Welcome to the Morgan Stanley Global Healthcare Conference. I'm Jeff Hung, one of the Biotech Analysts. For important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. For this session, we have from Cullinan Oncology, Chief Executive Officer Owen Hughes, and Chief Financial Officer, Jeff Trigilio. Welcome. Thanks, Jeffrey. For those who may not be familiar with Cullinan, can you provide a brief introduction? Sure. Thank you very much for that introduction, and happy to participate in the conference. 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 an operational arm. Our goal is to seek unique assets from across the globe. Generally speaking, assets that are 6 - 12, 18 months from an IND, and shepherd those assets from preclinical development into early clinical development. Upon successfully achieving proof of concept, to determine the best route to maximization or monetization for those assets and to maximize the assets or the value of the assets for shareholders. Our goal at this point isn't necessarily to become a fully integrated company, but to continue to actually churn this wheel, so to speak, in finding new assets, bring them through the development engine, and then trying to maximize our returns for shareholders, and then ultimately increase value both through equity appreciation as well as return of capital. Great. 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. I'm sure many of us have taken the CFA, spent some time in monetary class, economics classes, and have learned a bit about portfolio diversification just looking at our 401(k). 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. 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. That's why at any given time, we're trying to work on 6-8 assets. At this point in time, we have three assets that are in the clinic today. I'm sure one or two of those may not work. Our goal is to make sure that we can supplement that or complement those assets with other assets that we're working on preclinically, such that we have one or two assets in the clinic at each and every time. Those assets themselves are very distinct from one another. Your lead program, CLN-081, is an EGFR inhibitor. How does that asset compare to other EGFR inhibitors? Yeah. I may actually have Dr. Wigginton comment on that. Jon has many years of experience in the oncology field, and having treated patients and understanding the differences, I think he may be best to answer that question. Sure. 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. 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. We see rash commonly, we've not seen grade 3 rash. With respect to diarrhea, unlike competitor molecules that have been seen in some cases 80%-90% all grade and 25%-30% grade 3 or greater, we've only seen 22% all grade and a single case of grade 3 diarrhea at our upper highest dose level tested to date. Paired with that, we're seeing very encouraging activity across the entire dose range tested, across a spectrum of different exon 20 mutational subtypes, and in patients post who've been treated with other exon 20 EGFR inhibitors, and in patients who've been treated with other EGFR inhibitors or with prior immunotherapy. All in all, we're very encouraged by this profile. This is a oral molecule. It's differentiating nicely so far compared to the other EGFR TKIs in this space. We're very encouraged by that profile. Ami is obviously out there and approved. It's an IV drug given weekly times four, followed by every two weeks, has infusion reaction signal, et cetera. 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. How do you view the DZD9008 data, and what advantages do you think 081 has? Sure. Go ahead, Jon. Yep. Yeah. 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% 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's been some evidence of some early cardiac signal, which we don't have a lot of further insight on at this point. It does have a response rate that's in the 40%ish range, depending on the patient group that you're talking about. 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 in a way that's differentiated from what we're seeing so far with those out. Owen, you want to add anything to that? I just think with that in mind, as we think about the development of any 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. There we have a lot of confidence that our drug can achieve a meaningfully different profile relative other molecules in the space. Obviously, we need more data to confirm the hypothesis, but to date, what we've seen is very encouraging. 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. Yeah. In the fourth quarter, what we'd like to do, Jeff, is provide, at the same time, a clinical and a regulatory update. 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. 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 a 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 to see 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 N to 13. Our hope is that we can provide some additional information at that dose. I think, really, there's two 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. At the same time, if our hunch comes to fruition, which is that we will have a clear delineation in safety between 100 and 150, I think that'll be very beneficial for our discussions with the agency, and at the same time, nailing down the recommended phase II dose. 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 mg? Yeah. 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 swimmingly well. The Delta variant hit. Things honestly have slowed down in conjunction with the end of the summer. 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 read for you guys on the 3rd quarter comes around, third quarter earnings. Okay. Beyond the current exon 20 program, what other indications can you pursue with this program? Yeah. Do you want to touch on some of them, Jon? I'll touch on a few. Sure. Well, let me just break it down. 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 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? I'll just say, the drug is probably as potent, if not more potent than TAGRISSO in some of the traditional sensitizing mutations. Obviously, we'd be very naive to think that we can compete with TAGRISSO given the beachhead that is established and the revenue that it has. In certain TAGRISSO 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. 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 get this drug out of the exon 20 landscape. To date, we're confident that that's happening. Great. We have a question coming in from the audience. Are you enrolling any patients previously treated with amivantamab? We have not to date. Okay, great. Likely will not just based on the existing protocols that we have. When we started the phase I study, we did allow prior TKIs. I don't remember the specific number that had prior TKI, not pozi, not TAK-788. It's roughly 20%-30%. Yeah. Was that number about? Yeah. 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 prior exon 20. We had a small number of those patients, as I just mentioned. Yeah. 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's 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. That's a bispecific antibody. What are the limitations of current FLT3 inhibitors, and how is 049 potentially better? Sure. 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. 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 the FLT3. With that said, 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. We're starting at a relatively low dose, and we'll dose escalate over time. I'd say that's the key differences, intracellular versus extracellular and the attainment of the T cell rather than just FLT3 itself. Jon, would you comment anything else there? No. I think you captured it. Okay. Can you highlight maybe some pieces of the data that give you confidence in your approach? Sure. We've looked at a number of preclinical models, similar to what others have done. 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, the Amgen molecule. It was an Amgen BiTE molecule. Actually, there was also a FLT3 CD3 that came out of Rinat in San Diego from Pfizer. We've essentially all done very similar preclinical models, looking at longevity over time. I'd say that we all have a pretty similar data. I think it'll come down to safety and what type of TI we can establish relative to the other molecules. Anything else, Jon or? No, the only thing I'd add, Jeff, as opposed to the differentiation versus other FLT3 molecules is FLT3 itself. The rationale for our bispecific approach as relative to other bispecific approaches is FLT3 is, the expression is limited to the myeloid compartment, and so hopefully that helps us with the TI window that we expect to see in the clinic. Yeah, I think there was, early on as people looked at antibodies for AML, Jon actually developed 1 of these molecules. Most people gravitated to the CD123 and CD33. Our hypothesis is that targeting FLT3 may engender a larger TI, but obviously that remains to be seen. We're going to go test that in the clinic and see what happens. Great. Maybe moving on to CLN-619, that targets MICA and MICB. How do tumor cells use that as evasion mechanism? Sure. I'll have Dr. Wigginton talk on that. Sure. Well, MICA is normally overexpressed in malignant cells and in other stressed cells, right? 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. Yep. Okay. All right. That's how it normally works. NKG2D is expressed on cells in the innate immune system and the adaptive immune system. NK cells, NKT cells, and also CD8 positive T cells, importantly. What happens with cancer is cancers have learned how to cleave and shred soluble MICA. That does two 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 if it's soluble. It's essentially acting as an immune suppressive decoy. What our molecule is designed to do, 619, is to inhibit that shedding mechanism, right? That does a couple of things. It prevents elaboration of that decoy, so 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 serve as a mechanism to kill, right, the target cells and the tumor cells. In addition, CLN-619, because it's an antibody with an Fc, mediates ADCC. It's bringing together three mechanisms in concert to drive an effective innate immune response. How does 619 compare to other programs that are targeting MICA and MICB? Well, we are the first into the clinic 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. To be frank, there hasn't been a lot published on that just quite yet. We'll see. 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, MICA resides essentially on essentially all cancer cells. It's a stress release mechanism, that presents itself, interestingly enough, post-chemo and post-radiation. 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 want to combine with PD-1, there's actually a mechanistic rationale in terms of engaging the innate and adaptive immune system. 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 either chemo or radiation. Jon, anything else that you'd add there? I think the key points are, once again, it's expressed in so many different tumor types. There's retrospective data in the clinic showing that overexpression or high elevated levels of soluble Notch gain in circulation are associated with adverse clinical features. 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 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. Interestingly 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. Can you remind us when we might see initial data? I'm going to guess it's going to be in the second half of next year. We can give you 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 and combination modules? Sure. As I mentioned, this being a potent inducer of innate immunity, 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 -directed therapies. Our trial is designed to do several things in the component of one 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. Importantly, with a bifurcated design, we could, the recommended phase II dose is going to trigger module B, which will initially explore the safety of the combination of pembrolizumab with our drug, break into a randomized comparison of pembro with or without CLN-619 right out of the gate. It's not sized to answer a question statistically. It's an initial exploratory comparison, 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 a question statistically as well. We come out of this with monotherapy safety and activity, also importantly, this combo approach with checkpoint inhibition, which we think mechanistically makes a lot of sense. Great. Thanks. Maybe moving on to CLN-617. What are the historical limitations of cytokine delivery, and how does 617 address that? There's no one better to answer that question than Jon, given he spent 15+ years of his life working on this. Maybe, Jon, you can comment, and I'll perhaps add a little afterwards. Sure. No, thanks, Owen. As you know, cytokines have been around for a long time and 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 then about managing these patients in the supportive care, about how to dose and schedule these regimens. Frankly, the field as a whole, absent IL-2 that got approved and certainly interferon was approved, walked away from these cytokines because of the risk-benefit profile. It just did not compute, people didn't entirely understand how to develop them. 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 one molecule because it also has an arm that's designed to enhance a collagen binding domain that's designed to enhance tumor retention. By delivering that molecule intratumorally, we should deliver that potent biology of IL-12 into the tumor, and then our preclinical studies to date show already that we're beginning to generate data showing that we can enhance an abscopal effect, so confer systemic immunity. Ultimately, with these drugs, the drug is a properly activated T cell, right? Once we get that going with this drug, you want to see that abscopal effect, and we've got building data around that. 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've learned from you, Jon, is that IL-2 and IL-12 essentially upregulate one another. That's where the clear synergy comes in. 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 in the IL-2 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 higher. To date, we've seen no adverse effects across various species from a safety perspective. 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 one of the holy grails of drug development. Unlike a traditional molecule that needs to be dosed continuously, i.e., weekly or biweekly, our thought process and what we've done pre-clinically to date is actually a much more shortened schedule, where we're actually just giving this drug a couple of times and then stopping and letting the actual T cell effect take over. If we're successful in doing that and showing that from a human perspective, I think there will be a paradigm shift. There's certainly a negative connotation when people talk about intratumoral therapy, and yet, if you just walk down the hall to the surgical oncology suite relative to the medical oncology suite, you'll see a multi-billion-dollar business. In fact, I read something last weekend, which is that 76% of all tumors in the United States today have some surgical approach to it prior to getting to a medical therapy. 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 on our hands. Obviously, it won't happen until we show the data, but from a pre-clinical perspective, what we've shown thus far is very encouraging. Speaking of data, updated pre-clinical data for the program are expected later this month. What should we expect to see from that data? Jon, well, I'll answer that question, but Jon, were you going to say I saw your mouth moving. Were you going to say something else relative to what I said? No, I think you captured it. No? Okay. What you'll see, Jeff, is you'll see roughly a 90% complete response rate across all animals, B16-F10, MC38, and CT26 models. Essentially, the cancer, we're just eviscerating these tumors. 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. At this point, it's a very nice risk-benefit balance. Of course, this is in various models, so we need to see what happens in humans. We understand that. We're certainly very encouraged, and our hope is that we may have some additional data sometime early next year looking at this drug in another species, perhaps one that's a little more relevant to humans. The net is that what we will show this week, later this week at the conference, is among the best cytokine data that we've seen pre-clinically. Great. Maybe one last question. Are there any other programs in your pipeline that you'd like to highlight? 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 focused their attention. It's our responsibility to actually make them aware of it. They're looking at many, many different companies. What we need to do is we need to keep our head down. I would point to one program that is starting to emerge where it's actually a cell therapy. It's a lone 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 that they've ever discovered. Now it's up to us to make sure that this is safe and that we have selectivity versus cancer versus normal cells. Our hope is that toward the end of this year, perhaps early next year, we can shed some additional light on this particular program, which is called Cullinan Jade. Great. Well, looks like we'll have to leave it there. Thanks so much for your time. Appreciate it. Appreciate it. Thanks so much. Have a good one. Thanks, Jon. Take care.