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 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 Nadim Ahmed, CEO of Cullinan Oncology. Welcome, Nadim.

Good to be here, Jeff.

So for those who may not be as familiar with Cullinan, can you just provide a brief introduction.

Sure. Yes. So we're a company that takes a very unique approach to the discovery process, which we call modality-agnostic targeted oncology. So that means we start the discovery process by identifying high-impact cancer targets. -- and then deciding on the right vehicle to prosecute those targets. So in other words, for us, it's target first modality second, not the other way around, which you see with many of our peers. So that means, as a company, we're not contingent or dependent on a singular platform or even a singular product. So that's one thing. Secondly, we have a very high bar in terms of go, no-go criteria. So we front-load as much experimentation as possible as early as possible through what we call thriller or killer experiment. So if we get the killer result as the name suggests, we kill the program, move on, reallocate our resources. If we get the thriller result, then we think about how can we accelerate this program, how can we increase the investment. And so by doing this, we make sure that we only take the most promising, highly differentiated molecules into the clinic so that we can deliver on our mission to create new standard of care for patients of cancer. So that's kind of the theoretical construct. And I would offer 2 proof points to say this is working. So if you look at our pipeline today, we have a very diversified pipeline across targets, across modalities, across solid tumor and hematology all programs have the potential to be first or best in their class, which is important for us. And also in about 18 months, we've gone from 1 program in the clinic to this year, 6 programs in the clinic, which is a remarkable execution by the team as we've evolved from a research-based company to now a development stage organization and ultimately our goal of becoming a commercial stage biotech company. And then the final point I'd add, we're very fortunate to have a very robust cash position, which gives us runway into 2026, and the opportunity to create multiple value creation milestones over that period of time.

Great. Maybe let's start with zipalertinib, which is partner with Taiho. How is that differentiated from competing treatments? And how does it fit into the treatment landscape?

Sure. Look, the first thing I would say is that exon 20 non-small cell lung cancer is still a disease with a very high unmet need. So if you look at even in the frontline setting, today, platinum chemotherapy, which is a standard of care, produces a medium progression-free survival of 5 to 6 months. Checkpoint inhibitors don't seem to work in exon 20 disease or EGFR disease broadly. And then coming back to your question, Jeff, -- we have 2 agents already approved in the relapse setting, but we feel that there's still plenty of room for opportunity based on the observed clinical profile of those agents. So if you think about a drug like amivantamab, which is a good drug for the disease. You have an IV therapy, prolonged infusion times. We still see some of the wild-type EGFR-related toxicities we see a higher rate of infusion reactions, almost 2/3 of patients. So we think there's opportunity there for us with mobocertinib, you see quite a high rate of wild-type EGFR-related toxicities like rash and diarrhea. And so when you look at the clinical profile of zipalertinib, which we still believe has the potential to be best-in-class. We have a response rate of 41% that we saw in the Phase I/IIa study, which is at the upper end of the response rate we see with currently approved agents. We have a median progression-free survival of 12 months, which is favorable to the 7 to 8 months we've seen with the currently approved agents. We've shown activity in prior exon 20 treated agents, which I think is important for us. And in terms of the safety profile, again, all at the 100 mg BID dose, we don't see the typical Grade 3 and above wild-type EGFR-related toxicities like rash and diarrhea. So I would say in summary, we have an efficacious molecule at the upper end of efficacy that we see with current approved agents, a favorable safety profile, all combined with the convenience of an oral therapy.

Now last month, you and Taiho announced the start of the Phase III combination study. Can you just talk about the study and what you need to see for the study to be considered a success?

Sure. So the study is a randomized study, starting with a lead in safety phase, comparing the combination of zipalertinib plus chemotherapy-based treatment versus chemotherapy alone. And the primary endpoint is progression-free survival. Earlier, I said in the upfront setting today with platinum-based chemotherapy, we're seeing a meeting progression-free survival of 5 to 6 months at best with most series -- as I mentioned, zipalertinib in the second-line plus setting, we've seen a progression-free survival benefit of 12 months median progression-free survival. So we feel pretty confident that the combination of zipalertinib plus chemotherapy has the opportunity to have a significant improvement over chemotherapy alone, and we look forward to execution and ultimate reporting out of that study.

And for your Phase IIb study, can you just remind us like how enrollment is going in that study?

Sure. So our pivotal relapse study started at the end of -- at the end of Q4 2022, enrollment continues. And the study design actually is very similar to the approved agents. Amivantamab, mobocertinib, where we have about 100 patient study, primary endpoint of over-response rate, duration of response, single-arm study aiming for accelerated approval. As I said, enrollment continues. And so, we feel pretty good about where we are with that study and we look forward to reporting out those results.

Great. Let's shift to CLN-619. Can you just remind us the mechanistic rationale behind targeting MICA/B as a pan-cancer approach.

Sure. So MICA and MICB are both ligands for the NKG2D receptor that you find on NK cells and subsets of T cells. In a normal situation, you don't see the upregulation of MICA, MICB on normal cells. However, when cells undergo stress conditions like viral infections, like malignant transformation, you see an upregulation of MICA, MICB. What happens then is that those cells tend to kill me signal to the immune system so that the NK cells and subsets of T cells can come and destroy those cells. What happens in the situation of cancer is that proteases in the tumor microenvironment actually cleave MICA and MICB off the cell surface. So that's a way that the tumor can evade the immune mechanism again. What 619 -- CLN-619 does, it binds to and stabilizes MICA and MICB on the cell surface of those tumor cells, which then become visible to the immune system again and get flagged for destruction. And it works in multiple ways. And so through binding to the CD16 receptor on NKG2D cells, we see ADCC, ADCP, CLN-619 also enhances the direct interaction between NKG2D as well as the MICA, MICB interaction. And so you see that CLN-619 actually activates both the innate and adaptive immune system. And so for us, that bodes well from a development perspective in both monotherapy combination therapy. And then the other thing that's exciting about this program is that it has the opportunity at pan-cancer potential since MICA and MICB ubiquitously expressed across a range of solid tumors and hematologic tumors.

Great. Now at ASCO you reported initial data, can you just remind us what you saw.

Sure. So we have an ongoing Phase I dose escalation study, investigating CLN-619 as a monotherapy and in combination with pembrolizumab. So at ASCO, we were excited to report the monotherapy portion of that study, where we saw a single-agent activity. So we saw 3 objective responses at -- starting at the 3 mg per kg dose of CLN-619. So we saw a complete response in a patient with parotid gland cancer, and we saw 2 confirmed injective partial responses in endometrial cancer patients. So that got us excited about the program. And 2 of those 3 responses are in patients who had progressed on previous checkpoint inhibitor therapy. All of those responses were ongoing at the time of data cutoff. So that was very interesting for us. The other thing I'd say about the responses that we observed are that, each of these responses and CLN-619 were better than the responses these patients experienced on their prior therapies. So for example, the complete response we saw in the parotid gland in cancer patient, that patient had experienced the best response of partial response on prior checkpoint inhibitor therapy, but consequently experienced complete response, or subsequently on CLN-619 with the 2 endometrial cancer patients. One of those patients experienced the best response of stable disease on a combination regimen of checkpoint inhibition and lenvantinib. The other endometrial cancer patient, she didn't experience any sort of benefit on her 5 prior therapies. Both of those patients experienced a partial response on CLN-619, which for us was very exciting. The other thing that was interesting about this data set is, we did start to see a pattern of gynecological malignancy activity. So in addition to the 2 endometrial cancer responses, we saw prolonged stable disease, 3 of those in cervical cancer patients, 2 in ovarian cancer patients. So there was an early signal of gynecologic malignancy activity, but it wasn't limited to that. So we also saw a prolonged stable disease in a breast cancer patient, in a patient with salivary gland cancer. So it just showed that 619 has the opportunity to work across a range of different tumor types. And so obviously, we're very excited about the data that we saw at ASCO.

And what should we expect to see an initial combination data? And do you have a sense for when that might be?

Sure. So the thing to point out there is we took this parallel development path on monotherapy in combination therapy. However, the combination therapy was staggered because we had to establish some safety of monotherapy first before we could start the combination therapy. So those data will be forthcoming. We haven't disclosed when yet, but it will be at a future medical meeting.

And you talked about this parallel structure, but I guess, how are you thinking about the future development of 619?

Sure. So post ASCO, based on the monotherapy signal that we saw, we already declared monotherapy expansion cohorts in both cervical cancer and endometrial cancer. So other expansion cohorts will follow based on the signal we see both in the monotherapy arm as well as the combination therapy arm. So I think there's plenty of opportunity there. And then Jeff, I'll take just 1 example of endometrial cancer. There, we have a situation where we have a very clear regulatory path. And what I mean by that is in endometrial cancer, currently checkpoint inhibitors are the only approved therapy in the relapse setting. Those agents now, for example, the recent approval of dostarlimab in combination of chemotherapy and moving up into the upfront setting. So that leaves a very large and growing pool of relapsed patients, for which CLN-619 could enter a very clear regulatory pathway. So you have the potential to gain accelerated approval with a single-arm approach. And that would unlock a significant both clinical and commercial opportunity for us. But that's just 1 example of what we've seen early that can lead to a very clear path for regulatory approval and commercialization.

Great. Let's move to CLN-049. What are the limitations of current FLT3 inhibitors? And how is 049 differentiated?

Sure. So the first thing I would say is, look, now FLT3 is both a clinically and commercially validated target with now 3 tyrosine kinase inhibitors approved in that setting. The other point I would make is where CLN-049 is different to the tyrosine kinase inhibitors, remember, they target only the mutant form of FLT3, which is about 30% of patients. With CLN-049 -- because it binds the extra cellular domain of FLT3, it means basically it's agnostic to mutational status. So we can target both wild-type and mutant FLT3, which opens up about 80% plus of patients. So a much bigger patient pool also as a T cell engager compared to some of the agents in development that targets CD33, CD123. For us, FLT3 is a target that has a potentially broader therapeutic index because it's relatively highly expressed in blast cells compared to normal myeloid cells, for example. So that will be another aspect. And then in addition to blast cells, FLT3 is also expressed in pluripotent stem cells. So we have a potential for improved durability of response. And then as I mentioned earlier, the tyrosine kinase inhibitors and T cell engages a very different mechanism of action. So tyrosine kinase inhibitors target the FLT3 signaling pathway, whereas CLN-049 actually harnesses the power of T cells, a more potent approach, which we think, again, can enhance durability of response.

Great. And then how are you thinking about the potential opportunity in AML.

Sure. So AML is a disease -- in the U.S., about 20,000 patients diagnosed every year with this disease. And really, until today, the only curative form of therapy is allotransplant with high-dose therapy. The problem is these are elderly patients. So actually, probably 75% upwards of patients. actually are not eligible to receive this very intense curative approach. And so as you think about that, that makes a challenge in terms of security of drugs for the future. And when you look at the more recently approved drugs, they tend to target subsets of patients. So it's become a very fragmented disease, IDH1, IDH2, mutant FLT3, many. So there's clearly a need for an agent that's more broadly applicable and that can induce to durable responses. And I think that's where we see there's an opportunity for CLN-049.

Now you're currently running the first in-human study. Can you just talk about the initial safety data that you've seen for...

Sure. Of course. Look, we were pleased to have an abstract at the European Hematology Association this year of the initial safety data from the CLN-049 ongoing study. Look, we started out with a single ascending dose study, where we saw some cytokine release as well as low-grade CRS, which we thought was a good marker of the postulated mechanism of action. We then after completing the single-ascending dose study quickly pivoted to the multi-ascending dose study, which we started in December of 2022. And there, we also switched from IV therapy to subcu therapy, which seems to be the trend among T cell engagers now as you look across heme indications just because it can reduce the risk for CRS. And so that study is actively ongoing, and we look forward to sharing those data in the future.

Okay. Good. Maybe shifting to CLN-418. You even licensed rights from Harbour BioMed in February. So how is 418 differentiated?

Sure. So CLN-418 is a first-in-class clinic stage bispecific immune activator. It binds with high affinity to B7H4 because of the dual binding arms it has. It also -- because it's B7H4 and 4-1BB, it conditionally activates 4-1BB. So only when you're buying both B7H4, which is a tumor-associated antigen and 4-1BB, so that you're localizing activity into the tumor itself, which should then portend for a broader therapeutic index in terms of both efficacy and safety. It also has a silenced Fc domain, which means we don't see nonspecific T cell activation. And so our view is that this is an agent that has potential to be a pan-cancer opportunity and we are currently conducting a Phase I dose escalation study and guided to data in 2024.

And then so far on that data, like what should we expect to see in those results?

Sure. So again, this is a Phase I dose escalation study. So primarily, the initial data is going to be focused on safety. Of course, we are collecting response data, et cetera. But the primary objective of Phase I dose escalation study is safety, so that would be our first data set.

And then you recently started Phase I for CLN-978. Can you just talk about the rationale for 978 and CD19 as a target?

Sure. So CD19 is another target, which I'm sure you're familiar -- is that it's been both commercially and clinically validated now with both conjugated and unconjugated CD19 antibodies as well as CAR-T therapies in the marketplace now. The CD19 antibodies, either conjugated or unconjugated don't seem to be very effective in that setting. Of course, CAR-T therapy has been effective. CLN-978 is a drug that targets both CD19 and CD3. It has a human serum albumin binding domain for prolonged half-life. And it's also shown to have very high affinity for the target antigen CD19. So we see it binding in very low level expression settings, which we think is particularly attractive. And why do I say that? Well, there's at least 2 opportunities that we can think of in the lymphoma space. So given the potency of T cell engagers, it has the opportunity to deliver CAR-T-like efficacy, but as an off-the-shelf therapy. So that's 1 attractive opportunity for us. Given it's very high binding affinity to very low levels of antigen expression, we also think there's a role in the post CAR-T setting as CAR-T therapies now are moving, for example, to the second-line setting in diffuse large B-cell disease, CD19 losses often a resistance mechanism. So even in that post CAR-T setting, there's a clear patient segment where we think this drug has the opportunity to work. And then the other thing I'll add is that CD19 over -- in the last couple of years has become a very hot target in autoimmune diseases. And so when you look at CD19 approaches in autoimmune diseases like lupus, for example, it's all being CAR-T therapy. Well, the advantage of a CD19 T cell engager are clear and obvious relative to CAR-T therapy, especially in the context of an autoimmune setting. So that's another reason we're excited about that molecule.

Can you talk about the Phase I for 978? And then what should investors watch for in the initial data?

Sure. So we just started dosing in our Phase I dose escalation study, looking at a range of relapsed/refractory B cell non-Hodgkin's lymphoma subtype. So since we only started dosing about a couple of weeks ago, it's a little bit early to talk about the data per se, but we're obviously excited about that program.

Okay. Great. And then 617 is about to enter the clinic. What excites you about this program and how 617 differentiated from other approaches?

Sure. So the reason we're excited about 617 is, it's taking 2 very potent cytokines in IL-2, IL-12, putting it into a fusion protein. We also have a collagen-binding domain, which should retain the cytokines within the tumor, which is really important from a safety perspective. And we're doing this all through intratumoral injection. So we think that this is an exciting program. Our preclinical data package was very robust. It showed clear abscopal activity that you want to see, so that we saw activity in noninjected distal tumor sites. We also saw a T cell memory effect induced, which prevented regrowth of tumor. We also saw activity in PD refractory tumor models. And so look, this is a program that cleared an IND at the beginning of this year, and we look forward to dosing patients by the end of this year in our first Phase I study.

Maybe 1 last question is what, if anything, do you think that investors maybe most misunderstand about the Cullinan story?

Sure. So yes, I spoke about our strategy, which is differentiated. And I think we are bearing -- seeing the fruits of that strategy. We have a number of programs now in the clinic. Secondly, CLN-619, I think, is a very exciting and important molecule. We've seen monotherapy activity in Phase I, which is pretty uncommon. Like if you think about some of the excitement around LAG-3, TIGIT at this past ASCO, those specific agents didn't show any objective responses in Phase I. So we were very pleased to see that single-agent activity. We look forward to updating both the monotherapy data, combination therapy data. So I think that, for us, is clearly a very important program now. And we're starting to see where we have clear regulatory commercial parts. So that would be one. As I mentioned earlier, in 18 months, we've gone from 1 program in the clinic to 6 programs in the clinic. And I think by having 6 programs in the clinic, which seems a lot for a company of our size, but it also gives us strategic optionality. So as we turn those data cards over in the coming months, it also provides strategic optionality for us to decide which of the programs do we want to continue to develop ourselves, and which of those do we want to partner? And so that strategic optionality, I think, is underappreciated by investors. I think investors look at, wow, 6 programs, how are they going to do all this by themselves, but that's not how we think. I mean the way we've in-licensed in the past, we've taken important molecules, but it's a 2-way opportunity. And so I think having the opportunity to decide what you do in terms of 6 clinical programs actually gives us tremendous strategic optionality and to drive further value creation, whether it's internally at Cullinan Oncology or externally with partners.

Great. Thanks so much for your time.

Appreciate it, Jeff. Thanks a lot. Thanks, everyone.