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

Great. Thanks, everyone, for joining us this afternoon. It's my pleasure to introduce our next presenter from Cullinan Oncology, Nadim Ahmed, Chief Executive Officer. With that, I'll pass it to you, Nadim.

All right. So good afternoon, everyone. First live presentation in 2 years. So thanks for keeping the audience small, easing me back into it. So let me start out by saying a couple of things about Cullinan Oncology. So we're a company that's dedicated to creating new standards of care through a very unique approach to the drug discovery and development process. Here are disclaimer slides, I will be making forward-looking statements. One thing you'll notice about our company is that we have a very broad and deep pipeline across multiple modalities, different indications, hematology, solid tumors and at various stages of development. And then the other thing I would add, when you look at each program, we have assets that, potentially at least, have the opportunity to be either first-in-class and/or best-in-class. Our lead program is CLN-081, which is targeting non-small cell lung cancer patients that harbor the exon 20 insertion mutation and CLN-081 is currently in Phase I/IIa study. We presented an updated data presentation in December of last year. And from the original ASCO presentation, we still see a very well-differentiated clinical profile. Of course, recently, we were very pleased to receive Breakthrough Therapy Designation, which for us was external validation of the differentiated profile that we're seeing in the clinic. In addition to CLN-081, we also have 2 additional programs that entered the clinic in December of last year. So we're very excited about that. We have CLN-049, which is a T cell engager targeting FLT3 in AML patients. And we also have the pan-cancer potential monoclonal antibody, CLN-619, which targets the MICA/B pathway. Both of these programs drive the immune activation as well as having a first-in-class potential. We're very fortunate, and I suppose even more importantly today to be a company that's very well capitalized. And so we continue to look for ways to deploy that capital to accelerate our internal pipeline and programs as well as continuing to in-source innovation where we can find it. Behind our clinic stage programs, 3 of whom I discussed with you just now, we also have a deep preclinical research program of 5 additional assets, 2 of which are currently in IND-enabling studies, and we plan IND submissions for those 2 molecules in the middle of next year. And we also continue to in-source innovations. I spoke about how we're deploying capital effectively as evidenced by a recent collaboration with Mount Sinai for their novel HPK1 degrader program. At Cullinan, we also take a very disciplined criteria based approach to in-sourcing innovation and advancing our internal programs. So first, the asset has to have the potential at least to be first-in-class and/or best-in-class. We look at molecules that activate the immune system or target key oncogenic drivers. And preclinically at least we have to see evidence of single-agent activity. So we use these criteria to really think carefully about in-sourcing assets as well as advancing programs within our internal pipeline. Also at Cullinan, we really innovate without borders. So we seek out the most promising clinic-ready assets either through our internal discovery efforts or through excellence in engagement with external partners. So you can see in the top panel of this slide in the top left, as you look at it, we also position our assets for very early, what we call thriller or killer experiment. This makes sure we're doing early derisking and only bringing the most promising assets forward into the clinic. We do have a constant flow of deals and opportunities that we look at, and we look at over 100 opportunities each year. And our team is very good at what I'd call scientific ideation. So taking something from the concept stage all the way from candidate selection and through to clinical stage development. We're a company that has very deep biologics and small molecule expertise. And we also leverage our business model efficiency. We're always looking at the optimal mix of in-house capabilities versus external capabilities as well. So when you look at the top right-hand corner of this slide, you can see what I mean within that context of small molecules and biologics, we have a very diversified pipeline of monoclonal antibodies, T cell engagers, fusion proteins, tyrosine kinase inhibitors and now also protein degraders. In the bottom panel on the left-hand side, you can see we also have a focus on unique platforms and novel mechanisms of action, where we often do a lot of engineering or reengineering of those molecules. And then across the broader oncology -- Cullinan oncology team, we have deep scientific expertise that allows us to -- all right, that allows us to really accelerate the advancement of our internal programs as well as tap into an external network of partners in academia and other industry partners. So the result of all of these efforts gives you this diversified pipeline that I'm showing you, 8 programs across various stages of development, so our lead program is CLN-081, which I spoke about earlier, targeting EGFR exon 20 mutations, a really important program for the company. But beyond CLN-081, we also have a very deep pipeline following behind. With 8 programs, as I mentioned, 3 now in clinic stage, 2 in IND-enabling studies and some other earlier preclinical assets as well. So we're very pleased with the diversification of our pipeline. So let me take a moment now to dig into CLN-081, our lead compound. CLN-081 is a novel oral EGFR inhibitor with a unique chemical structure. So that means it preferentially targets the mutant form of exon 20 versus the wild-type area. And we believe this contributes to the therapeutic profile that we're seeing in the clinic. As I mentioned, it's in an ongoing Phase I/IIa study in patients who have failed prior chemotherapy, heavily pretreated patients, 2/3 of whom have received 2 or more prior therapies. And you can see from this slide, the response rate data that we presented in December. So we see a confirmed response rate of 39%, which is at the upper end of agents in this space. We also see 35 or 36 patients who experienced either stable disease or partial response as their best response to elicit an excellent disease control rate of 97%. You also see the data for 150 mg BID. So at the higher dose, we actually, paradoxically, see a lower response rate. And I'll explain, but we feel that this is based on the tolerability profile that we see at the 150 mg BID dose. So what do I mean by that? So you can see on this slide, clearly, a differentiated profile at 100 mg BID dose. So in this table, you can see the key toxicities, especially those related to wild-type EGFR toxicity. And you can see in this slide that at the 100 mg BID dose, we see no cases of grade 3 or greater rash or diarrhea. And in fact, the rash or diarrhea we observed at this dose is heavily skewed towards grade 1 as opposed to grade 2 at a 3:1 ratio. So that's encouraging also. And in the protocol, there was no requirement for systemic GI prophylaxis. At the 150 mg BID dose, you do see a step-up in toxicity. So in fact, we discontinued enrollment into that cohort after 11 patients. And you can see, we saw 2 episodes of Grade 3 diarrhea. We saw pneumonitis, I'll come back to that. Then we saw Transaminitis at both Grade 3 and Grade 4. So you see that step-up in toxicity as you go from 100 mg to 150 mg. And just as importantly, you see a significant increase in the rates of dose reduction as well as treatment discontinuation at the 150 mg dose. And this is where we think it's contributing to the efficacy profile where we have seen a lower response rate. And let me just say a word about the pneumonitis observed to date. Obviously, a toxicity that has been seen with this class of agent. But in both of these cases, there were additional confounding factors, which you can see in the footnote here. So in the first slide, I spoke about quantity of response, that 39% confirmed response rate. What we're really encouraged by based on the December data update, this is the first time we were actually able to assess durability. This was in the initial 13 patients that were enrolled in Phase I. And what we saw based on Kaplan-Meier estimate is a median duration of response of greater than 15 months and a progression-free survival -- median progression-free survival of 12 months, which again, compares very favorably with the durability of our other agents approved in this class or in the clinic currently, a very robust disease control rate of 92%. And we're also following on -- or following up the other patients in the Phase II cohort who were enrolled later on, and hopefully, we'll be presenting those durability data later on. So as I mentioned, Breakthrough Therapy designation was really important for us on 2 counts: one, as I mentioned, it provides external validation of our differentiated profile. It also demonstrates that the accelerated approval pathway is still open to us. So we were really pleased to receive that. And we are planning a regulatory update this month. So I would say, in summary, the data continues to show that we have a very strong differentiated clinical profile, both in terms of efficacy, with quality and quantity of response and a favorable safety profile in a heavily pretreated group of patients with a significant unmet need. So let me now turn to our other clinic stage assets, and I'll start with 049. As I mentioned earlier on, this is a novel T cell engager, which targets FLT3 in AML patients and is currently in a Phase I study. Let me start with the design of this molecule. In fact, the chap that designed this molecule is sitting here in the front row. So if you have any questions you can ask him afterwards. So CLN-049 is based on an IgG1 construct, the same construct that we've actually seen with some of the newer T cell engagers in lymphoma, where we're seeing high levels of activity and lower levels of CRS related toxicity. We also have an Fc-silenced region in this molecule. So that gives you a prolonged half-life, which hopefully should allow less frequent dosing. Let me spend a couple of minutes on the target now. FLT3 is a proto-oncogene, and it's a very well-validated AML target. As you can see by the approved small molecules in this space. FLT3 is expressed in the majority of AML patients, but with relatively low expression in healthy myeloid cells. So the advantage that we have with 049 as a potential first-in-class antibody targeting FLT3 is that we target the extracellular domain of FLT3. So that means we target both mutant and wild-type FLT3. So that means you have a much large addressable patient population of over 80% of patients compared to the 25% of patients who have mutant FLT3 that are targeted by the current small molecule, tyrosine kinase inhibitors. Also, as I mentioned, relatively low expression healthy myeloid cells, which means 049 should have a better therapeutic index than some of the other targets like CD33 and CD123. Now as I mentioned, 049 is currently in Phase I dose escalation, and we hope to have clinical data provided by the middle of next year. In the next slide, you can see the robust preclinical package we have generated with 049. In the top panel, turning to the left, you can see in a range of AML cell lines that express both wild-type and mutant FLT3, we see significant eradication of those tumor cells in vitro. And on the right panel, you can see compared to CD3 control antibodies, we see no activation of T cells with 049, which portends, potentially for a favorable safety profile in the clinic. In the bottom panel, you can see the efficacy data that we're seeing preclinically. In the bottom left, you can see a nice dose response survival curve in the tumor xenograft model, even at very low doses of 049. And on the right-hand side, we actually transfected AML blast -- human AML blast into a rodent model, and we saw complete eradication of those cells in the bone marrows of rodent. So we're very excited about 049. And as I mentioned, it's currently in the clinic. Our other clinical stage asset is CLN-619, which again is another potential first-in-class opportunity, a pan-cancer opportunity since MICA/B ubiquitously expressed across various tumors. So starting with MICA/B, it is a ligand for the NKG2D receptor on all NK cells and a subset of T cells. So what happens is in stress cells and tumor cells, you see an upregulation of MICA/B, which then sends a kill-me signal to the immune system, especially NK cells, inviting tumor cell destruction. But what happens, as we know, cancer is very clever. So within that tumor microenvironment, you often see proteolytic cleavage which causes the MICA/B to be shed from the cell surface so those tumor cells are able to evade the immune system. Shed MICA/B is also a poor prognostic market, and I'll show you that in the next slide. So as I mentioned, we have a first-in-class opportunity here. 619 is the first clinical stage MICA/B antibody with multiple modes of action. So I just described how MICA/B is shed on the cell surface to evade the immune system. 619 keeps MICA/B on the cell surface when it binds. So that draws in the immune system, especially NK-directed activity. But when it's bound to a cell, it also binds the FC gamma receptor on NK cells. So it has a mechanism of action through ADCC. So when you combine these mechanisms of action as well as additional mechanisms of action, you're really invoking both the innate and adaptive immune system in patients. So we're very excited about this molecule, especially the potential for pan cancer opportunity. And with 619 specifically, we have very good coverage of the MICA/B alios of over 95%. We're in an ongoing clinical study, as I mentioned, in Phase I. And at the same time, we're evaluating monotherapy with 619 as well as combination therapy with checkpoint inhibitors. And we plan to have data provided by mid-2023 next year. The next slide shows both the biological and clinical rationale for MICA/B. So starting with the top panel upper right-hand corner, you can see in a range of -- in a range of NKG2D ligands, MICA/B is more highly expressed and across a range of different tumors relative to the other ligands. And so again, there is that a pan cancer potential, as I mentioned earlier. In the top left, you can see how shed MICA is a poor prognostic marker. So in this analysis -- retrospective analysis of clinical study, you see patients that have a high level of shed MICA have a much poorer survival outcome. In the bottom panel, you can see the preclinical work we've done with 619 already. In the left graph, you can see complete tumor eradication at all doses for 619 tested. And on the right graph, from a pharmacodynamic perspective, you can see at all doses of 619, we see the complete prevention of shed MICA/B. Again, very excited about this program with clinical data middle of 2023. So let me now turn to our preclinical pipeline and speak specifically about our 2 IND-ready assets. 617 is our first-in-class cytokine therapy which is the fusion protein containing both IL-12 and IL-2. So beta cytokines that are well described in the literature that have potent antitumor activity. However, the issue with these cytokines is that historically systemic administration has led to significant toxicities. What we're doing is applying intratumoral administration with 617. So this fusion protein allows the co-delivery of IL-12 and IL-2. We also have a collagen binding domain that allows the cytokines to stay within the tumor, so prevents the leakage out into -- beyond the tumor to prevent systemic toxicities. And most importantly, we do see preclinically at least, and we'll see the results in the clinical experiments, both memory T cell response induction as well as an abscopal effect. So showing effects beyond the site of tumor injection. The interesting thing about this molecule is that we are delivering the wild type version of the cytokine. So we would expect to see reduced immunogenicity. And also, there's no reliance here on viral mechanisms of nucleic acid delivery system. So we're really able to control the dose that gets into the tumor. So for us 617 presents a pan-cancer opportunity either as monotherapy and as I'll show you, also in combination with checkpoint inhibitors. So in this slide, you'll see the very robust clinical -- preclinical package that were generated to date. So let's start with the top panel. In the top left corner, you can see a very refractory primary tumor xenograft model where essentially the administration of 617 in the tumor provides complete response in each of the 10 mouses tested. Mouse -- I should say mice, sorry. This has come from someone born in London. Okay, so we see complete eradication of the tumors with complete responses. You see a very weak signal with checkpoint inhibition as monotherapy, but even more interesting is when you take these cured mice and you reinject them with tumor without treatment, you see 9 out of 10 of these mice completely reject the tumor. And then in one case, you see significant delay in progression. So here, you're seeing a really strong T cell memory effect. In the bottom panel, starting to the left side, what we did here, we transfected 2 tumors into a mouse model system in vivo. On the left-hand side, you see the administration of checkpoint inhibitor monotherapy, the administration of 617 monotherapy and the administration of the combination. So with 617 monotherapy and the combination, you see complete eradication of tumor at the injected site. However, the more exciting aspect of this study is in the uninjected tumor sites, you see significant reduction or tumor eradication with 617 as monotherapy but even more interestingly, the combination of 617 plus checkpoint inhibitor completely eradicates tumor. This is why we're very excited about this program and hopefully entering the clinic next year. The last molecule I'll speak about is CLN-978, which is our T cell engager, which we believe has the potential to be a best-in-class T cell engager targeting CD19. I mean clearly, CD19 is a very well-validated target, both clinically and now commercially with the CAR-T agents as well as T cell engagers approved in this space. But what we did here is we really looked at the design of the antibody. So we engineered it to have a very long half-life to again allow for less frequent dosing, including continuous infusion. And also, engineers have very high affinity for CD19. So it's able to be active in very low CD19 expression setting. Why is that important? Well, if you look at current patients, for example, treated with CAR T, one of the resistance mechanisms we think is taking place is the down regulation of CD19. So you can imagine a scenario where you will be able to salvage patients in the post CAR-T setting with this agent. In other settings, potentially you could see the activity of CAR-T in an off-the-shelf treatment, which then, of course, opens up a much bigger pool of patients to receive treatment 978. We also think 978 could be competitive relative to CD19 target ADCs, where you need a higher level of antigen expression in order to be able to safely deliver the payload. And then if you look at the bottom right-hand corner of this slide, we did a head-to-head in vivo study, looking at 978 versus a currently approved CD19 monoclonal antibody and demonstrated clear antitumor activity. So we're really excited to take 978 also into the clinic and with an IND submission planned in the first half of next year. So let me just say, 2021, despite COVID-19 has been a really busy year for Cullinan Oncology. We have made various achievement of various milestones and progressed our pipeline. Starting with CLN-081, as I mentioned, we updated the Phase IIa data in December of this year. We recently received Breakthrough Therapy designation with CLN-049, our FLT3 targeted AML agent. We started a clinical study in December, 619, our MICA/B antibody, again, into the clinic in December. And with 617 and 978, we continued our progression along the IND-enabling study part. So over the next 18 months or so, starting from CLN-081 this month, we'll have a regulatory update. We'll also plan to start our pivotal registration study this year. With 049, we expect the clinical update mid-2023 and the same with 619. As I mentioned, these are studies that just started in December. So we're continuing to accrue patients and gather the clinical data. And we also are looking at getting 617 and 978 into the clinic next year. So a significant number of value-creation milestones over the next 18 months. If all goes well, we'll have 5 highly differentiated molecules in the clinic, which reflects our evolution into a later-stage oncology company as well as our ultimate ambition to become an end-to-end fully integrated biotech company. So the progression of our pipeline, I think, really represents significant value opportunity for our investors, but most importantly, will help us to deliver on the promise of bringing new therapeutic solutions to patients with cancer. And in closing, I'd like to say and really thank my teammates at Cullinan Oncology, who have shown relentless dedication to their work, especially during this global pandemic. I'd also like to thank my colleagues at Barclays who have created this opportunity for me to share the very exciting story of Cullinan Oncology. And with that, thank you for your attention, and I'm happy to take any questions. Okay. Great. Thank you very much. We'll be around in the room if you have any questions one on one. Thanks.