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

Good morning. Thank you for attending the conference. Thank you, Jeff, for being here. Pleased to present our next speaker, Jeff, CFO of Cullinan Oncology, ticker CGEM, oncology focused. We'll see, I think, and hear more about some of the exciting and broad pipeline that they have and their strategic focus in this field. And so with that, I'll just pass to you, Jeff.

Thanks a lot, Eric. Appreciate it. So just before we begin, a quick note, what we're talking about today, we will have forward-looking statements. Investing in our securities involves risks. I would advise you to please consult with our 10-K and 10-Q to get a better understanding of the risk factors. So yes, let me just pick up where Eric left off. So Cullinan Oncology, what are we all about? First and foremost, we like to find high-impact targets in oncology. What do we mean by high impact? A target that's either involved in tumor cell proliferation and survival or targets that can really engender and engage a robust immune cell response. And we've got examples of both of those in our pipeline. The second thing is once we've identified those targets, we try to keep an open mind about the modality, figure out really the best way to drug them. So instead of starting from a platform and a technology standpoint, we start from what's the best potential for a therapeutic medicine. And we pretty much play across small molecules, antibodies, fusion proteins. The only thing we stay away from cell therapy. And then the last point is we're very rigorous in what we choose to advance and what we don't. And so we look for molecules that have first-in-class, best-in-class potential, and we run what we call thriller or killer experiments pretty early to figure out what the drug can do. And so with that, given this is an investor conference, how should an investor be thinking about Cullinan? So first and foremost, we've got a really robust cash position. We ended the second quarter with over $650 million on hand. Gives us long-term runway. And in this market, I think that's a big differentiating factor. The second is one of our lead programs has produced really good proof-of-concept clinical data. It's an area of high unmet need, EGFR exon 20, which we'll talk about in a little bit. And that program is ready to move into a pivotal study this quarter. We've recently announced a partnership with Taiho Oncology to move that forward together in the U.S., and we'll look forward to updating you on that shortly. The third point is we've got 2 other programs in the clinic right behind it with data in the mid-2023, so not too far away. One is 049, which is a T cell engager, and the other is 619, an antibody engaging both innate and immune cells, and we'll talk about those. And then behind that, number four, we have a pretty robust pipeline. So we have 2 other programs that are on track for INDs in the first half of next year. So roll forward the clock 12 months from now, we could have 5 clinical stage programs across a number of studies. And I think that gives you a good sense of the breadth and depth of our pipeline. But just so you can see what that looks like visually, we've got our probably 8 most advanced programs on the slide here. The top 3 we covered are in the clinic, the lead one going into a pivotal study shortly, the other 2 with data expected mid-2023. We're going to spend most of the time today talking through those. Behind that, I'll touch on these other 2 programs, CLN-617, CLN-978. We don't have a lot of slides in the presentation today, but I could direct you to our website. And so I'll just give a quick overview of those. CLN-617. There's been a lot of excitement about cytokine development in cancer. IL-2 high dose is obviously approved, but there's been a number of other companies working on different ways to get cytokine into therapeutic reality. With our approach, we're the only company that's combining IL-12 and IL-2 together, and we've got a unique angle to keep those cytokines in the local tumor environment, kind of where they belong, to potentiate antitumor activity. And then the other program, 978, a next-gen T cell engager for CD19, which is obviously a well-validated target in cancer development. Our approach potentially gives advantages of picking up patients that have very low levels of target expression, which could be interesting -- sorry, my mic went out -- different settings in the heme space. And so both of those programs will have INDs in the first half of next year, but -- no slides in the deck today, but we could talk about those at another time. And so just jumping right into CLN-081, the top half of the slide here, we've got a snapshot of what the molecule looks like chemically. And the reason why is -- this, I think, highlights what we thought would lead to a differentiated program in the clinic. So number one, it's a distinct chemical scaffold that's different than all the other TKIs out there. Number two, we only hit EGFR exon 20. We don't hit HER2 exon 20. And so I think that's leading to some safety and tolerability advantages in the clinic. And then the third is, we established preclinically, it's got a very selective profile of hitting mutant EGFR over wild-type EGFR. And I think that's what is playing out with the therapeutic window we see in the clinic, which we'll talk about in a minute. So at the bottom half of this slide, a snapshot of the data that we've shown to date. On the left, very high confirmed response rate, 41%, that sits right on top of the agents that have accelerated approval. At the time of this data cut at ASCO earlier this year, we showed a DOR estimate of 21 months, hadn't technically been reached, but it was trending in that direction. And then also an estimated 12-month progression-free survival. So those 3 data points in a very relapsed patient population, we are very excited about. They compare very well to agents that have accelerated approval. And we also had a favorable safety and tolerability profile, which we can evaluate a little bit here. So a little bit more on that study. We dosed almost 75 patients across 5 different dose levels. We've highlighted here the dose -- the data that we've seen at the 100 mg dose relative to the aggregation of the lower doses below that and the highest dose we evaluated, 150 mg. And so the top half of the slide has the response rates that we talked about. 100 mg had the highest rate, and it also had -- with the best estimated DOR at the time. And what's playing into that, when you look towards the bottom half of the slide, we've highlighted some of the EGFR-associated toxicities, rash and GI issues. At the 100 mg, we didn't see any Grade 3 or greater events. And when you think about some of the approved agents, namely mobocertinib, which has a TKI for exon 20, they saw all grade diarrhea rates above 90% and Grade 3 rates above 20%. So we compare very favorably, and we think that's what's playing into the ability for patients to stay on drug, which is encouraging in supporting the DOR and the PFS rates we've shown here. And you could see that all culminated at the bottom, relatively low dose reduction, dose continuation rates at the 100 mg. And so we've got 39 patients there. Our next steps with the program are to start a pivotal trial, which we'll do on the accelerated approval pathway. And so we anticipate that study being nonrandomized and in a very similar patient population, which is second line plus non-small cell lung EGFR exon 20. The last point on 081 is, as I alluded to earlier, we did announce a partnership with Taiho Oncology, which is a subsidiary of Otsuka. That was the culmination of a competitive process, a lot of interest in EGFR exon 20, a lot of interest in our molecule after we put out that data at ASCO and culminated in this transaction. And so financially, we were able to achieve $275 million upfront. We also are eligible for up to $130 million in regulatory-based milestones for EGFR exon 20, so very much on brand. And we -- the last one on the lower left side of the slide is economically, we share equally in U.S. development and U.S. profits for 081. And that's across any indication that the drug is put in. So really nice financial deal that helped us get the cash balance of -- that we talked about, over $650 million. But also strategically, Taiho has a good targeted EGFR focus -- or targeted oncology focus, I should say, in the U.S. and the partnership is off and running and going well. Shifting gears to CLN-049. Just quickly on AML, I think it's pretty well understood by the investment community. But where we see the biggest unmet need in AML, I mean, there's been a lot of development with intensive chemo, there's been a lot of development with targeted AML agents. But what kind of remains as the unmet need is for patients who are older, who have the disease, who are ineligible for transplant, ineligible or can't tolerate high-dose chemo regimens. Something that's a broad immune activating approach. And that's where we came in with our approach for CLN-049. And just quickly on the target that we're pursuing, which is FLT3. The first and foremost, where we like it is, it's very validated. So there are tyrosine kinase inhibitors approved for mutant FLT3 patient populations. They work well, but they're kind of limited to about 20% to 30% of the patient population that has mutant FLT3 expression. By looking at both wild type and mutant, we can address a much broader patient population, potentially 90% of AML patients. The third is, FLT3 is expressed both on AML blasts as well as progenitor cells. So hopefully, we could see responses that are more durable and deeper. And then the last point is, relative to other T cell targets like CD33 and 123, FLT3, the expression outside of AML cells, so on healthy cells, is very limited, very low. And what we hope to see is a nice therapeutic window in the clinic. And so on this slide, Slide 11, you can see on the left, the mechanism of action of 049, where we're engaging CD3 on T cells and then FLT3 on the AML blasts. And so unlike the TKIs, we're absolutely lysing the cell and hopefully less vulnerable to any resistance mechanisms that you might see with the targeted approach as well. The other thing -- a couple of minor things here that are important. One is we have the 2 FLT3 binding domains. And so hopefully, that helps us pick up cells that have low levels of FLT3 expression. And then also, we have monovalent CD3 binding domains. And so what we hope to see there is a lack of T cell activation in the absence of target, which should further support the therapeutic window of CLN-049. And so this program is in the clinic. We started dosing patients about a year ago, and we expect to show initial clinical data in the middle of 2023. The third program I talk about today is CLN-619. The pathway we're engaging here and the target we're engaging is MICA/B. And so we put this in a subsidiary we call Cullinan MICA because we have gemstone names for our subsidiaries. But what you can see here on this slide is the sort of natural evolution of what happens with MICA/B and how they leads to cell lysis. And so any cell that's undergoing stress, whether it be from an infection, whether it be from oncology, some malignant transformation, it starts expressing these MICA/B proteins. And what those serve as is, as you can see on the right, they are signals to the immune cells, both innate and adaptive immune cell populations, to lyse the cell. And they do that through engagement of NKG2D on NK cells as well as T cell populations. And you can see on the top right corner of the slide, that's what should be happening that MICA/B is expressed and the NK cells and the T cells come in and lyse the cell. However, on the bottom right, what's happened with cancer cells is they have figured out ways to cleave MICA/B and shed it from its surface, and it effectively hides itself from the immune system. So what we're doing with 619, on Slide 13, is -- with this antibody is really stabilizing that MICA/B expression. And so our antibody, what you could see on the right, finds a binding domain on MICA/B and keep -- protects the MICA/B from being shed by the proteases in the tumor microenvironment. And by preventing that shedding, first and foremost, they can restore the engagement with NKG2D on immune cells. The second is our antibody has an Fc domain and so it actually directly [Technical Difficulty] cytotoxicity. And then the third is by stabilizing that binding, we sort of lower the threshold required for killing the cell. And all that's shown on the right. And actually, what's not on this slide, but a very late breaker was, yesterday at SITC, we had a poster that elucidated a fourth mechanism of action, which is we actually engage macrophages as well. So multiple pathways to mediate antitumor activity. One thing we like about 619, as we talked about earlier, strategically for us, it's a potential first-in-class play. We're the only program in the clinic in this pathway that's got an antibody. But as you can see on this slide, the validation of the pathway as an antitumor activity is growing. There's been other companies that have explored MICA/B therapeutically. To our knowledge, nobody has ever gotten an antibody into the clinic. However, at the bottom of the slide, you can see there's several cell therapy approaches that are in the clinic. The most relevant and most on target is Fate Therapeutics, which has a CAR NK that targets MICA/B with their engineered NK cells. And then Nkarta is in a similar pathway, but a little -- slightly different. They've CAR'ed NKG2D onto their NK cells, and they've shown interesting clinical activity in heme populations. And so definitely growing biology, but we're excited that we have a first-in-class opportunity there. And on Slide 15, what you can see is some of the differentiating points about what we're doing with 619. And so we talked about the fact that it has first-in-class potential. We talked about the fact that it's got multiple modes of action for antitumor activity. What we don't have today, but what you can see on our website, is we have a very strong preclinical package. We've showed that 619 can mediate antitumor activity as a single agent and have pretty robust tumor reductions at almost any dose level. We've also shown that in nonhuman primates, we can dose almost as high as we want. We never really reached a DLT, and we got to dose levels that were 10x what we're evaluating in human trials. So hopefully that portends to a wide therapeutic window. And then the last thing is, even though we've seen monotherapy activity preclinically, there's sort of a natural rationale for synergy with combination therapies. As a couple of examples on this slide, but one is any patient undergoing radiation therapy, radiation therapy stresses cells and upregulates MICA/B, so that could be an interesting therapeutic angle for us as well as combinations with immunotherapy. And similar to 049, we started dosing patients with 619 at the beginning of last year. It was in a solid tumor trial in all comers, and we will be reporting initial clinical data on that program in mid-2023 as well. So we have 2 clinical readouts next year. Here is a little bit of the study schema. It's a little bit busy, and so I'll just orient you on the top half. This is the monotherapy evaluation of 619. And then in parallel, at the bottom half, we are evaluating in combination with checkpoint inhibitor, specifically pembrolizumab given the breadth of its approvals. And then on the right, you can see that once we have established enough dose escalation and get to dose levels of interest where we've established the safety and clinical activity of the drug, we could expand into tumors of interest. So specifically, relapsed patients in non-small cell lung and cervical cancer as monotherapy, just given the unmet need there for an IO agent. And then on the bottom half, looking at targets of interest where we could potentially improve the efficacy seen with checkpoint inhibitors. And given our safety profile, hopefully just adding efficacy without adding any safety or tolerability issues. And so like I said, that study is ongoing, and we expect to have data in the mid-2023 time frame. So just to conclude, on our 5 most advanced programs that will hopefully all be in the clinic by mid next year, you can get a snapshot of our milestones. On our lead program with Taiho, what we anticipate starting a pivotal study in 081 very shortly, and we'll look forward to updating folks on that when that is in a pivotal study phase. 049 and 619, as we've talked about, expecting to have clinical data in 2023 for both of those programs. And then 617 and 978 are tracking for IND submissions in the first half of 2023, which would hopefully enable trial starts shortly thereafter in 2023 as well. So pretty catalyst-rich period for Cullinan. And luckily, we've got the capital and the cash to take it forward, and we look forward to updating people on our progress in the future. I'll pause here for any questions.

[Technical Difficulty] is the model to replicate for some of the key assets that you have to partner at a certain stage when you feel comfortable with the economics and the synergies make sense? So would you want to retain more of your lead assets going forward?

That's a great question, Eric. Thanks for asking. Yes, I think we're going to continue to take things on an asset-by-asset basis. And so we're excited about the Taiho deal. I think it made a lot of sense for EGFR exon 20 when you look at the competitive landscape. And I think given the strategic benefits of working with Taiho and the financial benefits to the deal and the fact that, that came out of a very competitive process, I think it all lined up for a partnership. Going forward, now with the resources we have in the company, both financial as well as some of the leadership changes we've made, CEO from -- who is the Head of Commercial at Celgene, Chief Medical Officer who's developed oncology drugs, I think we're very well equipped to take programs forward ourselves. But we're going to continue to make that on an asset-by-asset basis and do whatever is best for shareholders.

[indiscernible], HBM. A question on your corporate structure. Is that working out for you with these various subsidiaries that are developing the single assets?

Yes. Great question. The company was set up historically where each drug was put in its own subsidiary. We always kept all of the financial and human resources up at the parent level. And it worked from a scale perspective because we are only focused on oncology. And I think today, we have 3 subsidiaries, one Amber for our cytokine program, Florentine for our T-cell engager and then Mica for 619. And we own approximately 95% of the equity in each of those. And I think going forward, as a public company, we're probably going to shy away from creating new subsidiaries and try to keep things wholly owned. And CLN-978 is a good example of that. That is sitting in the parent company, and it's 100% owned. But I think it made sense when we were private and we were trying to preserve cash. And so we would give equity to some of the originators. But I think going forward, we're going to probably move away from that.

On the MICA programs, is that monotherapy possibility there? Or if you want to combine, with what?

Yes, it's a good question. I think monotherapy activity is possible, and we've seen it preclinically. We're in a very relapsed/refractory patient population in this all-comer study. And so the primary goal is establish that the drug is safe, establish the right dose. And we're going to look at the PK and PD biomarkers of MICA and NK-cell engagement and tumor microenvironment, et cetera, et cetera, to guide the dose selection and efficacy will be part of that mix. And the trial setup that we can look at efficacy, both monotherapy and combination. So TBD on what the ultimate plan is, but there's a possibility for either. Great. I don't see any other questions, but you know where to find us if you have any, and thank you for the time today.