Cullinan Therapeutics, Inc. (CGEM) Earnings Call Transcript & Summary

Good morning. Welcome to the JPMorgan Healthcare Conference. I know it's the final stretch on a Thursday, so I really appreciate you all being here. My name is Raji Gunasekera. I'm with the Healthcare Investment Banking team at JPM. Today, I'm pleased to introduce the team from Cullinan Oncology, and we have their CEO, Nadim Ahmed. I'll hand it over to you. Thank you.

Thank you very much. It's a pleasure to be here to share all of the exciting developments going on at Cullinan Oncology. The next slide is my disclaimer slide. At Cullinan Oncology, we take a very unique approach to developing first-in-class and best-in-class programs through what we call a modality-agnostic targeted oncology approach. What that means is at the start of our discovery process, we identify high-impact cancer targets. And it's only then that we think about the best vehicle to prosecute against those targets. So for us, it's always target first, modality second, rather than the other way around, unlike many other companies. And this means we're not dependent on a singular platform or even a single product. Secondly, we have a very high go-no-go bar across the R&D spectrum as we move molecules forward. We front-load as much experimentation as possible early into the discovery process through what we call thriller or killer experiments. So as the name suggests, when we get a killer result, we quickly terminate the program and reallocate our resources. When we get the thriller result, we look at how can we accelerate this program and increase our investment into this program. And so in this way, we only bring forward the most promising, highly differentiated molecules into the clinic. And our strategy is yielding results. We now have a robust clinic stage pipeline across targets, across modalities and across both hematologic indications and solid tumors. We've evolved very quickly in about 18 months from essentially a research-based company to now a development stage organization with our ultimate goal of becoming a commercial stage biotech company so that we can deliver on our mission to create new standards of care for patients with cancer. And as we've advanced these molecules into the clinic, we have a very exciting 2024 ahead of us with multiple clinical data readouts across our programs. Starting with CLN-619, this is our anti-MICA/B antibody, where we showed single agent efficacy last year when we presented the initial monotherapy data at ASCO. This year, we'll be presenting combination therapy data for the first time in 2Q '24, where we combine CLN-619 in combination with pembrolizumab. Based on the early signal we saw with the monotherapy data, we also initiated cohort expansions in both endometrial cancer and cervical cancer. And those data will report out in the first half of 2025. Zipalertinib is our potential best-in-class profile EGFR exon 20 inhibitor. And for that program, we plan to complete the accrual in the pivotal relapsed disease study by the end of 2024. CLN-049 is our first-in-class FLT3 x CD3 T cell engager, which is currently in a Phase I dose escalation study in relapsed/refractory AML and high-risk MDS, and we plan to present some data from this program in the second half of 2024. And CLN-418 is our first-in-class B7H4 x 4-1BB bispecific immune activator. And this is another program that's in Phase I dose escalation in solid tumors, and we plan to present the initial data from this program in the second half of 2024. So we have a very data-rich environment in this year. The other point I'll mention is that we're very well capitalized. So we have a robust cash position with $470 million of cash at the end of 2023, giving us cash runway into the second half of 2026, well beyond the near-term clinical data milestones that I've laid out. So the purposes -- for the purpose of this presentation, I'm going to focus on 3 programs today. Three key programs in our pipeline. CLN-619, our anti-MICA/B antibody; zipalertinib, our EGFR exon 20 inhibitor; and CLN-978, which is our CD19 x CD3t cell engager, especially in the context, all of the exciting data that we've seen with CD19 directed cell therapy in autoimmune diseases. So let me spend a few minutes talking about CLN-619, our anti-MICA/B antibody. As I mentioned, this is the first antibody in the clinic targeting MICA/B, and we were very pleased to share single agent efficacy from ASCO last year. Now MICA/B are ligands for the NKG2D receptor on NK cells and subsets of T cells, such as gamma delta T cells. You can see from this heat map that of all the NKG2 ligands that are out there, MICA/B are the most highly expressed across both hematologic malignancies and solid tumors. MICA/B is also not expressed on normal healthy cells. So therapies targeting MICA/B would be expected to have a broad therapeutic index. And MICA/B is upregulated in situations where cells undergo stress. So viral infection, malignant transformation. So when these cells express MICA/B, they then send a kill-me signal to the immune system via the NKG2D receptors that we find on NK cells and subsets of T cells. And these cells are able to then destroy the cells that are sending this kill-me signal through both the innate and adaptive immune system. In the next slide, on the left panel, you can see what happens in the case of cancer cells. So initially, because these cells become stressed, they do upregulate MICA/B. However, in the tumor microenvironment, proteases cleave the MICA/B off the cell surface. So then these cells once again become invisible and evade the immune system. In the middle panel, you can see how CLN-619 exerts its mechanism of action in multiple ways, again, invoking both the innate and adaptive immune system. So firstly, CLN-619 binds to and stabilizes MICA/B on the cell surface. So the immune system now is again able to see these cells. Secondly, CLN-619 also works through ADCC and ADCP by binding to the CD16 receptor on NK cells and subsets of T cells. And finally, CLN-619 also facilitates the direct interaction between MICA/B and NKG2D on these immune cells. And you can see on the far right panel, how checkpoint inhibition can enhance the effect of CLN-619 because now you're invoking the full repertoire of T cells. Currently, CLN-619 is in a global Phase I dose escalation study, investigating CLN-619, both as monotherapy and in combination with pembrolizumab. As I mentioned, we were pleased to see the initial monotherapy data at ASCO last year. And based on that early signal, we opened up expansion cohorts in both cervical cancer and endometrial cancer as well. The next slide shows swimmer's plot of the efficacy data showing activity by dose level. And so early on, we were able to start seeing stable disease starting at the 1 mg per kg dose. And then we started to see objective responses at the 3 mg per kg dose. So we saw 3 objective responses in 22 evaluable patients, 1 in a patient with aprotic lung cancer, that was a complete response and 2 objective responses in patients with endometrial cancer. So in summary, 10 of the 22 evaluable patients experienced either an objective response or stable disease. And now let me go into the efficacy data in a bit more detail. Interestingly, of the 3 objective responses we saw, 2 of these responses were in patients that had progressed on prior checkpoint inhibitor therapy, an important clinical finding. The other interesting aspects of these responses is that the responses that these patients experienced on CLN-619 treatment was better than the responses they experienced on their prior therapies. So for example, the parotid gland cancer patient had a best prior response on checkpoint inhibition of PR. This patient went on to subsequently experienced a complete response on CLN-619 monotherapy. One of the endometrial cancer patients previously had a best response of stable disease, and this was on a combination regimen of checkpoint inhibition plus lenvatinib. The other endometrial cancer patient didn't derive any clinical benefit from her prior therapies. Both of these patients went on to experience a partial response on treatment with CLN-619. We did see an early signal among gynecologic malignancies in this initial data cut of the Phase I study. So in addition to the 2 objective responses in endometrial cancer, 3 patients with cervical cancer also experienced stable disease and 2 patients with ovarian cancer also experienced stable disease. However, we did also see clinical activity beyond the gynecologic tumors. Obviously, we saw a complete response in parotid gland cancer but there was also a patient with breast cancer and a patient with salivary gland cancer that experienced stable disease. So we're very excited about these data, again, in the monotherapy setting. Now let's take a look at the safety data. The bottom line is the CLN-619 monotherapy data showed that this treatment is well tolerated. We saw no dose-limiting toxicities at any of the dose levels tested. And in fact, most of the adverse events were either grade 1 or 2 and most of them were infusion-related reactions, which is typical for monoclonal antibodies. We did see one grade 3 laryngeal edema but that was in a patient who did not receive their protocol mandated steroid pre-medication. So we feel very good about the safety profile, both for ongoing monotherapy development, but it also makes CLN-619 an ideal combination partner also. I mentioned we saw a signal in gynecologic malignancies. So let me talk a little bit more about endometrial cancer and how we're thinking about that opportunity in this next slide. Endometrial cancer is a very underdeveloped disease with very few approved or even effective treatments. Every year in the U.S., 66,000 women are diagnosed with endometrial cancer. 25,000 patients receive systemic therapy. The other aspect of endometrial cancer is, patients often have multiple comorbidities. So there is indeed a high unmet need, not just for more efficacious treatment, but treatments that are also well tolerated, which is obviously important in the context of CLN-619. And the clinical landscape is also changing with endometrial cancer. The main approved treatment in endometrial cancer are checkpoint inhibitor-based regimens and they were originally approved in the relapse setting. Those treatments are now moving up into the frontline setting in combination with the current standard of care which is platinum-based chemotherapy based on large randomized Phase III studies. So as checkpoint inhibitors move up to the frontline setting, this leaves a very large and growing pool of patients in the relapsed disease setting for whom there are no effective therapies. And so for us, this opens up a significant clinical opportunity as well as a commercial opportunity. And even the best treatment in this relapse setting post PD-1, you see about a 15% response rate. And so as we think about next steps for CLN-619 in endometrial cancer, given this lack of approved treatments, there's a very clear regulatory pathway here, especially in relapsed disease. I mentioned we've already opened up a cohort of monotherapy patients with endometrial cancer. And we're also now planning a combination therapy expansion cohort in combination with checkpoint inhibition. And the data from both of these cohorts will be really important to inform our next steps as it pertains to a registration strategy in endometrial cancer for CLN-619. I will add, though, endometrial cancer is the beginning of the story, not the end of the story, given the broad profile we've seen of activity across tumor types. And so in summary, we're very excited about the opportunity with CLN-619, especially given the fact that we've seen single-agent activity, including objective responses. The molecule has shown us a very favorable safety profile, which makes it an ideal combination partner as we think about combination strategies in the future. We've clearly seen clinical benefit across a range of tumor types, including objective responses in patients who have progressed on prior checkpoint inhibitor therapy, an important clinical problem. I mentioned we've seen an early signal in gynecologic malignancies. And so we've opened up expansion cohorts already in endometrial and cervical cancer and those are ongoing. And I also outlined that there's a very clear regulatory path in this disease and a significant commercial opportunity for a drug like CLN-619. And our study is ongoing in both monotherapy and combination therapy. So we look for additional signals that will allow us to open up even more expansion cohorts with this important treatment. And again, summarizing and recapping, we'll be presenting the initial combination therapy data from our ongoing Phase I study in second quarter of 2024 as well as the follow-up monotherapy data following the initial ASCO data presentation, and in terms of the current expansion cohorts, we expect to report those data out in the first half of 2025. And now let me turn to another important program in our pipeline, addressing another significant unmet need and that's zipalertinib, EGFR exon 20 inhibitor. The exon 20 patient population makes up a substantial proportion of all mutated EGFR patients with an annual incident in the U.S. of approximately 3,000 to 4,000 patients. Now this is a disease with a really high unmet need and I'll demonstrate that by the data that's published out there. So even in the frontline setting, patients with exon 20 non-small cell lung cancer with the standard of care, which is currently platinum-doublet chemotherapy, experienced a median progression-free survival of only 6 months. So there's clearly a need for more effective therapies to address this disease. And in the next slide, I can outline the profile for zipalertinib. We believe we have a best-in-class profile with this molecule, which bodes well and positions us well relative to the competition. So zipalertinib does have a unique chemical structure, which allows it to target the exon 20 insertion mutation, specifically relative to wild-type EGFR. It also doesn't bind to HER2. So this combination of attributes should portend for a favorable safety profile. In terms of efficacy in our early Phase I/II study, we have shown that zipalertinib is at the top end of efficacy that we've seen with the other approved agents. And we have breakthrough therapy destination for this molecule, which for us is additional external validation of the best-in-class profile that we have with this drug. We are codeveloping zipalertinib with our partners at Taiho with the option to co-commercialize in the future where we have 50-50 profit share in the U.S. And zipalertinib is currently in 2 pivotal ongoing studies, both in the frontline setting and in the relapsed disease setting. And now let me dig into a little bit more about the clinical profile that we've seen in the initial Phase I/II study. So we tested a range of dose levels with zipalertinib. And we found the 100-milligram BID dose to give us the best balance of tolerability and efficacy. We saw a 41% objective response rate, which is at the higher end of the current approved agents in this space. We saw a median progression-free survival of 12 months which, again, compares favorably with the 6 to 8 months that we see with not only the approved agents, but the other agents that are currently in clinical development. We saw no grade 3 or greater rash or diarrhea typical EGF related toxicities. And we think this is due to the specificity of the molecule for the exon 20 insertion mutation. And we saw a relative low rate of dose reductions and dose discontinuation. So 100 milligrams BID is a dose we've taken forward into our pivotal studies. And so we believe zipalertinib has the best overall therapeutic profile supported by efficacy at the higher end of what we've seen, a differentiated safety profile, combined with the convenience of an oral therapy. We also have, you can see in the next slide, a broad development plan with our partners at Taiho through the REZILIENT suite of studies. So REZILIENT1 is a study we're conducting a pivotal study in the relapsed disease setting where we're enrolling patients who have received prior chemotherapy. And we also have a very important cohort that we're enrolling, and that's patients who have received prior chemotherapy and prior exon 20 approved agents, which will be very important data both from a commercial perspective and from a regulatory package perspective. Our partners at Taiho are conducting the REZILIENT3 study, which is our frontline study combining zipalertinib plus standard of care versus standard of care. And our partners at Taiho are also exploring zipalertinib in other important patient populations such as patients with active brain mets, patients with uncommon EGFR mutations and also exploring zipalertinib monotherapy in the frontline setting. Okay. So now let me switch gears to another important program, a clinical stage program, and that is CLN-978, which is our T cell engager, which targets both CD19 x CD3. We're obviously very excited about all of the developments we've seen with CD19 directed therapies in the autoimmune disease space. And we believe that this is a molecule that could be disruptive in this space. Now CD19, obviously, now has been clinically and commercially validated across B-cell malignancies, both leukemia and lymphoma and it's also emerging as a very important therapeutic target in autoimmune diseases. T cell engagers as a modality have obviously shown remarkable efficacy across a range of B-cell malignancies, again, including leukemias, lymphomas, multiple myeloma and in many cases, have shown CAR-T-like efficacy, without the issues associated with CAR-T such as the logistics, practical administration and some of the safety aspects. Speaking about CLN-978 specifically, this is a molecule that we have engineered to seek out very low levels of CD19 expression. And in vitro, we've already shown very impressive tumor cell [ co ] at very low levels of the antigen expression. CLN-978, as I mentioned, offers off-the-shelf convenience in the form of subcu dosing, and we look forward to continuing to advance this molecule. In the next slide, let me go through the structure of CLN-978, very briefly. So as I mentioned, very high affinity binding for CD19 at extremely low levels of CD19. In fact, at low levels, levels that are so low, sometimes are considered CD19 negative disease, it has a human serum album binding domain, which significantly extends the half-life of the molecule. And all components of this antibody are fully human. And so lowering the risk of things like ADAs, et cetera. As I mentioned, in vitro, we've seen robust tumor cell killing at very low levels of CD19 expression and very importantly, in our nonhuman primate studies, with 1 single dose of CLN-978, we were able to see profound and complete B-cell dose depletion, which is very important as we think about the application of this molecule in autoimmune diseases. As I mentioned, CLN-978 is currently in an ongoing Phase I dose escalation study in relapsed/refractory lymphoma. Now many of you may be aware of, obviously, the exciting data we've seen with CD19 directed cell therapy in autoimmune diseases. And I'm showing here the original work from the group at the University of Erlangen in Germany, where they were able to show very deep and durable remissions in lupus. And again, they also updated the data at ASH where they were able to extend these deep and durable remissions into other autoimmune diseases. So obviously, that's got our attention, and it's exciting for us. We believe that CD19 for autoimmune diseases is a much better target than CD20 given the breadth of coverage you get across B-cell lineage. And relative to CAR-T or cell therapy CLN-978 offers a potent off-the-shelf therapy. You don't need lymphodepletion regimens. It's not associated with some of the secondary primary malignancies that the FDA are reviewing cell therapies for. So we believe this could be a powerful alternative to cell therapies in this space. And as I mentioned, we have an ongoing Phase I study in lymphoma, but that will also probably give us additional important data, especially as it pertains to B-cell depletion in patients, which will be important considerations as we think about autoimmune indications. And so this is a very high-priority program for us, and we're very excited to have the opportunity to take an off-the-shelf potent CD19-directed therapy into the space of autoimmune diseases. And now let me conclude. So today, I covered 3 key programs in our pipeline. I mentioned we have a strategic approach that takes only the best first-in-class or best-in-class molecules into the clinic. And so we have multiple shots on goal. Not only do we have multiple shots on goal. We have multiple high-quality shots on goal. I mentioned that we have set ourselves up for a very data-rich 2024 going into the first half of 2025. So multiple value creation opportunities based on important clinical data readouts across our portfolio. We have a robust cash position of $470 million of cash at the end of 2023, which gives us runway into the second half of 2026, comfortably beyond the near-term data milestones I mentioned, allowing us to continue to advance our pipeline. 2024 will be a very important and exciting year for Cullinan Oncology. And so finally, I'd like to thank JPMorgan for the opportunity to showcase the work of my brilliant colleagues at Cullinan Oncology, and thank you very much for your attention. Happy to take questions.

We'll now be taking questions from the audience. We just ask that you wait for the mic, so folks on the webcast will be able to hear you.

Yes. So you did a trial combining zipalertinib plus platinum-based chemo in the frontline. Have you reported any data of zipalertinib in combo with that chemo already?

We haven't. Actually, this study does have a safety run-in phase as well so that we get the data that you're alluding to. The one thing I will add is what we've seen with Janssen and the PAPILLON study, which was positive clearly, was that probably the best approach for the frontline setting is to combine with standard of care rather than take the approach of monotherapy TKI for example, that didn't work with Takeda, right, because that confirmatory study failed. And some of our competitors are actually repeating that experiment. But when we were designing this study, we heard very clearly from U.S. investigators, you need to combine with standard of care so that you fully optimize patient outcomes.

Any other questions from the audience? All right. I'm actually glad you have this slide up. So you have 6 programs. How do you expect to advance all of these?

Sure. We do have a lot going on. But I can tell you, it's a better problem than the opposite problem, where you don't have any assets. And look, just about 18 months ago, the only program we had actually was zipalertinib in the clinic. So the team has done a remarkable job of execution going from one program in the clinic to now 6 programs in the clinic. As I mentioned, we're very disciplined about hitting go and no-go criteria. So as I think about your question, zipalertinib is obviously already in the clinic in pivotal studies, right? So that's on its path to regulatory approval and commercialization with our partners at Taiho. CLN-619, I share the important efficacy data. So in a way, that's already hit our go criteria and we're looking to how can we exploit that opportunity. And then we have 4 programs in Phase I. And so the way we think about it is Phase I clinical trials is a relatively low cost base relative to the Phase II and Phase III studies you need to do afterwards. That's one thing. Secondly, we have seen, especially over the past year or so that if anything is going to move the needle, it's clinical data, not preclinical data, right? And so for each of these additional 4 programs, I went through some of the data outlines through 2024 and 2025. We need to complete the experiment, turn the cards over, and then we'll know how many programs we have. And so there'll be very clear go/no-go criteria at the end of each of these Phase I experiments. If we don't hit our go criteria for one of our Phase I programs, we're very good at killing those programs and then thinking about redeploying capital. But the other thing I would add is, look, we're in a business of attrition as you go through the various stages of development, right? And so while we have 5 programs in Phase I, I would love every single one to work. The history on the data shows that's probably not likely to be the case. So we would expect some level of attrition. And then look, if we do hit more upside potential in terms of clinical data, then we expect, well, that drives value in the company. And again, we have the opportunity for strategic optionality and talking to partners from a strategic opportunity perspective as well. So that gives us just like we did with zipalertinib and Taiho. So for us, I think we feel very good about the programs we have in flight. Yes, the quantity is high. But when you account for attrition, when you account for data that you get, we feel we're in a very good place. And in the relatively near term, we're going to be turning over the data cards for each of these programs and looking forward to doing that.

And speaking of data, could you talk about what we can expect in terms of updates this year, specifically our Q2 update coming out for CLN-619?

Sure. Happy to do that. So as a reminder, this is the first time we're presenting the combination therapy data in combination with pembrolizumab. Last year, we presented the monotherapy data. So we'll present updated monotherapy data following what we presented at ASCO. For the combination therapy cohort, we started the dose escalation at a higher dose level since we saw the data in the monotherapy cohort. And so there, we'd probably have maybe a couple of dozen patients and probably about 40 patients in the monotherapy arm. And for us, there's always the challenge of how do you interpret combination therapy data, right? And so the things we'll be looking for is in the combination cohort, are we seeing activity in tumor types where you typically don't expect checkpoint inhibitors to work? Are we seeing activity in patients who have already progressed on prior checkpoint inhibition therapy? So I think we'll have some useful data here. But again, this is the first cut of the data.

And now why do you think that CLN-619 is so active in gynecological tumors? And what do you think is the regulatory path or efficacy bar for endometrial cancer?