Very happy to have Cullinan Therapeutics with us for the next fireside chat, CEO Nadim Ahmed and Jeff Jones, CMO. Nadim, do you want to kick it off with a brief overview of Cullinan, and then we will get into the Q&A?
Sure, yeah. Happy to do that. I think the first thing I would say is we are very pleased to have a portfolio of leading T-cell engagers across oncology and immunology, and they are both, all three are clinical stage. At the same time, we are heading into a really exciting period over the coming weeks and months with multiple milestones ahead. Very exciting for us as a company and for patients, of course, as well. CLN-978 is our T-cell engager addressing CD19, being developed for rheumatic diseases. This past summer at EULAR, we presented the first company-sponsored data for CD19 T-cell engager, and now we just announced in our corporate update this morning that we are planning to present the first multi-dose data in December. Looking forward to those data.
We also have a BCMA T-cell engager also addressing autoimmune diseases, but here we are focusing on those diseases that are driven by long-lived plasma cells. At ACR just this past week, our partners in China, Genrix Bio, presented proof of concept data in SLE, which was super exciting. Again, as I mentioned, this is a molecule where we really are focusing in on plasma cell-driven diseases, and we are starting that with our own global phase I/II study in autoimmune cytopenias. We just cleared our IND in the U.S. and Australia, so excited about that program. Our third T-cell engager is in oncology. CLN-049 is a T-cell engager addressing FLT3 in AML. This summer, we were very pleased to have a very successful end of phase I meeting with the FDA, and we have started our pivotal study in relapsed/refractory AML, actively recruiting patients into that study.
The last program I will mention, it is not a T-cell engager, it is our tyrosine kinase inhibitor addressing exon 20 non-small cell lung cancer. There, in September, we presented data from our frontline study in exon 20 non-small cell lung cancer, where we presented the best results seen to date from a median progression-free survival perspective in exon 20 disease in the frontline setting. That is a program we are partnering with Taiho, and we also announced that we have initiated our submission for that frontline indication under Real-Time Oncology Review, or RTOR. The other aspect of that program for us strategically is super important.
As part of that collaboration with our partners at Taiho, it also allows us the opportunity for near-term non-dilutive capital in the form of both regulatory milestones, where we're owed $130 million, with upcoming regulatory approvals, as well as a 50/50 profit share in the U.S., which then allows us to invest that capital back into our T-cell engager program. Hopefully that gave you an overview, a snapshot of what's happening this quarter and then into 2027.
Great. Yeah, and I think what would be helpful, let's start with CLN-978. You presented the first datasets back in June at EULAR to walk through what we saw both in SLE and RA, and then I want to walk through kind of the arc of what we should expect in December.
Sure. Yeah, happy to do that. The first thing I would say is the data we presented at EULAR earlier this summer for us really supports our belief that CLN-978 could be a breakthrough treatment for patients with autoimmune diseases. We presented single target dose data at EULAR, and there we saw clinical remissions, we saw impacts on disease-related biomarkers, and also markers of immune reset. This was above our expectations from what we would expect from single target dose data. As I mentioned, we updated the street this morning, announcing how we're going to show data in the multi-dose setting for CLN-978 coming up in December.
I think we're super excited about that opportunity there as well. As we think about all of these autoimmune diseases, what we've said is building on what we had this summer, the multi-dose data allows us the opportunity to look at initial clinical activity as well as safety and also impact on disease-related biomarkers. This really gives us an opportunity to assess clinical activity in that multi-dose setting, and then of course, we'll continue to follow patients for durability into 2027. Very exciting time for us.
Yeah, so maybe in terms of sort of from a scoping perspective, just can you talk about numbers of patients, both multi-dose for SLE and RA, and then I want to get to Sjögren's, and then what kind of follow-up we might get from some of the single-dose cohorts from earlier this year?
Yeah, sure. So, in the multi-dose setting, we announced this morning that we will have approximately 20 patients total across three different indications. We will have more lupus patients because our studies in lupus started much earlier.
We will also present data on the doses of 20 micrograms and 30 micrograms. So again, it allows us the opportunity to look at multi-dose data from a single target dose data perspective. If you remember this summer, we presented the data at EULAR. It was initial clinical activity.
Yeah.
Now, for some of those responders that we saw with the single target dose data-
Yeah
we'll have longer follow-up, so that's exciting. We'll also have some longer follow-up for the multi-dose patients that were accrued earlier.
Yeah.
Although for the newer patients, obviously, we need longer-term follow-up. The new piece of information really is in Sjögren's disease.
Right
where we'll have both single target dose data and multi-target dose data as well.
Yeah. What kind of follow-up should we expect from some of the earliest single target dose cohorts?
We'll have at least six months follow-up.
At least six months?
Yeah.
In both SLE and RA, or mostly SLE?
For single target dose, both.
Both. Okay. I think in general, how should we think about the progression from the single target dose data to the multi-dose data in terms of what should the data sets look like in terms of PD translation and clinical efficacy translation?
Yeah. Jeff, do you want to take that one?
Yeah. I think, Alex, what we've always said is that we saw these remarkable responses after a single dose in some patients, but we would like to translate that into a similar effect in a larger group of patients, more consistency of clinical response, and similarly, the accompanying biomarkers. If we saw a depth and durability of peripheral blood B cell depletion-
in a limited number of patients, we'd now like to see that in a larger fraction of patients, or a response that's deeper and/or more sustained with longer exposure to the drug. I think that's true of all of the indications that are under assessment.
Yep. The main for Sjögren's obviously is another complex rheumatologic disorder. There's clearly some mechanistic overlap between SLE and RA. I guess, what should the expectations be for some of these early Sjögren's data sets?
Yeah. I mean, there are a lot of ways of thinking about Sjögren's, but probably the most fundamental and one that's vital to the diagnostic criteria for the disease is a polyclonal B cell lymphoproliferative disorder. So exocrine glands are impacted by a B cell infiltrate that's demonstrable on biopsy of salivary glands, and that's what leads to a lot of the symptomatology of Sjögren's disease. So a B cell depleting therapy is one that is kind of well-matched to the pathophysiology of the disease. And in many cases, Sjögren's disease dramatically increases the risk for progression to a clonal B cell lymphoproliferative disorder. Again, really matches the biology. And we've seen some recent data looking at antibody depleting therapies-
and it's not been successful. I think the B cell approach makes biological sense. One of the things about the data set that we will ultimately present is that we are, just as we are in our RA study, obtaining biopsies of affected tissue. So salivary glands, again, identification of a B cell infiltrate is diagnostic, and we'll be able to look in paired biopsies at the impact of B cell depletion of CLN-978 on B cell depletion in the gland is also restoration of normal glandular architecture, which is important in resolving symptoms associated with glandular dysfunction.
We should expect to see biopsy data in December?
Yes.
Okay. Sort of like what you saw, what you showed back in June, essentially.
Yeah. I mean, again, we're not obtaining these universally from our patients.
Sure.
It is a lot to ask of patients. But where we are able to obtain it, I do think it's very helpful for us in understanding the PK/PD relationship.
That will inform further development.
Then, maybe again at a higher level, can you talk about the safety profile that you've seen so far, and particularly as we move into more multi-dose cohorts, how you expect that to evolve?
Yeah. So at the doses that we explored and shared back at the beginning of the summer, we saw mostly grade one, grade two CRS, really mostly grade one, one case of grade two, one case of grade three in a patient who probably would have benefited from a multi-step-up regimen to mitigate CRS. So with the doses, target doses of 20 and 30, we saw a very favorable safety profile that we think is amenable to further exploration, which is really the focus now as we try to identify regimens we want to carry forward into phase II. In terms of further escalation above the 30 microgram dose, that is something that we might potentially explore.
That is not really our focus now. But if we did, the data we have accrued so far shows that that would be best approached through a multi-step-up regimen.
And that is typical, right? With T-cell engagers, it is not the absolute dose that is associated with the risk, it is the absolute dose as well as the path you get there. And you can mitigate a lot of the CRS risk by optimizing the step-up dosing scheme.
Okay. So then, moving forward from this December update, what do you need to collect at this point to move into phase II studies next year?
Yeah. As I said, we are really trying to find a regimen that we think consistently delivers a deep B cell depleting effect, and there we are looking holistically across indications.
So that we can compare not only peripheral blood B cell kinetics, but also tissue level B cell depletion kinetics to identify a dose and schedule that we believe is likely to achieve a consistency of response with a preserved therapeutic index. And there is probably not one single solution.
We do plan in the next phase of development to explore more than one dose or schedule to satisfy regulatory requirements for dose selection, and to generate the initial efficacy data at those doses that is necessary to inform regulatory discussions and model registration-enabling studies.
Mm-hmm. I think maybe at one of the bigger picture questions in this space remains what ultimately does the product profile look like in terms of both absolute efficacy, getting to remission over some short period of time, and then durability? I guess, where are we at right now in terms of understanding what the 978 product profile could ultimately look like?
Yeah, I mean, I think there's some specifics of the contour that await further data.
Sure.
As Nadim said, we will provide some information in our December update on some of even the single ascending dose patients who achieved a DORIS response in the case of SLE or a DAS28 response in the case of RA, suggesting some of the potential for durability of clinical benefit. If you think about what we're conceptually trying to do is to achieve a deep treatment-free response in a significant fraction of patients, and that fraction of patients probably depends on the indication.
Yep.
The durability that's clinically meaningful probably depends on the disease setting. For SLE, when we've had conversations with investigators, they've told us that achieving a DORIS response in 30% of patients, durable for six months, would be very compelling for adoption. If there were predominantly grade one and low, meaning single-digit rates of grade two CRS, no grade 3 CRS.
would be very attractive for adoption. In the case of RA, we've seen a potential for response in patients who've relapsed after six-plus disease-modifying therapies. In those patients, a response of like a DAS28 response rate in the 20% range, durable for four or five months, might be sufficient since there's nothing that can achieve that currently available to physicians.
Yeah, I think the important point to add to what Jeff just said is, the types of patients that we're enrolling in our studies-
they're even more heavily pre-treated than some of the phase III studies that have been conducted recently.
Sure.
For example, in RA, JAK inhibitor studies prior to DMARDs, we're four, five, six DMARDs, multi-decade disease. That's one aspect of it. The other thing that I think is also important that often gets overlooked is the fact that when patients come into our study, they are off their background therapy.
Yeah.
What we're seeing is a clean monotherapy signal, not on top of background of care versus placebo.
As you think about moving into phase IIs generally across SLE, RA, et cetera, do you expect to enroll these similar populations in phase IIs, or do you want to move towards a broader, more representative moderate to severe type population?
Yeah, I think it's probably both/and.
Yeah.
I think for SLE, the patient population that we've currently been enrolling is relatively similar to the patient population with unmet medical need in the U.S., and I expect it will be similar. I think we will also enroll a cohort of patients with lupus nephritis specifically as part of this next phase of study. There, the unmet need is exceptionally high despite recent approvals like obinutuzumab. The majority of patients still require further therapy, and we have seen some initial success with CAR T companies in seeking a single arm registration pathway in that patient population based on compelling efficacy data.
We think generating data there can inform regulatory discussions. In RA, still, I think at this stage of development, European regulators are still interested in us generating initial efficacy data in a very refractory patient population. But we and our investigators think that the greatest opportunity for the drug is in earlier lines of patients.
Mm-hmm. Then maybe let's pivot to velinotamig a little bit. You just presented some more, or I guess Genrix just presented some more data at ACR. And Nadim, you alluded to this a little bit, but can you talk about how BCMA fits into your autoimmune strategy?
Yeah, I think, once we had started developing CLN-978, we continued to think about, what makes sense strategically to add to that portfolio?
Yeah.
What became very clear is that CD19 gives you very good coverage across the B cell compartment. For example, it didn't make sense for us to bring in CD20 because you get broader coverage with CD19. However, at the more mature end of that B cell lineage, when you think about plasma cells, there was a gap because CD19 tends to be more dimly expressed or no expression later on.
Yeah.
For us, it made sense for us to bring in a plasma cell depleter also to complement the B cell depleter.
There it was a matter of, well, what's the right target? Most of the data was in, say, BCMA versus GPRC5D, for example. Then it was about finding the right molecule at the right price. With our partners at Genrix Bio, we managed to bring in velinotamig, upfront cash payment of $20 million versus the recent $2 billion transaction.
Sure.
That was a really good deal for us. Since then, we also, as part of that deal, we agreed that Genrix Bio would do the first clinical study just because of the ability to speedily accrue patients in China.
We just saw that data in ACR. I think our view is that CD19 and BCMA are the best targets to pursue in autoimmune diseases. So having molecules that address both, for example, with CLN-978-
Sure
CD19. As we've just discussed, we're really focusing in on rheumatic indications
Sure
where pathogenic B cells are driving the disease, and you want broad B cell depletion. For velinotamig BCMA, we're really focusing in on those diseases where the pathogenic autoantibodies are being generated by long-lived plasma cells.
Yeah.
That's why we chose autoimmune cytopenias, for example, for our first global study. We continue to look at things, indications related to nephrology, for example, neurology, endocrinology. Our view is that having both in our portfolio
Yeah
really gives us a lot of opportunity to address more diseases across the autoimmune disease spectrum than either target alone. It gives us the opportunity to really try to redefine standards of care in those settings
and bring forward two what we think are highly attractive commercial molecules.
And then you obviously alluded to recent acquisitions in this space, focused on BCMA in particular, but at least Candid had some other programs as well, more broad than just BCMA. I guess between CLN-978 and velinotamig, where does Cullinan fit in kind of the broader T-cell engager landscape right now for autoimmune?
Yeah, I think the way we're thinking about this is from an executional perspective. Both of our molecules are in the clinic.
Some companies, one molecule's in the clinic, one's preclinical, whether it's BCMA or CD19. I think for us, this is why it's really important to continue to move forward with speed.
Yeah.
This is why with Genrix Bio, we wanted to do the first study in China. If you think about it, with CLN-978, we were the first company to clear an IND in the U.S. We were the first company to present company-sponsored data earlier this year at EULAR. We will be the first company to present multi-dose data. In that space, we are really closely following Roche.
Yeah.
Now they have moved to another molecule. This is starting again from phase I, so we are ahead there. Novartis decided to pivot to another modality. I think actually the competition has decreased, and we are pleased to be at the very front of the pack. With BCMA, obviously you mentioned Candid and the inheritor company, same with Ouro Medicines. There, we are catching up very quickly because we have just now cleared the IND. Jeff is running a phase I/II study in autoimmune cytopenias, and we are looking at additional indications that we can pursue. For us, it is the executional advantage as well as the molecular structures that we believe are differentiated.
On the autoimmune cytopenias fronts, obviously a good population to do more dose ranging in potentially. How quickly might you move into some of these other plasma cell-driven diseases? Do you need to finish that cytopenia basket study first, or could you move rapidly somewhere else?
I think we can move rapidly into phase II and other indications, based on the initial data that Genrix Bio has generated in China. We are pursuing the autoimmune cytopenia study utilizing subcutaneous administration of the drug. Ultimately, we think that is most patient-friendly, practice-friendly. The IV administration of the drug, data that we presented, as we were talking about at ACR, demonstrated a remarkably safe profile. When utilizing an optimal step-up schedule, starting from a low dose of three micrograms per kilogram, you saw no higher than grade 1 CRS with IV administration.
Yeah
of a BCMA T-cell engager. I think there are opportunities for initiating studies in other indications, either our own or under Genrix Bio's execution, using IV administration and ultimately introducing subcutaneous administration into the program. I think to be competitive here, demonstrating the initial proof of concept as broadly as is feasible in diseases where plasma cells are a key part of the pathophysiology, where rapidly depleting autoantibodies is likely to be therapeutic, is vitally important for the success of the program. We are looking at a number of different ways to think about broadening the indications and continuing to move forward quickly.
Great. Maybe pivoting to oncology, but before we get to CLN-049, I guess, have you said whether or not the autoimmune CLN-978 update will come before or after ASH in December?
We have not, but they will be fairly proximal. Not many days left between the end of the year.
Okay. Maybe let us start with CLN-049, the FLT3 program. I guess maybe it would be helpful to kind of put the ASH abstract data into context and sort of what we should expect to see at the presentation relative to the abstract.
So maybe take a step back a little.
Sure
further. As Nadim mentioned earlier, we've initiated a phase II study.
If I were looking at our abstract, and what I hope we can communicate is why we believe that phase II study is likely to be successful. Why are we exploring the doses we are? What gives us confidence to believe that this study is, again, likely to be successful? We've stated that the primary dose around which we have interest in further development is a 12 microgram per kilogram dose. That should really be the focus. What makes us think that that's likely to meet a threshold for clinical and regulatory success in phase II? If you look at the regimen that we expect to take forward, focus on the group of patients who were treated at the 12 microgram dose utilizing a step-up scheme, two-step-up dosing from a 1 or 1.5 microgram per kilogram starting dose.
You'll see there that the composite CR rate of CR and CRh is 26%. What we know is that recent approvals and relapse refractory of AML have been achieved with a response rate between 20% and 30%. Incremental to the data from the abstract, to your question, we'll be able to characterize the other really important metric for clinical benefit, which is the durability of that CR. We'll be able to provide much more granular detail about the durability in patients who did not go to transplant, as well as our success in those patient group of getting patients to the ultimate potentially curative therapy of transplant. I think that will be very important incremental data in the poster.
There will be further granular data on adverse event profile, but the totality should say, why did Cullinan make the decisions that they made, and why do they think they can be successful in phase II?
Yeah.
I think we will paint that picture.
Yeah, I would add to what Jeff said also, in a way, we were the victims of our success with the ASH 2025 data.
Sure.
Once those data came out, all of the investigators wanted to put all of their heavily pre-treated patients. The patients we enrolled since ASH 2025 were much more heavily pre-treated as well. The way we are mitigating against that in our phase II pivotal study, which Jeff mentioned, which is already up and running with dosing patients, we are limiting it to two prior lines of therapy.
I think that will help adjust, make sure that is where the true efficacy test is. The other thing I would point out is if you go back to the initial phase I studies for the menin inhibitors, you saw composite complete response rates as low as 10% in some groups of patients at the approved dose.
And duration of three months. Really, phase I is not where you optimize efficacy, it is where you optimize safety and bring forward the dose, as Jeff said, into the true test of efficacy, which is in your pivotal studies, and that is what we are planning to do.
What kind of follow-up should we expect on the durability data?
Yeah, I mean, I think you will see the follow-up in the clinically relevant range of four-plus months.
Okay. So maybe zipalertinib, obviously you had the frontline data and the RTOR engagement. What are the next steps here, and what are also the implications for second-line approval as well?
Yeah, so second-line approval is second-line indication is under review
Yeah
with a PDUFA date in February of 2027. We have initiated, or Taiho's initiated the frontline submission. We expect to complete it soon, and then it will be two months beyond when we will get formal acceptance of the application and receive the PDUFA date for the frontline indication.
That is anticipated in early 2027.
Does that impact the second line at all in terms of the FDA review process, or no?
Potentially, but I think we need to see further details from the agency when they provide acknowledgment of the acceptance.
Okay
which again, is two months, typically two months beyond the time that we complete the application.
Yeah. FDA has a lot of flexibility here.
Yeah
in how they time.
Yeah, and then maybe obviously the frontline data, you stopped it in the trial early, right? How should we think about the maturation of that dataset over the next year or so?
Yeah, it is a good question. The primary analysis was planned at a larger number of PFS events. That is also the timing for the actual primary overall survival analysis. So that is still, as was initially guided by Taiho, anticipated before the end of this year.
I think they are still on track for that. That is the next most important landmark. Just as a reminder, at the time of an interim analysis with only 30% information for overall survival, there was already a strong trend towards improvement in overall survival in patients treated with zipalertinib plus chemotherapy. I think there is a still potential opportunity for that to improve as the data matures.
Great. You alluded to you have these milestones related to approval and then a 50/50 profit share. With that context, how are you thinking about your cash runway as you move into broader autoimmune studies, move CLN-049 forward? How does that all fit together?
Sure. At the end of September, we reported over $300 million in cash, taking us into 2029.
Which also assumes all of these programs moving forward. We have built in the zipalertinib milestones in that. I think, again, thinking about the opportunity to use the cash from zipalertinib to reinvest into the business.
That allows us the opportunity to continue to move forward with our T-cell engagers. Clearly with CLN-049, it is very specifically addressed for AML.
with a pretty cost-efficient development plan to unlock both the second line, frontline opportunity. I think with the T-cell engagers and autoimmune diseases, I think we have the ability to add more indications for both velinotamig 978 and keep those moving forward as we expand into phase II next year and ultimately registrational studies.
How quickly might zipalertinib become profitable? I guess, get some of that profit share out of that deal?
Very quickly.
Okay.
Our partners at Taiho, they run a very lean commercial organization.
Okay.
They already have products in the bag, so that gets green very, very quickly.
Okay. Great. Nadim, Jeff, thanks so much. Appreciate it.
Thanks.