Hi, everyone. Welcome to our Fireside Chat with Cullinan. I'm Li Watsek, a biotech analyst at Cantor, and we're thrilled to have Nadim and Jeff joining us from the management team. Congratulations on the IND approval, by the way. So I guess, to start, maybe give us an overview on what's coming up for the company.
Yeah. Look, I'd say, at Cullinan Therapeutics, we're a biotech company that's really focused on creating new standards of care for patients. You can see with our pipeline, we have molecules that address the underlying drivers of disease, as well as harness the immune system to destroy cells that are diseased across autoimmune and cancer indications. And so we've assembled a portfolio of assets that span modalities and have the potential, each of them have the potential to be first or best-in-class. So that's the kind of differentiated approach we take to drug discovery and development. With CLN-978, our CD19 by CD3 T cell engager, we believe we have an off-the-shelf potential disease-modifying regimen that can be applied to address a range of unmet needs across autoimmune diseases.
We were thrilled earlier this week to make an IND submission for our first indication, which is SLE, and then the next day, we announced that we got ethics committee approval from Australia to proceed with this global study, so really excited about that. And at the same time, we've also announced our second indication as rheumatoid arthritis, where we'll be working with the pioneers in this space, the University of Erlangen in Germany, as well as the Gemelli University Hospital in Rome, and so super excited about this program.
And at the same time, our oncology pipeline still continues to progress, so, for example, at ASCO this year, we presented data on CLN-619, which is our monoclonal antibody targeting very novel pathway, the MICA/MICB pathway, where we were able to show responses in patients who typically wouldn't be expected to respond to checkpoint inhibitors.
So that was really good. And then even more recently, as of last week, thinking about ESMO, so Zipilertinib, a tyrosine kinase inhibitor targeting exon 20. We've completed our relapse study ahead of schedule, we said end of this year, and we also presented data, in the relapsed patient population, importantly, in the post-Amivantamab setting, which is a growing unmet need patient population. So that's a molecule that we believe still has potential best-in-class profile. We saw a response rate of around 40% in the post-Amivantamab setting, and a favorable safety profile.
And then I would say, you know, in our earnings release in August, we announced that at the end of June, we had $665 million of cash, which takes us into a cash runway going into 2028, which then gives us all the resources we need to continue to advance the oncology pipeline, but also fully unlock the value of CLN-978, our T cell engager for autoimmune diseases. So very excited about the progress and the future ahead.
Yeah, very exciting. So I guess before we dive into the programs, obviously, you expanded, you know, from oncology to autoimmune. I guess just from a corporate development perspective, I guess, do you need to bring extra capacity, expertise in-house in order for you to fully tap the autoimmune opportunity?
Sure. Yeah, look, I would say, yeah, firstly, our strategic expansion to immunology was driven by CLN-978 and the opportunity that represents for us. Secondly, if you look at our discovery and development efforts to date, we've always been focused on immuno-oncology, and if you look at our assets, most of them do harness the immune system. At the same time, the biology of oncology and immunology continues to converge. So for us, this expansion was a very natural adjacency for us as a company and an excellent strategic fit.
Secondly, you know, we have a core group of scientists that have broad industry experience, including in immunology, by the way, and at the same time, Jeff and his team have been busily recruiting external expertise in immunology and autoimmune diseases, especially in the areas of clinical development, research, regulatory. We are really building out this immunology unit to make sure that we can fully unlock the value of CLN-978.
A great point. I guess diving into your CD19 T-cell engager program, obviously, there are a lot of, you know, different approaches out there, CAR Ts, and some are, you know, off-the-shelf. They're trying different sort of lymphodepletion regimen. So I guess, where do you see sort of T-cell engagers play relative to some of the other, you know options out there?
Yeah, look, as somebody or both of us have been very actively involved in the development and commercialization actually of CAR T cell therapies, yeah, those therapies have been transformative in oncology, especially hematology. However, I do think that the risk-benefit is different when you bring these potent treatments into the autoimmune disease setting. So that's the first thing I will say. Secondly, as you think about CLN-978, so we have an off-the-shelf potential disease-modifying treatment, with the convenience of sub-Q administration. You know, we don't have the known risks of secondary cancer that you see with cell therapy, and significantly reduced ICANS and risk of CRS, so we know that already.
The other important point is, you know, ultimately, with T cell engagers, and specifically CLN-978, it's a treatment we believe we can take to patients in the community versus patients having to go to a CAR T certified center for treatment. The other element of this that I think is very underappreciated is that T cell engagers give you much more dosing flexibility. So if you do need to provide additional doses to extend remissions, you can do that with a T cell engager. You can't keep treating patients with CAR T cell therapy, at least not in the current construct that we have. You mentioned, you know, the NK cell approach there, and I think, yeah, that's intriguing.
I do think, however, if you look at oncology, you know, durability and efficacy does seem to be a little bit in question, given the persistency of NK cells. So I'm not sure that you'll see the same efficacy necessarily as you do with the T cell-directed approaches, whether it's CAR T or T cell engagers. And then look, for us, it's important to point out that we believe that both the modality and the target are important, and we believe we have the ideal combination with a T cell engager and CD19 as the target.
So speaking of target, obviously, even within T cell engager space, we're looking at CD19. Obviously, that's what you guys are focusing on, and then you're looking at maybe CD20, BCMA, and then we actually saw some case reports coming out from some medical journals. So, just curious, what is your take on that, and why do you think CD19 is sort of the best target here?
Yeah, I mean, it's a really great question, and I think maybe to start with sort of a general statement, I think CD19 is probably the single best target, and it's because it conveys such broad coverage of the B-cell compartment, extending all the way from pre-B cells to plasmablasts and even very likely mature plasma cells. And so let's compare that to what's achievable with CD20. So CD20 is almost solely expressed on mature B cells, and so you won't have the reach into the plasma cell, the antibody-producing end of the B-cell continuum. On the other hand, BCMA, while it is expressed on some mature B cells, it's also expressed on long-lived plasma cells. And in taking out the long-lived plasma cells, there's a substantial risk for impairing your humoral immune response or antibody immune response.
Patients who were treated with BCMA, including the recent case reports, became deplete in their normal antibody levels, leaving them at risk for infection, and their memory immune response, the antibody immune response that we retain after vaccination, was also impaired. In looking across the targets, CD19 provides this great breadth of coverage while sparing long-lived plasma cells, and so we think it has many of the attributes that make BCMA favorable, but without its infection liability in particular.
So obviously, you are going after lupus, and potentially RA. Maybe just walk us through, you know, why you think it can work, because obviously you have your own, you know, data, but that's in oncology. But you also have some external data here that can support your case. Maybe touch on that.
Yeah. I mean, what captured everyone's imagination now for several years is the potential for T-cell redirecting therapy to alter the natural history of SLE. And up until that, there had never been treatments that had routinely achieved treatment-free remissions in patients with SLE. There were criteria to define what that would be, but nothing achieved it, and that's what was really amazing about the CAR T experience, and it appeared to be because deep B-cell depletion reset the immune response.
What was most remarkable about the data that's now been shared for both Blinatumomab and RA, and more recently for Teclistamab, in both, lupus, and RA, is that this same kind of immune reset is achievable by deep B-cell depletion with an alternative approach to T-cell redirecting therapy, a T-cell engager, an antibody, a drug, as Nadim was sharing, off-the-shelf therapy that can achieve the same outcome. In thinking about SLE, this is a place where, as I just said, no disease-modifying therapy has really been available. Treatments were largely symptom-directed and not very effective even to that extent, but it's a sizable group of patients, more than 160,000 here in the U.S., who are in need of disease-modifying therapy to portend progression to really significant end organ damage.
So we think there's substantial unmet clinical need that can be satisfied by an off-the-shelf therapy that, as Nadim states, meets patients in the clinical settings where they are likely to be treated, which is largely in the community. And I think as we put those things together, scientific rationale and the unmet need that should drive all drug developments, we think that SLE is one of those indications. Because CAR T led, because it has established the proof of concept for all that will come after, it's also important to benchmark our data against what's been achieved by CAR T. If we didn't do the study, people would wonder, why not? And it's very important, I think that we share that.
In the case of RA, the data for Blinatumomab really paved the way several months ago, showing that a T-cell engager could achieve a similar immune reset in that disease. There's an established role for B-cell depleting therapies. Rituximab is long approved for that disease, but the T-cell engager mechanism of action just is expected to bring greater potency there. It's often said that it is a crowded space, but I think there are still many patients who ultimately end up refractory to multiple disease-modifying agents, the so-called difficult-to-treat RA patients, and there's a substantial need there, but for a highly effective disease-modifying therapy, a clear opportunity to move it up in earlier lines of therapy over time.
What do we think about the dosing regimen that you will be using in autoimmune and also durability? I think that's another question that came up a lot because we've seen some relapse with CAR-T therapy. So what are your thoughts there?
Yeah. So, maybe just to start with the observation that with CAR-T, we've seen a single application of CAR-T achieve transient but deep B-cell depletion. So, the effect seems to be more one of depth than durability of B-cell depletion. And so when thinking about how to dose a T-cell engager, we have always thought, as we've rolled out this program, that it's likely application of a B-cell depleting dose for a defined duration of time, likely weeks, not many months, that can achieve a CAR-T-like effect. Now, we actually have data that suggests that that contention is probably the case. So in the Blinatumomab example, we saw two five-day continuous infusions, one week apart, in RA achieve deep responses in refractory patients.
Now, two weeks ago, for teclistamab, we saw that patients who were treated with only two doses of the therapeutic dose of teclistamab, approximately four to 12 weeks apart, depending on the patients in the case series, could achieve a similar deep and durable response to treatment. With respect to durability, those are, of course, questions that have to be answered in the clinic, but one of the features of a T-cell engager as compared to a CAR-T, that Nadim has already highlighted, is that flexibility of dosing. It's very hard to imagine, routine re-administration of CAR-T at time of relapse, whereas a T-cell engager, if patients were to relapse, if they were to require some sort of maintenance or intermittent therapy, it has that flexibility that CAR-T does not, at least not the current iteration.
So I think for both of those reasons, we think that this is just a more appealing modality for application in the usual clinical setting where autoimmune disease patients are treated.
Talk a little bit about your anticipation for enrollment. Obviously, we've seen some challenges in the CAR-T space, but given that it's a T-cell engager, how do you think that's going to sort of play out in terms of recruiting patients?
Several things. We've stated, of course, that we are conducting a global investigational program, and so we are looking to leverage a global site footprint, understanding that that will certainly help us achieve our enrollment goals. Secondarily, we have, in our SLE trial in particular, decided to enroll general SLE patients rather than lupus nephritis patients, understanding that lupus nephritis patients who are sick enough to meet eligibility criteria but well enough to be enrolled on a phase I trial are actually hard to find in clinic. As a modality, we've already talked about how there's much greater flexibility of clinical settings in which an antibody can be administered. That's also true of conducting a clinical trial.
Unlike CAR-T, which has to be administered in CAR-T-certified centers, our antibody can be administered in a much broader range of phase I trial settings. We've also worked to try to minimize the complexity of enrollment criteria in a number of ways to make this trial more flexible for implementation in a wide variety of clinical settings and to make it easier for clinicians and patients to enroll. I think those things together are very important. Then lastly, I think centers who have been interested in the potential for CAR-T but don't have the facility to collaborate closely with hematologists and oncologists or are not CAR-T centers are very compelled by the potential of our drug.
It's very important that we have a highly engaged group of investigators, and that's also been a priority as we think about our global site footprint.
When should we expect to see initial input?
Yeah, so give us a chance. We've only just got the HREC approval, submitted the IND. And so I think right now, Jeff and the team, rightly so, are really focused on study startup activity so that we can optimize accrual, and then, you know, we'll come back to you with future guidance.
So maybe switch to your oncology pipeline. I think MICA, MICB is a very interesting target, and maybe for those who are less familiar with this target, just tell us a little bit about why are you so excited, and some of the data that you generated so far?
Yeah. So, most of the approved immune therapies have been targeted T cells, PD-1, CTLA-4. MICA is a unique target. So all cells, when they become damaged, whether it's by radiation, chemotherapy, malignant transformation, they get flagged for destruction by the immune system. And one of those flags is MICA and MICB. And these are cell surface ligands of a receptor on multiple cells of the immune system, NKG2D, and that's found on cells like NK cells, as well as T cells, gamma delta T cells, and some subsets of CD8 T cells. So when a cancer develops, MICA goes up. It should be flagging the cell to be removed by the immune system, but cancer has found ways to evade the immune response by cleaving off the MICA and MICB in the tumor microenvironment.
CLN-619, our antibody, binds near the site of where those proteases cleave off MICA and MICB. It reestablishes MICA and MICB as an eat-me flag on the cells and identifies them for removal by NKG2D-bearing immune system cells. It also is a functional antibody. It induces ADCC and ADCP, so it has multiple mechanisms of action. But this is the first antibody of its kind to reach this stage of clinical development, and we've been very excited by the initial clinical data, both as monotherapy and more recently in combination with PD-1, that we've presented at successive ASCO meetings.
So maybe let's dive into your ASCO data a little bit. Obviously, you've seen some pretty encouraging signal there, so just talk to that, and what are the tumor types that you're looking at?
In talking about our ASCO data, we've presented both data for monotherapy and in planned dose escalation with PD-1. One of the most interesting observations is that for the monotherapy for what is a novel immune therapy target in oncology, we saw monotherapy responses in dose escalation, and there we saw three responses in a group of 28 response-evaluable patients, including two patients with multiply relapsed endometrial cancer, including one relapsed after PD-1 prior treatment, and then in a patient with a head and neck tumor, who had also relapsed after PD-1.
In a broader group of patients that included patients with platinum-resistant ovarian, hormone receptor-positive breast cancer, as well as, a rare subtype of, sarcoma, we saw stable disease that extended for nearly, a year in most cases, and in the case of platinum-resistant ovarian, extending beyond a year. So in that group of monotherapy patients, a clinical benefit rate of monotherapy in phase I dose escalation of 41% in the response evaluable patient population. In the PD-1 combination, we saw, a very favorable safety profile, as we had in monotherapy, and there we also saw activity in patients who would not normally respond to PD-1 treatment.
So there we saw two objective responses in EGFR and ALK positive non-small cell lung cancer, which you will all know are actually label exclusions for PD-1, since PD-1 has not shown either monotherapy activity or really significant clinical benefit in combination with chemotherapy in those diseases. So across both arms of the trial, favorable safety, amenable for combination, and very interesting activity in diseases that had progressed after PD-1 or where PD-1 is not typically active. So we're continuing to explore in disease-specific expansion with monotherapy in combination in endometrial and oncogenic driver expressing non-small cell lung cancer, as well as beginning to explore chemotherapy-based combinations in ovarian cancer, where we had seen stable disease.
Chemotherapy can induce the stress that increases that cell marker MICA for removal by the immune system, and so we think there's strong preclinical rationale for chemotherapy-based combinations as well.
Just on endometrial cancer and just cervical cancer, I agree with you, the data look quite interesting. Maybe remind us what the next update will be, and do you think you're gonna go forward with the mono path or could be combination? How do you think through that development path?
Yeah, our guidance around that is the first half of twenty twenty-five for both cervical cancer and endometrial cancer, 'cause they were our first combination cohorts. Jeff, do you want to address the mono versus combo question?
Yeah, I mean, I'd say, as we always will say the data will drive us, but I think there is a potential development pathway in both cases. For monotherapy, patients who have relapsed after PD-1 and chemo, right now, their existing standard of care is single-agent chemo that achieves no better than 15% overall response rates and is typically less durable than six months. That's a low, sadly low bar for success. In the case of PD-1, PD-1 is now approved in a frontline with platinum doublet chemotherapy, but before was the only thing very effective approved in the second line. So now in the second line, there's high unmet need after PD-1 failure. There is interest both in monotherapy there, as well as options to reutilize PD-1 again, in combination.
And so we think that in exploring both monotherapy and PD-1, we set ourselves up with optionality for both a monotherapy and potentially in combination therapy, with the data to guide us.
Just lastly, on Zipa, which is your EGFR exon 20 inhibitor. You shared some data at ESMO. Maybe just talk about, you know, sort of the key takes from that update.
Yeah, you know, we're speaking about data that we presented just this weekend at ESMO, showing activity of Zipilertinib, robust clinical activity in patients who had received prior treatment with the approved drug, Amivantamab, which is now fully approved. I'd say, while it's important to show activity after the approved drug, both for clinical and regulatory reasons, I think the data is also important because this group of patients was even more heavily pretreated than the patient population we had treated before. These patients had received a median of three prior lines of therapy.
Fifty percent had prior history of CNS metastases from their disease, and yet we still saw a 40% overall response rate, similar to what we'd shown in phase 1, 2a in patients who had two prior lines of therapy, relapsed after only chemotherapy, 30-ish% with brain metastases, so robust activity, and then finally, the median progression-free survival in this group was 9.7 months in a fourth-line patient population at median, and just as a reminder, amivantamab, approved in with chemo in the frontline, the median progression-free survival in the frontline of ami chemo is 11.4 months.
So we think that this is just really, you know, important data to help us get the drug approved, but also really continues to tell the story of a really great clinical profile, both with respect to efficacy and safety for Zipilertinib.
Okay, great. Looks like, that's all the time we have. So, thanks very much, Nadim and Jeff, for a terrific discussion.
Thanks, everyone.