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

Welcome to the Morgan Stanley Global Healthcare Conference. I'm Jeff Hung, one of the biotech analysts. For important closures please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. [Operator Instructions]. CEO, Owen Hughes; and CFO, Jeff Trigilio, welcome.

Thank you.

Thank you.

For those who may not be familiar with Cullinan, can you provide a brief introduction?

Sure. Jeff, thank you very much for the introduction and happy to participate in the conference. So Cullinan is a bit of a unique animal in the sense that we fashion ourselves to be a bit of a hybrid between an investing arm and operational harm. So our goal is to seek unique assets from across the globe, generally speaking, assets that are 6 to 12, 18 months from an IND and shepherd those assets from preclinical development into early clinical development. And upon successfully achieving proof of concept to determine the best route to maximization or monetization for those assets, trying to maximize the assets or the value of the assets for shareholders. So our goal at this point is necessarily to become a fully integrated company, but to continue to actually turn this wheel, so to speak, and finding new assets, bring them through development engine and then trying to maximize returns for shareholders. And then ultimately, increased value, both through equity appreciation as well as return of capital.

Great. And as you mentioned, your company takes a different approach than most companies. Maybe can you talk a little bit about your view on correlation within the portfolio?

Sure. So I'm sure many of us have taken the CFA, spent some time in monetary class economic classes and have learned a bit about portfolio diversification just looking at our 401k. And we're actually using the same exact principles, which is that in order to actually maximize the efficient frontier, there is a balance between the modalities, indications, mechanisms that we're trying to utilize in the oncology field. And so our goal is to actually have assets that are uncorrelated so that each can stand on their own. So that if one actually does go down, it has no negative correlation or effect on our other assets. And that's why at any given time, we're trying to work on 6 state assets. At this point in time, we'll have -- we have 3 assets that are in the clinic today. I'm sure 1 or 2 of those may not work. And so our goal is to make sure that we can supplement that and complement those assets with other assets that we're working on pretty clinically such that we have 1 or 2 assets in the clinic at each every time, and those assets themselves are very distant from 1 another.

Your lead program, CLN-081, is an EGFR inhibitor. Now how does that asset compare to other EGFR inhibitors?

Yes. I may actually have Dr. Wittington comment on that. Jon has many years of experience in the oncology field and having treated patients and understanding the differences may be best to answer the question.

Thanks, Owen. Well, coming into the clinic, we were very encouraged by the preclinical profile that suggested CLN-081 could have a highly differentiated and selective profile for inhibiting exon 20 EGFR versus wild type. And in fact, that's actually what the data appears to be showing as we've advanced it into the clinic. The safety profile appears to be differentiated with respect to key EGFR toxicities like rash and diarrhea. Although we see rash commonly, we've not seen Grade 3 rash. We also, with respect to diarrhea, unlike competitor molecules that have been seeing, in some cases, 80% to 90% all Grade in 25% to 30% Grade 3 or greater, we've only seen 22% all Grade in a single case of Grade 3 diarrhea. Compared with that, we're seeing very encouraging activity across the entire dose range tested across the spectrum of different exon 20 mutational subtypes and in patients post -- who have been treated with other exon 20 EGFR inhibitors, and in patients that have been treated with other EGFR inhibitors or with the prior immunotherapy. So all in all, we're very encouraged by this profile. This is an oral molecule. We think that it differentiates -- it's differentiating nicely so far compared to the other EGFR and TKIs in this space. We're very encouraged by that profile. Our [ Amgen ] is obviously out there and approved. It's an IV drug given weekly times 4, followed by every 2 weeks as infusion reaction signal, et cetera. So we think there's a big need for a convenient, orally administered drug that is active and well tolerated, and that's the profile we think that's emerging to date.

And how do you view the DZD9008 data? And what advantages do you think 081 has?

Go ahead, Jon.

Yes. Yes. Well, first of all, we think the data looks very interesting so far. It's a molecule that has clinical activity to be sure. We think that there are some -- back to the wild-type EGFR toxicity issue, last, we saw, I think they're tracking right around 54% of all Grade diarrhea, 5% Grade 3 diarrhea. We don't know how much of it's Grade 2, which can be quite meaningful as well. There have been some evidence of some early cardiac signal, which we don't have a lot of insight -- further insight at this point. It does have a response rate that's in the 40%-ish range depending on the patient growth that you're talking about. So it's certainly something that we have our eye on, but our activity, so far, we think, is within the comparable range. And hopefully, our safety profile will continue to mature. Owen, do you want to add anything to that?

No. I think with that in mind, as we think about the development of an EGFR TKI targeting exon 20, and ours, in particular, is that the real revenue opportunity is in the frontline setting, given the potential duration of these molecules. I think to compete effectively there. Certainly, you need an efficacy bar. But I think a lot of it will come down to the safety. And there, we have a lot of confidence that our drug can achieve a meaningfully different profile relative of the molecules in the space. And obviously, you need more data to confirm the hypothesis. But to date, what we've seen is very encouraging.

And for the update that you guys will be having in fourth quarter, what should we expect to see and how many patients will be included in that data readout?

Sure. Jeff can take that.

Yes. So in the fourth quarter, what we'd like to do, Jeff, is provide, at the same time, a clinical and regulatory update. And so given we recently expanded at the 100 mg, we'll have close to 36 patients of safety and efficacy data. What we're in the middle of doing now is packaging that together for the agency to talk about the development path forward for the molecule and what we think is the right recommended Phase II dose. And hopefully, when those conversations culminate in mid- to late November, towards the back half of Q4, we can provide that external clinical and regulatory update.

In addition to the 100 mg patients, we made the decision in the late summer to expand to 150. You may remember, Jeff, we certainly had some clinical activity at the ASCO data at the 150 dose. We started seeing a slight elevation in the safety signal. But nevertheless, we had not reached our MTD. So as a team, we made the decision to increase the end to 13. Our hope is that we can provide some additional information at that dose. I think there's 2 objectives going to 150 is we certainly want to maximize the efficacy and minimize the safety for patients. And I think the right thing to do is to explore that dose. And at the same time, if our hunch comes to fruition, which is that we will have a clear delineation and safety between 100 and 150, I think that will be very beneficial for our discussions with the agency.

And given that you decided to expand the number of patients there, I guess, is it too early to speculate about how many patients you might see with that data update on 150 milligrams?

Yes. Let us get through the third quarter earnings. We'll probably have a better sense just given the enrollment cadence. I would say that things were going extremely well and then the Delta variant hit. And things, honestly, have slowed down in conjunction with the end of the summer. So I'm not too surprised. Let's see what type of cadence we have coming out of the summer, early fall, we'll have a better brief you guys on the third quarter comes around third quarter comes around -- third quarter earnings.

Okay. And then beyond the current exon 20 program, what other indications can you pursue With this drug.

Yes, do you want to touch on something, Jon, I'll touch on a few?

Sure. I mean I think that -- well, let me just break that. Within exon 20, certainly, we think that there are other opportunities worth considering like sinonasal carcinoma. We also think that there may be any number of different combination strategies that could be considered, including cytotoxic therapy, immunotherapy and/or other targeted agents. There are -- there is some rationale to look at it in other mutational subsets as well. That's something that we're working through and thinking through at this juncture. I don't know, Owen, you want to add to that?

Yes, I'd just say the drug is probably is as potent if not more potent than Tagrisso and some of the traditional sensitizing mutations. Obviously, we'd be very naive to think that we can compete with Tagrisso given the beachhead that it has established and the revenue that it has. But in certain traditional failures, we believe the drug can actually work as a monotherapy. And as Jon touched on, both in the exon 20 field as well as in some of the mutational subtypes, we believe combination therapy may be very beneficial for patients. So as we embark on the second line study and get the first-line study up and running, we will look to investigate certain areas outside of exon 20. The important thing from our perspective is that as long as the safety continues to hold, and we think there's an opportunity to have this drug out of the exon 20 landscape, and to date, we're confident that that's happening.

Great. And then we have a question coming in from the audience. Are you enrolling any patients previously treated with amavatinab?

We have not to date on the existing protocols that we have. When we started the Phase I study, we did allow prior TKIs. And I don't remember the specific number that had prior TKI not posing and not attack. It's roughly 20% to 30%.

Yes, 40% about have had prior TKI and then we had a handful of patients that were only allowed on during the dose escalation component to have exon 20, we had a small number of those patients, as I just mentioned.

Yes. Well, once we saw efficacy, we went down to a defined patient population that we would have in our pivotal study with the hope being that we can convince the agency of the clear risk benefit of our existing drug as well as the patient population that has been studied so that we can use that patient population as a harbinger for the initiation of the pivotal study.

Okay. Great. Maybe moving on to CLN-049. So that's a bispecific antibody. What are the limitations of current FLT3 inhibitors? And how is 049 potentially better?

Sure. So All FLT3 inhibitors today are small molecules that act on intracellular FLT3. This approach is radically different. We're trying to address the extracellular FLT3. And so our hope is that we can address a much larger patient population and, frankly, not be concerned about the specific mutations or the phenotype of FLT3. With that said, this is a -- it's an antibody. So it's certainly different than that of a small molecule. From a clinical development perspective, there are some implications of using a bispecific relative to a small molecule in this patient population. Obviously, it's a very sick patient population, and we need to be cognizant of potential CRS. So we're starting at a relatively low dose and will dose escalate over time. But I'd say the key difference is intracellular versus extracellular and the attainment of the T cell rather than just FLT3 through itself. Jon, would you comment anything else there?

Think you captured it.

Okay.

Can you highlight maybe some pieces of the data that give you confidence in your approach?

Sure. So we've looked at a number of preclinical models similar to what others have done. And I would say that there was one specific program that was actually in the clinic that was recently terminated, which was the JNJ molecule -- excuse me, excuse me, the Amgen molecule -- it was an Amgen BiTE molecule. And actually, there was also a FLT3 CD3 that came out of Reno in San Diego from Pfizer. And we've essentially all done very similar preclinical models, looking at longevity over time. And I would say that we all have, I'd say, a pretty similar data. I think it will come down to safety and what type of TI we can establish relative to the other molecules. And so -- anything else, Jon?

No, the only thing I'd add, Owen, as opposed to the differentiation for other FLT3 molecules is FLT3 itself, the rationale for our bispecific approach as relative to other bispecific approaches FLT3 is the expression is limited to the myeloid compartment. And so hopefully, that helps us split with the TI window that we expect to see in the clinic.

Yes. I think there was -- early on, as people look at antibodies for AML done actually develop one of these molecules, most people gravitated to CD123 and CD33. Our hypothesis is that target in CIT may engender a larger TI. But obviously, that remains to be seen. We're going to test that in the clinic and see what happens.

Great. Maybe moving on to CLN-619, that targets MICA/MICB. How do tumor cells use that as division mechanism?

Sure. Dr. Wittington talk on that?

Sure. Well, make other stressed cells, right? And when it binds to its counter receptor NKG2D on effector cells, that's a pathway for killing. The screen looks like it's buffering. Are you hearing me okay?

We can hear you.

Okay. So that's how it normally works. And NKG2D is expressed on cells in the innate immune system and the adaptive immune system. So NK cells, NK T cells and also CD8 positive T cells importantly. What happens with cancer is cancers have learned how to cleave and shed soluble MICA. So that does 2 things. That soluble MICA essentially serves as a decoy -- And if you think about an effector cell coming in and binding either soluble, MICA or MICA on the surface of a cancer cell, there's nothing to kill that's soluble, so it's essentially acting as an immune suppressive decoy. What our molecule is designed to do, 619, is to inhibit that shedding mechanism, right? And that does a couple of things. It prevents elaboration of that decoy. So it takes away that -- it's intended to take away that immune suppressive mechanism. If it's not being shed, there's more of it on the surface, more of it to be detected, bound to and service a mechanism to kill, right? The target cells and the tumor cells. And then in addition, CLI-619 because it's an antibody with an FC, mediates ADCC. So it's bringing together 3 mechanisms in concert to drive an effective innate immune response.

And how does 619 compared to other programs that are targeting MICA/MICB?

With this type of approach, we are aware of other assets preclinically. The major difference at this point appears to be the ADCC component of the antibody, it doesn't appear that the other antibodies have much contribution from an ADCC perspective. But to be frank, there hasn't been a lot published on that just quite yet. So we'll see. But the differentiation at this point really is the fact that we're the first, and we're testing, frankly, some unknown biology. With that said, it's terribly exciting, a whole new pathway. If you think about it, Jon mentioned it before, but MICA resides essentially on -- essentially all cancer cells. And it's a stress release mechanism that presents itself, interestingly enough, postchemo and postradiation. So there's a number of different avenues that we can take to develop this molecule. We hope to see single-agent monotherapy type of responses. With that said, it also has the ability to be combined with PD-1 not just because we wanted to combine with PD-1, but there's actually a mechanistic rationale in terms of engaging in the adaptive immune system. And at the same time, looking where PD-1s have gone with the chemo, it also makes sense to combine this with chemo given the actual increase of MICA/MICB shed post chemo or radiation. Jon, anything else that you'd add there?

No. I mean I think that -- I think the key points are, once again, it's expressed in so many different tumor types, and there's retrospective data in the clinic showing that overexpression -- or high elevated levels of soluble MICA in circulation are associated with adverse clinical features. So we think it speaks to the importance of this pathway, and something we can target with a variety of different combinations as well as monotherapy.

What I can say, Jeff, is that if we do have a single-agent activity, we'll be the happiest sailors on the sea. Because that's just going to open up an enormous amount of opportunity for us to actually develop this drug across a whole range of first solid tumors. Interesting enough, we also have some very interesting data in some liquid tumors. And so you could really see this be a very nice beachhead across a whole host of cancer indications.

And can you remind us when we might see initial data?

I think -- I'm going to guess. It's going to be in the second half of next year. We can give people a better update once we understand the cadence of the enrollment. Our hope is that, with the sites that have signed on thus far, and the excitement around the program, we can go relatively quickly in a very innovative design that Jon was responsible for. As I said, once we get into early next year, we'll probably have more definitive timing for everyone.

Okay. Great.

Just building on that, I think one thing we didn't touch on is, Jon, would you mind walking us through the trial design and kind of the monotherapy in combination modules?

Sure. As I mentioned, this being a potent inducer of innate in the Unity also having both what we think could well be direct and indirect effects on adaptive immunity, really speaks to the importance of actually your opportunity to combine with T cell-directed therapies. And so our trial is designed to do several things in the component of 1 study. Module A is monotherapy, dose escalation just like a conventional antibody. We'll break out into tumor-specific cohorts to characterize the initial efficacy in lung post-checkpoint inhibitor and cervical as well, either post or checkpoint or treatment naive. We can get into reasons for that later if there's interest. And then importantly, with a bifurcated design, we then, at the recommended Phase II dose, going to trigger module B, which will initially explore the safety of the combination of pembrolizumab with our drug and then break into a randomized comparison right out of the gate. It's not sized to answer a question statistically. It's an initial exploratory comparison. And then depending on what we see from a safety and efficacy perspective, we'll make a business judgment as to whether to resize it and answer your questions statistically as well. So we come out of this with monotherapy activity -- monotherapy safety and activity and then also, importantly, this combo approach with checkpoint inhibition, which we think mechanistically makes a lot of sense.

Great. Maybe moving on to CLN-617 what are the historical limitations of cytokine delivery? And how does 617 address that?

So there's no one better to answer that question than Jon, given he spent 15-plus years of his life working on this. So maybe, Jon, you can comment and I'll perhaps add a little bit afterwards.

Sure. Sure. No, thanks, Owen. So worked actually specifically on the IL-12, IL-2 combination for many, many years back in the NCI and moved it from our preclinical studies that showed profound synergy into the clinic actually. We know that it synergistically enhances both T and NK cell function and profound antitumor activity in preclinical models. In the clinic, much as was the case with IL-2 the risk-benefit profile was tough to navigate simply because, frankly, we knew a lot less than about managing these patients in the support of care about how to dose and schedule these regimens. And frankly, the field as a whole, absent IL-2 that got approved and certainly interferon that was approved, walked away from these cytokines because of the risk-benefit profile, we just did not compute and people didn't entirely understand how to develop them. So what's unique about this molecule is that it is intended to solve a lot of those problems. First of all, it's putting a highly active combination into 1 molecule because it also has an arm that's designed to enhanced collagen binding domain that's designed to enhance tumor retention. By delivering that molecule intratumorally, we should deliver that potent biology of IL-12 and 2 into the network, beginning to generate data showing that we can enhance the scope effect, so confer systemic community. Ultimately, with these drugs, the drug is it properly activated T cell, right? So once we get that going with this drug, you want to see that scope lift after you've got building data around that. So this solves a lot of issues in terms of feasibility, and we're excited about the biology that we're seeing so far. Owen?

I would just say what I learned from you, Jon, is that synergy comes in. And when you look at the data that we have thus far relative to others that are taking other approaches, whether it's being concerned about the alpha versus beta and the [indiscernible] realm or trying to use a masking technique is when you look at the amount of drug that actually is being delivered to the tumor microenvironment and that is staying there, in our approach relative to other approaches, we are multiples and multiples up higher. And to date, we've seen no adverse effects across various species from a safety perspective. And so I imagine that if you can deliver a higher amount of cytokine to the tumor microenvironment and keep it there, you ultimately can do what Jon said, which is you can induce the systemic vaccination, which essentially is 1 of the holy grails of drug development. And unlike a traditional molecule that needs to be dosed continuously, i.e., weekly or biweekly, our thought process, and what we've done preclinically to date is actually a much more shortened schedule. We're actually just giving this drug a couple of times and then stopping and letting the actual T cell effect take over. And if we're successful in doing that and showing that from a human perspective, I think there will be a paradigm shift. There's a -- certainly a negative connotation when people talk about intertumoral therapy. And yet if you just walk down the hall to the surgical oncology suite relative to the medical oncologist, you'll see a multibillion-dollar business. In fact, I read something last weekend, which is that 76% of all tumors in the United States today had some surgical approach to it prior to getting to medical therapy. And so I'm convinced that if we can actually show the data and really harness the power of IL-2 and IL-12. We potentially have a paradigm shift in our hands. And obviously, it won't happen until we show the data. But from a preclinical perspective, what we've shown thus far is very encouraging.

And speaking of data, updated preclinical data for the program are expected later this month. What should we expect to see from that data?

Jon -- I'll answer that question. But Jon, going to say -- sorry, you going to say something else relative to what I said?

No, I think you captured it.

Okay. So what you'll see, Jeff, is you'll see roughly 90% complete response rate across all animals, B16F10, MC30 and CT26 models. The essentially the cancer, we're just eviscerating these tumors. And so profound efficacy, very nice safety. For most of the models, we have -- these animals are gaining weight, slightly delayed relative to control, but certainly gaining weight over time. And at this point, it's a very nice risk to benefit balance. Of course, this is in various models. So we need to see what happens in humans. We understand that. But we're certainly very encouraged, and our hope is, is that we may have some additional data sometime early next year looking at this drug and in other species, perhaps 1 that's a little more relevant to humans. But net-net is that what we will show this week, later this week at the conference is among the best essentially cytokine data that we've seen preclinically.

Great. Maybe one last question. Are there any other programs in your pipeline that you'd like to highlight? Or are there any aspects of the Cullinan story that you think that either investors have underappreciated or maybe not focused enough of their attention on?

What I say is certainly not underappreciated, not to focus our attention. It's our responsibility to actually make them aware of it. So they're looking at many different companies. So what we need to do is we need keep our head down. I would point to one program that is starting to emerge. We're -- it's actually a cell therapy. It's a loan cell therapy inside of Cullinan today. It's going after a totally novel target. We have been made aware by our partner that it's actually one of the most potent human TCRs as they've ever discovered. Now we need -- and it's up to us to make sure that this is safe and that we have selectivity versus cancer versus normal cells. And our hope is that, towards the end of this year, perhaps early next year, we can shed some additional light on this particular program, which is called Cullinan J.

Great. Well, looks like we'll have to leave it there. Thanks so much for your time. Appreciate it.

Appreciate it. Thanks so much. Thanks, Jon.

Take care.