of things that are unpredictable these last couple of days, too. Good afternoon, everyone. I'm Andy Barrons. Thank you for joining us. Sorry we're a few minutes late. We have with us Cullinan Therapeutics, Nadim, and Jeff Jones. Thank you, gentlemen, for joining us.
Happy to be here.
For those of you that are not familiar with the story, can you just give us an overview of the company? I know it's evolved recently from pure oncology now. You've expanded, so tell us on that, please.
Yeah, happy to do that. Thanks for hosting us. 2025 really is an inflection point for Cullinan Therapeutics. We're a biotech company that's dedicated to creating new standards of care. We've strategically built a pipeline of five clinical stage assets that are either targeting inhibition of key disease drivers or harnessing the immune system to eliminate disease cells in both cancer and autoimmune diseases. As you alluded to, Andy, last year, we extended our R&D efforts into autoimmune diseases to explore the potential of CLN-978, which is our CD19 by CD3 T-cell engager, exploring that across a range of autoimmune diseases. The question comes at strategically oncology, immunology, and a couple of things I'd like to say. One, we know that at Cullinan, over the three or four previous years before expanding into immunology, we have always been a company that's been focused on immuno-oncology.
If you look at our oncology assets, all of them harness the immune system in some way or another. The biology of oncology and immunology has continued to converge over the last couple of years, or three, four years, I would say. If you think about cancer, it's often driven by a suppressed immune system, whereas autoimmune diseases are often driven by an overactive immune system. Expanding into immunology was a very natural strategic adjacency for us. I would say we're uniquely differentiated as a company that's focused on restoring the natural balance of the immune system. That's one way of looking at how we approach oncology immunology. With CLN-978, we have a potent disease-modifying treatment as an off-the-shelf regimen, which could be applied to a broad range of autoimmune diseases.
We are currently, or we were, the first company to clear an IND in the U.S. with a development stage CD19 T-cell engager. I am pleased to say we are still the only company to have achieved that. Right now, we are expanding our global study for lupus across Europe, the U.S., and Australia. At the same time, we are also planning a study in rheumatoid arthritis with the leaders in T-cell engagers in autoimmune diseases. That is the University of Erlangen, which was Georg Schett, Riccardo Grieshaber-Bouyer , the original group that came out of the CAR-T data, as well as the Gemelli University Hospital in Rome. For our lupus study, we have guided to data in Q4 of this year. For our RA study, we have guided to initiating that study in Q2 of this year.
On the oncology side, we have a diversified pipeline of assets that we would say are first or best in class. For example, CLN-619 is our MICA/MICB antibody. We presented data at ASCO last year, where we showed responses in patients that are typically unresponsive to checkpoint inhibitors, and more specifically, non-small cell lung cancer that harbors oncogenic driver mutations. We currently are in an expansion cohort of CLN-619 in endometrial cancer, cervical cancer, and non-small cell lung cancer. We've guided to data in Q2 for endometrial and cervical cancers. We also have a study in relapsed refractory multiple myeloma with CLN-619. Just recently, just a few weeks ago, we announced with zipalertinib, our EGFR exon 20 tyrosine kinase inhibitor, that we met the primary endpoint in terms of overall response rate for our relapse study in exon 20 non-small cell lung cancer.
We've guided to sharing those data mid-year at hopefully a medical conference. With our partners at Taiho and pending discussion with the FDA, we're planning for our first NDA as a company in the second half of this year. That's an exciting milestone for us. At the same time, at the end of December last year, we reported over $600 million in cash. That gives us runway into 2028, which allows us to fully unlock the value of CLN-978 and keep our oncology pipeline moving forward. The last thing I would say is, given all the macro headwinds in the market, especially over the last week or so, I would say we're currently trading at or below cash relative to enterprise value. We're getting no credit for our pipeline whatsoever. At the same time, though, we have cash in hand. We have multiple near-term catalysts.
We believe that we actually have a compelling value proposition to invest in the company now ahead of what promises to be a transformational year for Cullinan Therapeutics.
Great. Thank you for that overview. I guess there's no comfort in this, but you're not alone trading below cash. A lot of our companies are, given the macro conditions. Why don't we talk a little bit about zipalertinib before we jump into some of the non-partnered assets that people are interested in? Can you just remind us of the financial arrangement for that? The approval, we'll see the data potentially in a couple of months, and then a potential approval. What could that generate for the company? What have you disclosed about the relationship?
Sure. Yeah. We have a partnership with Taiho, which we entered into in 2022. At that time, we got $275 million in upfront cash. We still have $130 million outstanding for regulatory milestones, specifically the U.S. approvals for second line plus and first line exon 20 non-small cell lung cancer. At the same time, we also have a 50/50 profit share in the U.S. with an option to co-commercialize. Taiho is leading the commercialization efforts. They already have three products approved in this kind of targeted therapy space. They will be leading those efforts. We have not yet decided whether we would take the co-commercialization option or not. It is an area that is very exciting. Lots of changes in the landscape over the recent years with multiple people dropping out of the race. We are excited about the opportunity ahead.
When would you have to opt in or opt out on that commercial arrangement?
We have a lot of time yet. I'll describe it that way.
Okay. You would be supporting your sales force that would promote in conjunction with Taiho. That's how it would work?
Yeah. The way that would work is, I mean, it allows us to have a very cost-efficient way to build out a US commercial infrastructure. Ideally, you'd want to do it with the rest of your pipeline progressing as well. Either way, we pay for it, whether it's Taiho's feet on the streets or it's our feet on the street. That's what the 50/50 profit share encompasses.
Right. Okay. Right. That's right. Okay. Why don't we shift to the TCE? Just remind us of the data that the Schett Group has shared that kind of triggered a lot of interest in this area for you guys, as well as a lot of investors in other companies. How has that evolved over time? What would be the advantage and potential disadvantage of using a TCE versus cell therapy?
Jeff, go ahead.
Beginning in the middle of last year, investigators at the University of Erlangen and their colleagues, who had been initially investigating CAR-T as a potential therapy for autoimmune diseases, began sharing data for various T-cell engagers, primarily blinatumomab, the CD19 T-cell engager, and then more recently, teclistamab, a BCMA T-cell engager from Johnson & Johnson that is approved for multiple myeloma. Last spring, in the initial patient set, it was a handful of patients with rheumatoid arthritis who were treated at the lowest or starting dose of blinatumomab, 9 micrograms, given quite awkwardly as a continuous infusion. While it is typically given for several weeks and escalated to 28 micrograms, they conservatively selected the lower dose of 9 micrograms, and they gave it for only five days and then repeated again for another five days after a week interruption. A very attenuated dose and schedule.
Yet, they still saw complete peripheral blood B-cell depletion. In three patients who had synovial biopsies available, they saw depletion of B-cells in the tissue. They also saw in the peripheral blood immunologic aspects of what has been called an immune reset. That is, eradication of more mature B-cells and recovery of a naive B-cell immunophenotype. This has been very similar, at least directionally, to what had been shown with CAR-T cell therapy in similar indications, albeit with what we would say is an awkwardly administered molecule administered at probably a subtherapeutic dose. Since that time, there have been some other case reports of patients treated with blinatumomab, one in scleroderma, who also achieved clinical benefit and evidence of peripheral blood B-cell depletion, albeit treated at a higher dose of 28 micrograms.
More recently, we've seen data for taclustamab, which will deplete both some mature B-cells as well as plasma cells. There again, we saw patients with SLE, rheumatoid arthritis, inflammatory myositis being the most important ones who achieved therapeutic benefit and, again, immunologic features of an immune reset. I think this really provides initial proof of concept that T-cell engagers have potential for therapeutic benefit across a wide variety of autoimmune diseases. As compared to CAR-T, off-the-shelf convenience, no need for pheresis, no need for cytotoxic chemotherapy preconditioning, no exposure to genetically altered material, and a potential risk for secondary malignancies, both from that and the cytotoxic preconditioning. The therapeutic benefit is still to be fully ascertained once any molecule is dose-optimized. I think one of the challenges of sort of extrapolating too far from that data is that these were not part of studies.
These were patients treated with compassionate use. As a consequence, the data was not always generated in a context that would be ideal for drawing conclusions about dose and schedule.
Okay. What are some of the advantages or disadvantages targeting CD19 versus CD20 or BCMA?
Yeah. I think one of the features of the immune reset as characterized by the Erlangen Group is sort of essentially carpet bombing the B-cell compartments all the way from pre-B-cells all the way to some subsets of mature B-cells that have still some CD19 expression. It seems to be that breadth and depth of B-cell depletion that is tied to the ability to achieve an immune reset. CD20 will not reach as far on either end of the maturation continuum. If you're looking at the single best target to broadly deplete B-cells, that will be CD19. There are not a lot of places where CD20 would appear to provide an advantage over 19. BCMA, on the other hand, will deplete the entire plasma cell compartment, including B-cells that are plasma cells, the long-lived plasma cells that are associated with maintaining the humoral memory immune response.
That means that patients typically become hypogammaglobulinemic, require antimicrobial prophylaxis, and in some cases, will need revaccination upon the time of B-cell recovery. There are certainly some autoimmune disorders that are probably more proximally associated with the long-lived plasma cell compartment where the antibodies are clearly being produced by those cells. Those may be better treated by BCMA. If you think about the single best target, it would be CD19, where the infection risk does not appear to be as great.
Okay. You mentioned that you guys were the first in the clinic in the U.S. Who else is developing CD19 TCEs at this point that you're aware of?
Yeah. There are a few companies out there developing both subQ and IV formulations. Obviously, they all have their own benefits and disadvantages. I think we view our molecule as particularly differentiated, even in that CD19 by CD3 T-cell engager subset. For example, we have very high affinity for CD19, which will be really important for some of the cells that Jeff just mentioned in the B-cell compartment, especially the more mature cells. We have picomolar affinity for CD19, nanomolar affinity for CD3. That relative affinity difference also, we believe, gives us a wider cytokine window where we can see active killing of B-cells but low production of cytokines in terms of CRS, et cetera. We have seen that preclinically. We also have a molecule that is much smaller.
CLN-978 is about 65 kilodalton in terms of weight versus many of the other CD19 T-cell engagers that have the typical monoclonal antibody IgG format, 150 kilodaltons plus. Size may be important when it comes to tissue penetration or clearing B-cells from the tissue compartment, of course, with subQ dosed. When you look at all of those molecules, they are all being developed ex-U.S. There is the molecular differentiation. I would argue we have the executional differentiation too as the only company that has a CD19 T-cell engager currently in active development in the U.S. We are focused on maintaining that lead through rapid execution. The last point I would add is, if you look at all these large companies who are entering this space or active in this space, they have all chosen a CD19 T-cell engager.
Both the target and modality are important, CD19 and T-cell engager. We feel very good about where we are. We think we have a potentially best-in-class molecule. We want to make sure we keep our execution momentum with the right leadership position.
Okay. We have not seen any data from non-oncology patients, but you did have, I think, three patients in NHL. Can you just remind us what you saw in regards to the immune system?
Yeah. First, we treated only three patients in that study at a starting dose of 30 micrograms administered subcutaneously on a weekly schedule. With that, we saw that one of the three patients achieved a complete response to therapy. A patient with mantle cell lymphoma relapsed after transplant. Clearly, at the 30 microgram dose, we were at the cusp of an efficacious lymphoma dose. We would have had to continue dose escalating, certainly. With that, we saw no higher than grade 1 CRS on the first dose only in two of the three patients. In fact, the complete responding patient had no CRS. We did not see any adverse events that met criteria for ICANS. At a potentially threshold dose for lymphoma activity, a very clean safety profile with respect to class-related adverse events.
In two of the three patients, we were able to measure peripheral blood B-cells. We saw that peripheral blood B-cell population fell greater than 95% following the first dose. The PD observations here are somewhat confounded by the fact that the patients had a substantial burden of malignant B-cells, which were clearing a lot of the drug through target-mediated drug disposition. I think together, we see the potential of the drug to deplete B-cells quite deeply, both peripherally and in the tissues, as evidenced by the response, and doing that at a dose that still maintains a therapeutic index that would be appropriate in patients with autoimmune disease.
Okay. Some of these questions, we probably don't know the answers to yet. It seems like some of the cell therapies have actually, patients have relapsed, which poses a challenge for cell therapy. There are only so many procedures I'm sure patients can tolerate or have access to. What do you expect to see with the TCEs in terms of durability? If you can successfully reprogram the immune system, how durable do you think this will be?
Yeah. That's a great question. I mean, I don't think we fully know the answer yet. I think the most important point to make here, and I'll use lupus as an example, that with current standards of care, patients are not able to get into treatment-free remissions, let alone talk about durability. That just doesn't happen at the moment. For example, if you look at the antibodies that are currently used in lupus, including one that just reported out phase III data, it's always on top of background therapy. Patients are not able to come off their background chronic immunosuppressive therapy. In contrast, the T-cell redirecting therapies, like CAR-T and T-cell engagers, have allowed patients to come off their background therapy to actually enter into treatment-free remission so that you can actually start talking about durability. I just want to provide that background context first.
Certainly, when we have spoken to rheumatologists, they're very enthusiastic about having a disease-modifying regimen that has the convenience of being off the shelf and a favorable safety profile, as well as the accessibility of an antibody treatment. In terms of, I would say, target product profile, what rheumatologists tell us is that if you have a T-cell engager as an off-the-shelf treatment, if you can get 20%-30% minimum of my patients into a treatment-free remission with a duration of 9-12 months, you should expect widespread systemic adoption across multiple autoimmune diseases. That's really important to point out. Secondly, the advantage of T-cell engagers is that you have the opportunity of flexibility of dosing. You can do multi-dosing. You can't really do that with cell therapy, right, for obvious reasons. The multi-dosing can help you enhance efficacy.
Even in the case of retreatment, let's say a patient receives treatment, and at some point down the line of their treatment journey, they need retreatment, you can do that with a T-cell engager. That is where we see the advantage. Certainly, rheumatologists are looking at comparing to what's in their toolbox today in terms of standard of care. Investors are looking at the 100% cure rate of the SHET data. That is where there has been a bit of a disconnect. I think it is starting to come together now.
What about using a TCE or a self-therapy, getting a patient into remission and then giving more of a traditional, you know, a rituximab or something?
I think it's an interesting point. If you were to speak to the investigators at Erlangen, they had relatively modest ambition when they did their blinatumomab study. These were very refractory RA patients. They'd failed multiple disease-modifying therapies. Their intention was simply to restore sensitivity to well-tolerated longer-term maintenance therapies. That's what they did. They showed that they could put the patients back on Orencia, not the most effective RA drug, but very well-tolerated, relatively low toxicity, and maintain their remission. I think initially, that was viewed as somehow a failure of their experience. Actually, for the patients involved, having disease control and being able to maintain it is a great thing.
That was with a very low dose, by the way. With the higher doses, they may not even have needed that maintenance treatment afterwards.
Yeah. Okay. I know we're over, but maybe we can answer one more question. The lupus data is obviously going to be huge for your company. What can we expect to see in that initial data outside of the oncology setting for the first time for this molecule? What are you looking for for success?
Yeah. Look, the first thing I would say is we're going to be, given the competitive intensity we just spoke about, we're going to be very thoughtful and careful about how we're describing that data ahead of the actual data themselves. I will say, look, a reminder, it's a dose escalation study. The primary endpoint is making sure you have a safe dose. Then secondary endpoints that we'd like to see activity in one or more of those parameters will be PK/PD data, impact on SLEDAI score, clinical activity, of course, autoantibody reductions, normalization of complement. We'll be looking for all of those things with the first data set. I will say, whenever we give guidance on data, we always frame it in the context of it should be meaningful and interpretable for the people who are viewing those data.
That is what we plan to do here as well with this data set.
Okay. What's been the enthusiasm among patients and clinicians to be?
You know, I think as we initially started exploring this program last year, there were people who particularly in the U.S. who were unfamiliar with T-cell engagers as a modality. I think what's really been remarkable about the last year is the way that the understanding that T-cell engagers are an important new modality for exploration in autoimmune disease has really taken on. We have had very enthusiastic discussions with investigators. We are starting to get unsolicited inquiries from prominent investigative sites about the opportunity to participate in our program, not only in SLE, but in potentially other indications. People who are interested in helping us do correlative science as part of the studies or companion projects. A lot of enthusiasm.
From the patient advocacy end, we've built relationships over this last year with both the Lupus Research Alliance and the Lupus Research Foundation to access both investigators and clinical sites in the case of LRA and the LuCIN network, and then to have patient-directed outreach through the LRF, where they maintain a strong communication network focused primarily on connecting patients to clinical opportunities.
Great. Thanks for the updates. Congrats on all the progress. We look forward to the updates when they come.
Appreciate it. Thanks everyone.