Cullinan Oncology Inc Aktie

Good morning. Thank you for standing by, and welcome to the Cullinan Therapeutics zipalertinib REZILIENT3 Results Conference Call. As a reminder, this call is being recorded. A slide deck that you may find helpful while listening to this call is available on the Events section of Cullinan's Investor Relations website at investors.cullinantherapeutics.com. It is now my pleasure to turn the call over to Nick Smith, Head of Investor Relations at Cullinan Therapeutics.

Hello, everyone, and thank you for joining us on today's call to discuss the results of zipalertinib plus chemotherapy from the Phase III REZILIENT3 trial in first-line EGFR exon 20 insertion mutation non-small cell lung cancer. My name is Nick Smith, and I'm the Head of Investor Relations at Cullinan Therapeutics. Before we begin, I would like to remind you of the safe harbor provisions outlined on Slide 2.

During today's presentation, management will be making certain forward-looking statements, which are based on current information, assumptions and expectations that are subject to change and involve risks and uncertainties, which may cause actual results to differ materially from those contained in such forward-looking statements. These risks are fully described in the company's filings made with the Securities and Exchange Commission, including our annual report on Form 10-K.

You are cautioned to not place any undue reliance on these forward-looking statements. In addition, this call contains time-sensitive information accurate only as of the date of the live broadcast, September 14, 2026. Cullinan undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this call.

As shown on Slide 3, joining me on the call today are Nadim Ahmed, Cullinan's Chief Executive Officer; and Dr. Jeff Jones, Chief Medical Officer. It is my pleasure to now turn the call over to Cullinan's CEO, Nadim Ahmed. Nadim?

Thank you, Nick, and welcome, everyone, to our call today to discuss the remarkable and potentially practice-changing results for zipalertinib in combination with chemotherapy from the Phase III REZILIENT3 trial in first-line EGFR exon 20 insertion mutation non-small cell lung cancer. Today, we're very much looking forward to providing you with an overview of the results and also our perspective of the exon 20 commercial opportunity, where we firmly believe zipalertinib combination therapy will become a first-line standard of care treatment.

These results were showcased last night as a late-breaking oral presentation during the Presidential Symposium at the World Conference on Lung Cancer in Seoul, South Korea. The fact that the study was selected for this plenary session is a clear testament to the significance of these results. I will also point out that the Presidential Symposium is focused on featuring notable advances in lung cancer research and treatments with the potential to change clinical practice.

And so before I ask Dr. Jeff Jones, our Chief Medical Officer, to dive into the REZILIENT3 results, I would like to take a moment to emphasize key elements of the compelling profile of zipalertinib for patients with exon 20 non-small cell lung cancer. Zipalertinib, which we're co-developing with Taiho Oncology, is an oral EGFR inhibitor with unique design characteristics that enable a potentially best-in-class efficacy and safety profile.

It was just a few weeks ago when we first announced that the REZILIENT3 trial met its primary endpoint of median progression-free survival early at a planned interim analysis. This is the first and only study in first-line exon 20 non-small cell lung cancer to achieve its primary endpoint at the interim analysis. The 6-month improvement in median PFS demonstrated by zipalertinib combination therapy is the best PFS result observed to date in the frontline setting. And in fact, the first treatment that has shown a median PFS longer than 12 months in this patient population.

In addition, Phase II studies have already demonstrated the differentiated and broad clinical profile of zipalertinib across multiple patient subsets. Zipalertinib monotherapy has demonstrated clinically meaningful results in relapsed patients, in patients with brain metastases and patients harboring uncommon mutations. And with our comprehensive clinical development program, we have the opportunity to establish zipalertinib as a future standard of care across multiple EGFR non-small cell lung cancer indications.

Firstly, in the second-line setting, our NDA for treatment of relapsed exon 20 non-small cell lung cancer based on the results of the Phase II REZILIENT1 trial is under active review by the U.S. FDA. The results of the Phase III REZILIENT3 trial, the subject of today's presentation, enable potential indication expansion into the frontline setting. Our parallel REZILIENT2 Phase II study is enrolling a cohort of patients with uncommon mutations in the metastatic disease setting, where we showed promising response rates already. And finally, Taiho has the Phase III REZILIENT4 trial, an ongoing adjuvant study in patients with exon 20 and uncommon mutations, and we look forward to sharing these data in the future. And with that, let me turn it over to Jeff to dig into the zipalertinib REZILIENT3 pivotal results. Jeff?

Thank you, Nadim. As Nadim said, we are excited to share results from the randomized Phase III portion of the REZILIENT3 study. To begin, let's review the study design. REZILIENT3 is a Phase III clinical trial to evaluate the efficacy and safety of zipalertinib in combination with chemotherapy in adult patients with previously untreated locally advanced or metastatic non-small cell lung cancer harboring EGFR exon 20 insertion mutations. Patients were randomized 1:1 to 1 of 2 treatment arms.

In the investigational arm, patients were treated with oral zipalertinib 100 milligrams twice daily in combination with platinum-based chemotherapy. In the control arm, patients received only platinum-based chemotherapy. As of the May 2026 data cutoff, the study enrolled 279 patients, of which 140 were treated with zipalertinib plus chemotherapy and 139 were treated with chemotherapy alone. The primary endpoint for the study was progression-free survival as assessed by blinded independent central review per RECIST criteria.

While the primary analysis was expected after 162 progression-free survival events, a preplanned interim analysis was to be conducted after 122 progression-free survival events. Of the 140 patients randomized to zipalertinib plus chemotherapy, an impressive 62% of patients were still receiving treatment as of the data cutoff. Slide 7 summarizes key attributes of the enrolled patient population. While EGFR exon 20 insertion mutations occur with higher frequency in Asian populations, nearly 60% of patients were enrolled in centers outside of Asia, primarily in the U.S. and Europe.

More than half, nearly 60% of all enrolled patients had an ECOG performance status of 1. But most notably, approximately 31% of patients enrolled had a history of brain metastases, a rate far higher than the previous PAPILLON and WU-KONG28 studies and a rate more representative of real-world patient populations. As noted previously, the primary endpoint of this Phase III trial was progression-free survival depicted by treatment group on Slide 8. Zipalertinib plus chemotherapy delivered a remarkable statistically significant 50% reduction in the risk of disease progression or death.

Zipalertinib plus chemotherapy demonstrated an unprecedented median progression-free survival of 14.5 months compared to a median of 8.5 months for chemotherapy alone, a statistically significant and more importantly, clinically meaningful difference of 6 months. Extending beyond the previous ceiling of less than 12 months, the progression-free survival of 14.5 months and an absolute benefit of 6 months over chemotherapy alone is truly without precedent and underscores the potentially practice-changing strength of these data. Other efficacy variables are summarized on Slide 9.

Zipalertinib plus chemotherapy demonstrated a 65% objective response rate, comparable to the results previously reported for the PAPILLON and WU-KONG28 regimens employing amivantamab and sunvozertinib, respectively. What stands out, however, is the durability of response and clinical benefit. Zipalertinib plus chemotherapy demonstrated a median duration of response of 14.2 months, again, unprecedented in this patient population. Turning now to Slide 10. While the results were still maturing at the May 2026 data cutoff, initial overall survival outcomes are promising.

While not yet statistically significant, the hazard ratio of 0.72 favoring zipalertinib plus chemotherapy is very encouraging. The management of CNS metastases in patients with non-small cell lung cancer remains a critical unmet need. So the subgroup analysis of patients with CNS metastases depicted on Slide 11 is very important. Survival outcomes in this patient group were favorably impacted by treatment with zipalertinib plus chemotherapy. Patients with CNS metastases experienced a notable improvement in progression-free survival when treated with the combination regimen, a PFS hazard ratio of 0.38.

Now moving on to Slide 12. While patients who received zipalertinib plus chemotherapy did experience a higher incidence of adverse events and treatment discontinuations, dose reductions and supportive care may favorably impact patient management. Importantly, higher grade adverse events were most frequent during the first 4 cycles of platinum combination chemotherapy, particularly hematologic adverse events, and higher-grade hematologic adverse events were notably less frequent and less severe thereafter. Adverse events occurring in more than 25% of patients are detailed on Slide 13.

In general, the safety profile of zipalertinib plus chemotherapy was consistent with the safety profile of the individual agents and consistent with the previously reported zipalertinib monotherapy data. The most common treatment-emergent adverse events in this study were low-grade EGFR-related dermatologic toxicities and chemotherapy-related cytopenias. While direct cross-trial comparisons cannot be made, treatment with zipalertinib plus chemotherapy demonstrated a differentiated profile with regard to Grade 3 or higher diarrhea and rash. Both adverse events are well-known on-target toxicities associated with EGFR tyrosine kinase inhibitors.

The overall incidence of rash and diarrhea was also lower. Now to summarize. For patients with EGFR exon 20 insertion mutations, these data represent some of the best results yet reported in the first-line setting. The combination of zipalertinib and platinum-based chemotherapy reduced the risk of disease progression or death by 50% and delivered a statistically significant and clinically meaningful 6-month median PFS improvement as first-line treatment for patients with EGFR exon 20 insertion mutation non-small cell lung cancer.

While the survival data are not yet mature and the observation is not yet statistically significant, at the interim analysis, there was already a favorable trend toward improved overall survival among patients with zipalertinib plus chemotherapy. Importantly, the observed safety profile of the zipalertinib combination regimen was manageable and largely consistent with the safety profile of the individual components of the regimen.

Lastly, the independent data monitoring committee recommended unblinding the study and crossover to zipalertinib monotherapy will be allowed. Continued follow-up is ongoing to further characterize the overall survival benefit and other exploratory endpoints.

Now I'll turn the call back over to Nadim, who will highlight how zipalertinib fits into the exon 20 treatment landscape and the commercial opportunity in that population.

Thank you, Jeff. Despite the data sets from the PAPILLON and WU-KONG28 studies, there is still a persisting unmet need for patients with exon 20 non-small cell lung cancer. The REZILIENT3 study results for zipalertinib combination therapy clearly demonstrate the regimen's potential to be a best-in-class treatment for patients with first-line exon 20 non-small cell lung cancer. Zipalertinib combination therapy demonstrated a median duration of response of 14.2 months and median PFS of 14.5 months.

While direct comparisons across studies can't be made, the 6-month difference in median PFS is an unprecedented result relative to the results observed to date in the frontline exon 20 setting, where previously a 3 to 4.5 month median PFS benefit has been observed for monotherapy and combination therapy, respectively. These data also support a combination approach over monotherapy treatment with a tyrosine kinase inhibitor for improved clinical outcomes in the frontline setting. REZILIENT3 also enrolled the highest percentage of patients with brain metastases as compared to other first-line trials in this patient population.

The results for zipalertinib combination therapy in this specific patient population with difficult-to-treat disease are also very encouraging given the unmet need and growing population of patients with brain metastases. We also previously shared the promising results of zipalertinib monotherapy in patients with relapsed exon 20 non-small cell lung cancer from the REZILIENT1 study, where, again, there was a higher proportion of patients enrolled with brain metastases. The progression-free survival results in the relapse setting are also encouraging, indicating that both responding patients and those with stable disease derived clinical benefit from zipalertinib treatment.

Relative to amivantamab plus chemotherapy as well as sunvozertinib monotherapy, we're also encouraged by the safety profile of zipalertinib combination therapy. Overall, zipalertinib combination therapy demonstrated a differentiated safety profile for adverse events associated with EGFR inhibition, including skin toxicity and diarrhea, which supports the proposed mechanism of action being more selective for mutant versus wild-type EGFR. The observed safety profile taken together with the unprecedented efficacy results discussed today and robust clinical activity across different segments of patients with non-small cell lung cancer, provides a clear opportunity for zipalertinib to become a new standard of care across multiple disease settings, which has always been our focus for the program.

On Slide 18, looking at the potential opportunity for zipalertinib in the U.S., approximately 16% of non-small cell lung cancer cases harbor EGFR mutations with insertions of exon 20 accounting for up to 12% of these mutations. This results in a relatively conservative annual U.S. incidence of approximately 3,000 first-line patients and 1,500 second-line patients and, importantly, represents an important $1 billion-plus total addressable market opportunity. With the clinical data delivered by zipalertinib regimens in the frontline and relapse settings, we would expect significant uptake and large market share across patient segments.

With our partner, Taiho, we also have future opportunity for continued revenue expansion by generating important data in our ongoing REZILIENT2 and REZILIENT4 studies, where Taiho is exploring zipalertinib in uncommon EGFR mutations in the metastatic setting and as an adjuvant therapy in both exon 20 and uncommon EGFR mutations. In addition to the previously received upfront payment of $275 million, zipalertinib offers Cullinan a very attractive strategic and economic opportunity as a potential source of nondilutive capital and our collaboration with Taiho offers a very cost-effective commercialization approach to unlock the near-term $1 billion-plus exon 20 total addressable market opportunity.

Recall that with our partner, Taiho, we have a co-development and co-commercialization agreement in which Cullinan retains a 50-50 development cost share and a 50-50 commercial profit share in the U.S. Importantly, in addition to the profit share, Cullinan is also eligible to receive a total of $130 million in additional near-term payments for U.S. regulatory approvals of zipalertinib in second-line and frontline exon 20 non-small cell lung cancer. Importantly, our partner, Taiho, is leading the commercialization activities and Taiho already has 3 commercially approved products with an established and efficient infrastructure for the commercialization of zipalertinib.

To conclude, on Slide 20, the compelling and potentially practice-changing results from the REZILIENT3 study established zipalertinib combination therapy as a highly competitive regimen with the potential to become a new standard of care in the frontline setting for patients with exon 20 non-small cell lung cancer. Importantly, these data also support combination therapy as the optimal approach in the frontline setting compared to single-agent tyrosine kinase inhibitor treatment by demonstrating the best observed median PFS, the best observed median duration of response, significant clinical activity in patients with brain metastases at interim analysis, an early positive overall survival trend has already been observed and manageable rates of EGFR-associated adverse events.

From a regulatory perspective, in April 2026, we announced our NDA in relapsed exon 20 non-small cell lung cancer was accepted for review by the U.S. FDA and our next step together with Taiho will be to discuss these first-line results with the FDA. Lastly, as we approach these important regulatory approvals, our collaboration with Taiho offers significant near-term nondilutive capital, which also allows continued investment in our promising T-cell engager pipeline across immunology and oncology.

Thank you for your attention, and I'll now turn the call over to the operator to take your questions.

Our first question comes from the line of Brad Canino with Guggenheim Securities.

Congratulations on the great data this weekend. Two questions from me. One is just as you speak to physicians with these data, what are you hearing about potential market share in their practices for this regimen versus the monotherapy or amivantamab? And then second, anything that you saw in the study around rates of AEs around the heme tox and management of it that was different across regions? There was a pretty big difference in the hazard ratio in the forest plot for the different regions. And I'm wondering if that was a cause of that or if that's just something that happened in the numbers?

Thanks, Brad. I'll take the first half of your first question, and then I'll pass it over to Jeff for the rest of question 1 and 2, since he is on the ground in Seoul. So I think from an uptake perspective, something we've heard very consistently for use, for example, in the combination therapy setting with the PAPILLON study and amivantamab is that the EGFR-related toxicity, especially related to skin toxicity is quite difficult to manage. And so we have seen in the frontline setting, even post the PAPILLON results that some physicians have still opted for platinum-based chemotherapy in the face of some of these adverse events, and we've been told that physicians have been waiting for our results.

So I think certainly from a EGFR-associated toxicity, I think we have a very strong profile, and we would expect large market share in that frontline setting. The second thing I think that's important to note as well is that between both the PAPILLON study and now our study, it's clear that the combination therapy approach is going to be more optimal than a TKI monotherapy approach just based on the progression-free survival alone across both of those studies, certainly compared to sunvozertinib data to date and the fact that we're starting to see an OS benefit as well, which was shared in that same symposium with combination therapy approaches.

So I think our view is from a positioning perspective, especially in a disease like exon 20 non-small cell lung cancer, which has particularly poor prognosis that most patients are going to opt and physicians for combination therapy. And then within that combination therapy, I think we do believe we have a potential best-in-class profile. But let me turn it over to Jeff to address both what he's hearing on the ground from physicians as well as your question around regional AE rates. Jeff?

Yes. So I would just underscore that in almost all situations in oncology, patients do best when you lead with your best efficacy. So I think far and away, achievement of a 14.5-month progression-free survival in the zip plus chemo arm cannot be discounted in any way. It's remarkable. It's the first time that a randomized study has demonstrated progression-free survival in excess of a year. Every way you cut it across all relevant subpopulations, patients are benefiting. And I think that's the overwhelming impression that people walk away from these data.

Now in terms of the adverse event distribution, there are a number of factors that could explain some of the adverse events, particularly hematologic adverse events as well as management of adverse events. So Taiho are continuing to look at the data to understand regional variation in AE management, the issue that you raised, Brad, which could potentially explain some of the observations. Some of the hematologic toxicity could be different depending on the platinum agent used with carboplatin being much more likely to induce higher grade cytopenias. So a lot of that analysis is yet to come since what was presented here at World Lung was based on top line data from the interim analysis. So still a lot of data to mine to better understand the pattern of adverse events and their management.

Yes. And I would just add to what Jeff says before moving on, Brad, is, look, any way you look at the PFS Kaplan-Meier curves, we see the separation very early and it stays consistent. So even in the face of any additional AEs or any sorts of discontinuations, the benefit accrued to patients is very early and very persistent. And as Jeff says, we haven't seen a median PFS of longer than 12 months in this setting previously. So obviously, we're very encouraged by the results.

Our next question comes from the line of Matthew Phipps with William Blair.

Congrats on the very strong data here. Just wondering if you saw any difference in activity between near loop versus far loop mutations that was brought up by discussant as an outstanding question? And then can you remind us maybe how many patients would present with brain mets at diagnosis in your expectations given the very strong results there?

Yes. Maybe the last part of your question, I'll take it and then I'll pass it over to Jeff. I mean, qualitatively, at least, Matt, I would say that patients do tend to accrue brain mets over time through lines of therapy. So you do tend to see it grow between the frontline setting as you go through the relapse setting just based on the biology of the disease. But let me pass it over to Jeff now.

Yes. So Matt, while that was brought up by the discussant, I would emphasize that right now and with the discussant, no one is making treatment decisions based on near loop, far loop, helical, like location of a mutation in exon 20. The data is insufficient from any study to guide practice in that respect. In the REZILIENT3 study, that data is being collected, but has not yet been analyzed. So it is something that we will ultimately be able to answer, but can't today.

Yes. And then just to close out on the brain mets question, Matt, I think this is one where now consistently across both the frontline and the relapse setting, our studies have accrued more patients with brain mets, relatively speaking, in both of those settings. And we clearly saw very encouraging response rates in brain mets in the relapse setting, active brain mets, I'm talking about now. And in the frontline setting, we're obviously pleased with the subgroup analysis showing the robust PFS in the brain met population, which we haven't seen with other molecules in this setting. Thanks for your question.

Our next question comes from the line of Andrew Berens with Leerink.

Congrats on the data, and I appreciate you guys doing the event. Yes, another one for me on the brain mets. Just can we get some additional color on the activity you're seeing? And did notice that there was an imbalance in the brain mets patients in the arms of the trial. Any reason for that? And do you think that there's any implications given that the upper boundary does approach 1, although it is below 1?

Thanks, Andy. Jeff, do you want to take that question?

Yes. So any imbalance in the arms is simply a sort of artifact of randomization. So there's no other reason for it than that. But what we know from the REZILIENT2 study, this is a Phase II study where Taiho is very carefully characterizing the intracranial response rate of zipalertinib is that the drug has about a 30% intracranial response rate in patients with active brain metastases, including some patients with leptomeningeal disease, the hardest-to-treat subset of patients with CNS metastases.

So the drug does have documented demonstrable evidence of intracranial activity. And I think in this study, as the discussant pointed out, not only was it that patients could have previously treated brain metastases, patients in this study could have untreated brain metastases, some of which were up to 2 centimeters in size. So not only is there a higher frequency of patients with brain metastases, these are not the same patients with brain metastases as in the WU-KONG or PAPILLON comparator trials. So I think that makes the outcomes here all the more remarkable in that patient population.

Can I just clarify to the -- and the reason that previously treated versus non-previously treated is important, I think, is because some patients come into the trial after getting radiation and there could be a delay in the actual activity that you see in shrinking the tumors. Is that why it's such important?

Well, I mean, it's because those patients will have had actual treatment for brain metastases, yes. So their brain metastases are more likely to be under control than a patient with a larger brain metastasis or one who hasn't had. It's less a delay in -- I'm not sure if you're meaning a delay in starting systemic therapy or you're saying that it could potentially delay progression in the CNS from having prior treatment?

Yes. No, I just -- I've heard from some KOLs that sometimes patients come into the trial, they might have gotten radiation therapy a few weeks before the trial, month before and that some of the shrinkage then is seen from the prior therapy and [indiscernible] single-arm trial.

Yes. But in this instance, we're not assessing the patients. I mean the outcome is progression-free survival. So we're not assessing shrinkage of the patient's tumor because of prior radiation or any other prior therapy. I mean, this is where patients often fail in the CNS. But I think this is a really robust outcome in those patients.

Thanks, Andy. And just to clarify on the question of imbalance, the brain mets in both arms was around 31%. So they were very similar. Thanks, Andy.

Our next question comes from the line of Alex Thompson with Stifel.

Let me add my congrats on the data. Maybe 2 from us. I guess on the sort of progression of the data and the maturation of the data over time, can you speak a little bit to how you would expect discontinuation rates to evolve over time from here? And then secondly, can you talk a little bit about the nuts and bolts of sort of the profit sharing here and how you plan to recognize revenue?

Yes. I'll take the second one first, Alex, and pass the first 1 back to Jeff. So Taiho will book the sales, and we'll -- we take in the 50% of the net profit. So it's fairly straightforward from that perspective. Jeff, do you want to take the other question about what we expect to see with discontinuation rates over time, given most patients have now been treated?

Yes. So as Dr. Tian pointed out in the presentation, the higher-grade adverse events were largely confined to the first 4 cycles of treatment when patients were receiving zipalertinib in combination with platinum chemotherapy. And the higher-grade adverse events, particularly hematologic adverse events, really fell off dramatically in the subsequent 4 months and beyond. So I expect, as we saw with zip monotherapy in the relapsed/refractory setting that the drug is well tolerated for longer-term administration when it's not being given in combination with platinum.

In terms of what we continue to look for, we'll, of course, continue to look for the adverse event profile over time. But I would also reemphasize the really positive trend in overall survival that was already emerging at only 30% information for overall survival. Again, not yet statistically significant, but an early separation in the curves that is very encouraging given the magnitude of the progression-free survival outcome.

Our next question comes from the line of Samantha Semenkow with Citi.

Congratulations on this data as well from me. Just another one on the brain mets. I'm wondering how we should think about adoption in terms of how physicians are assessing whether the patient has brain mets or not at the start of treatment. How much emphasis do physicians tend to put on the subgroup analysis for driving treatment decisions? And then just from the commercial opportunity perspective for zipalertinib, how should we think about time to profitability for the collaboration for Cullinan?

Thanks, Sam, for your question. So I'll take the second one first, and Jeff can take your first question around brain mets and the importance of treatment decisions upfront in the face of brain mets. So from a commercial perspective, I think, look, we're very, very pleased with the results. I think painting the broader picture of how do we think ultimately patients with frontline exon 20 will be treated. I think 2 things I'll point out.

It's become very clear between both the PAPILLON and REZILIENT3 results that you get the best efficacy results when you use combination therapy over TKI monotherapy, if you compare the results relative to what we've seen at least so far with sunvozertinib. And as Jeff said earlier, in oncology, the approach is use your best treatments first. So we see the vast majority of patients receiving combination therapy upfront. There may be a group that are contraindicated for chemotherapy or that are frail that they may be candidates for monotherapy. We expect that to be the minority of patients.

I'm also going to address your first question by one about in some ways from a commercial perspective, at least. I think the fact that we now see clear activity in patients with brain mets in both the frontline and the second-line setting and that we have studies that have overenrolled patients with brain mets.

I think that's a very strong commercial position. So when clinicians are going to choose between combination therapies, I think they're going to look at the fact that we've had the longest PFS reported to date, we've broken that ceiling of median PFS of 12 months, as Jeff said earlier, and the fact that we have very robust activity in patient brain mets. I think our view is that within the combination patient segments, which will be the majority of patients, that the first choice will be zipalertinib plus chemotherapy. In other words, the zipalertinib combination therapy regimen. But let me hand it over to Jeff now to address the brain met question.

Yes. I think, Sam, it's an important question since for EGFR patients in general, exon 20, perhaps more so, more than 50% of them will ultimately have CNS metastases. So it is literally an important and growing problem as survival continues to improve for this group, being able to address CNS disease is an important consideration in improving outcomes for the group as a whole.

So I think it's a very important consideration in selecting therapy. Again, patients with most cancers do best when you lead with your best therapy. And I think that's just one of the characteristics that really make the data that we presented yesterday morning quite compelling.

Our next question comes from the line of Phil Nadeau with TD Cowen.

Let us add our congratulations on the impressive data. A few questions from us. So first, on submitting the first-line data to the FDA, can you talk a little bit more about your strategy? Is there a chance that you can get a simultaneous approval for first line and second line?

Second question on overall survival. Can you remind us of the statistical analysis plan? When will the next analysis looking at overall survival take place? And then last, just in terms of the PFS, it did look like the control arm PFS in this trial was a bit longer than in some of the precedent studies. Any thoughts as to why that could be?

Great. Thanks, Phil. Let me -- I'll take your first question around FDA interactions, and then I'll pass over the other 2 questions on OS analysis timing and also your PFS question. So I think, look, I don't want to get ahead of our partners, Taiho, who are the IND and NDA holders. So I think our view is we're very excited about these results, and we want to continue to have discussions with the FDA.

I'm not going to speculate about what those sorts of approvals look like. But I do think these results are compelling, and I think the FDA will find these results compelling, and we'll update you in the future on that question. Jeff, do you want to take the question around subsequent OS analysis timings and the other question on the outperformance of the -- on PFS on the control arm in the study?

Yes. Let me take the last one first because I can't explain it. I don't think we have a good answer for why chemotherapy would have done better in the patients that we -- were enrolled to REZILIENT3. But in general, it would tend to bias the outcome of the study against us. And so not only did it not, but we were able to read out this really important progression-free survival outcome at the time of the interim analysis.

And so even with fewer events, the magnitude of benefit emerged, as Nadim mentioned, very, very early as progression-free survival curves separated. In terms of the overall survival analysis, it was timed again to be conducted when we reached the number of events required for the -- that would have been required for the primary analysis, which is expected later this year.

Sure. The thing I will add to what Jeff just said also is the fact that we have a 6-month improvement in progression-free survival at interim analysis. So we're seeing that early. We're obviously very excited about what the OS results could become. But obviously, we'll follow those patients up for survival.

Our next question comes from the line of Kaveri Pohlman with Clear Street.

Congratulations on great results. Just on the CNS benefit, is there any literature or clinical experience or emerging evidence suggesting that stronger CNS activity during initial treatment could translate into reduced risk of developing brain metastases as the disease progresses, supporting first-line use of zipalertinib?

And just like an additional follow-up as the data matures, which secondary endpoints or longer-term efficacy measures do you view as most important in influencing physician adoption and treatment preference? And from the regulatory perspective, also, do you expect you would be comfortable moving forward with filing based on current data set or you want to wait for the mature data?

Sure. Thanks, Kaveri. Let me take questions 3 and 2 in that order, and then I'll pass on the question to Jeff around brain mets and risk of subsequent relapse. So from an FDA perspective, I will point out that our view, and if you follow the precedent, for example, the PAPILLON study is that we don't need OS for regulatory approval. So the base of approval typically has been progression-free survival.

So our view, Kaveri, is we don't need any additional data for a frontline approval. Of course, OS is clinically meaningful, and we will continue to follow those patients. And again, the fact that we see such a large PFS benefit early at the interim analysis makes us feel very encouraged about what the OS benefit could be in the future. But our view is that PFS is what you need for regulatory approval.

Secondly, in terms of endpoints, it links back to what -- to the answer to this question. Obviously, OS is going to be important. We're going to continue to follow that. PFS2 is looked at these days as well. So you want to see from randomization to, for example, the second relapse, are you continuing to see the benefit. So that will also be an important endpoint to continue to follow. But again, I'll emphasize that it's PFS that's required for regulatory approval, and that's what we're going to be moving forward with. Jeff, the question on brain mets and subsequent risk of CNS relapse?

Yes, it could. I think the most robust data supporting that CNS control is in part what drives improvements in progression-free and overall survival in EGFR-mutated non-small cell lung cancer comes from osimertinib. I mean the FLAURA study demonstrated greater intracranial control and that, in part, drove improvements in progression-free survival. When you add chemo to osimertinib, you get further improvement in intracranial control. You saw further improvement in both progression-free and overall survival. So I think that's the precedent.

Our next question comes from the line of Julian Harrison with BTIG.

Let me add my congratulations on these impressive results. On the topic of brain mets driving relapses in this setting, to what extent do you expect zipalertinib CNS activity to perhaps translate to a longer-term overall survival benefit? And then second, I'm wondering what the physician feedback has been on the higher-grade cytopenias. Can you give us a sense for how manageable these adverse events are and how they're typically navigated?

Great. Thanks very much. Jeff, do you want to take those 2 questions?

Yes. Oncologists know how to manage cytopenias. We learn from the day we start prescribing chemotherapy. So to the extent that these adverse events occurred during the chemotherapy combination part, the platinum combination part of the trial, physicians have a number of ways of managing this. One can be giving a different platinum, cisplatin, having a lower rate of hematologic adverse events, dose reductions, as well as growth factor support. So all of those things are a part of the armamentarium. All practicing oncologists are used to mobilizing to manage hematologic adverse events.

So in general, when we say that the adverse event profile in that respect is manageable, I think that's quite true. And notwithstanding the heme adverse events, patients benefited from therapy despite dose reductions. So I think that's generally the case in oncology, and I think that's demonstrated here. And then you had another part of your question, I believe.

Yes, brain mets. And do we expect an impact on OS by managing to address patients with brain mets, Jeff?

Yes, absolutely. So as we were talking about just a moment ago in response to Kaveri's question, that's kind of the experience that's been demonstrated in the FLAURA trials for osimertinib. And I think the same logic applies here. So very early, so only 30% information for overall survival already impacted by a significant number of crossover patients in the chemo arm for -- at the time of disease progression and yet a hazard ratio of 0.72 for overall survival, not yet statistically significant. But with the magnitude of progression-free survival, I think it's quite encouraging for what we expect to see in the future.

Our next question comes from the line of Sean Laaman with Morgan Stanley.

This is Catherine on for Sean. And my congrats on the data. Just on the adverse event profile, you discussed the drop-off in heme tox after cycle 4. I'm just wondering if you could separate how much of that reflects, like, completion of platinum versus dose reductions or other treatment modifications? And then can you clarify whether you observed efficacy being maintained in patients who required those modifications?

Jeff?

Yes. So for the first part of your question, I think it's largely discontinuation of platinum is a lot of the heme tox there is driven by the platinum and combination. In terms of your second question, I'm not sure I completely heard all of the question.

Yes, patients who had dose modifications, were they able to achieve efficacy.

While we haven't broken out a specific efficacy analysis for patients who had dose reductions, the efficacy reported reflects the patients as they were treated. So notwithstanding any dose modifications, the patients in the zip plus chemotherapy arm still experienced a median progression-free survival of 14.5 months, a 6-month improvement over chemotherapy alone, the first time that magnitude of benefit has been demonstrated in the frontline for zipalertinib. So I don't think in this instance that the dose modifications adversely impacted outcomes for the patients treated with zip plus chemo.

Our next question comes from the line of David Dai with UBS.

Also add my congrats on the great data here. A couple of questions from me. So during the discussion session, the discussant highlighted 9% rate of adverse event-related deaths compared with the lower rates recorded in competing Phase III studies, including 3 patients with treatment-related septic shock. Can you maybe provide some color on what gave rise to the deaths? Are these related to mainly patient characteristics? And how do you think the physician will view the reward here? And then second question on assuming potential approval for zipalertinib, which physician or patient segments do you believe represent the greatest early adoption opportunity?

So I think, David, it was hard to hear fully, but I think your first part of the question was around the AE profile, including deaths. And then I'll come back to you on the adoption question, but why don't we have the first question to Jeff. Jeff, are you there?

Sorry, managing from Seoul. So it's a little late in the evening here. So in terms of the adverse events leading to death, those are detailed in the presentation, and many of them were respiratory tract related events. So these are things that commonly occur in patients with lung cancer. And when you looked at the adverse events that were adjudicated to be treatment related by the investigators, that was only 3 patients in the zipalertinib and chemotherapy arm, the 3 patients with septic shock, as you mentioned.

And then I would add, David, in terms of adoption, again, I would go back to the fact that we see the PFS benefit so early and sustained. And remember, and we tend to forget this, but a reminder that exon 20 patients have a much poor prognosis than many of the other EGFR mutations. And so the point that Jeff made earlier, this is why it's important to address these patients with combination therapy upfront because this is a poor prognosis disease. So you need to be aggressive in your treatment.

And then any time we had any sort of dose modification or dose adjustment as physicians should do, especially in the first 4 cycles, that risk or tolerability risk was far outweighed by the PFS benefit we saw of over 6 months. And again, going beyond the previous 12-month median PFS ceiling we've seen in the frontline study. So I think, again, the overall benefit completely outweighs the competing risk from a tolerability profile perspective. So I think our view still is that we're going to get very large adoption across patient segments, starting with the frontline setting with zipalertinib combination therapy.

Our last question comes from the line of Boris Peaker with Jones Trading.

And let me add my congratulations on the data. I just want to probe a little more on the brain mets. Can you comment on what proportion of patients in each arm, the combo or the chemo arm experience CNS as their primary progression versus systemic outside of CNS progression? And a financial question, there's about $100 million in milestone upon frontline approval. I just wanted to kind of get a sense of is that one payment? Are there several conditions that add up to $100 million? And what could the timing of recognizing that milestone be?

Sure, Boris. I'll take that second question. That's straightforward. So it's a onetime payment following the U.S. approval in the frontline setting of $100 million. And then for the second line, it's $30 million to give a total of $130 million. Jeff, the question of site of relapse?

Right? Yes. So in the REZILIENT3 trial, we've not yet analyzed the patients by pattern of disease progression. So we're not sure, so I can't answer that question yet. In terms of patients as a whole, we know that the rate of CNS metastases is in excess of 50% ultimately in the lifespan of most patients with exon 20. So the risk increases as survival improves if they are not treated with CNS active therapy.

At this time, I'm showing no further questions. I would now like to turn the call back over to Nadim Ahmed, Cullinan's Chief Executive Officer, for closing remarks.

Thanks, Shannon, and thanks, everyone, for dialing in today. And our view is that these results are yet another example of Cullinan's strategy to match the right modality to the right target as well as our executional strength. It was a few years back, we entered into a partnership with Taiho with significant economic upside for Cullinan.

And together with Taiho, we're very excited about the potential to address the significant unmet need in exon 20 lung cancer and also being able to offer zipalertinib combination therapy as a best-in-class first-line treatment option for patients in need of efficacious, durable and tolerable therapies. So thanks again, everyone, for dialing in, and we look forward to keeping you updated in the future.

This concludes today's conference. Thank you for your participation. You may now disconnect.

All right. Well, good morning, everyone, and welcome to Cullinan Therapeutics Immunology Day. Today is an important milestone for Cullinan and also the way autoimmune diseases may be treated in the future. As you'll see when we share the highly promising data that we've now generated across our immunology programs.

At EULAR this past weekend, we were the first company to present company-sponsored data for a CD19 T cell engager. And today, we're excited to share with you additional new data. That is to say the initial multi-dose data for RA and also the first autoimmune disease data for velinotamig. I also want to offer you my personal perspective on the data we've generated. Many of you that know me know that I rarely use superlatives. But this data set not only exceeded our expectations, it blew them away with a single target dose of CLN-978 treatment.

Ladies and gentlemen, we may have a medicine in the making or 2. So today, we're going to walk you through our pipeline strategy, talk about our exciting data for both CLN-978 and velinotamig and the upcoming wave of near-term catalysts that we believe will drive significant value for patients and for shareholders. So let me start with our disclaimer statement. If we can go to the next slide. Okay.

During this event, management will be making certain forward-looking statements. So please consult the risk factors discussed in our SEC filings for additional uncertainties that could cause the actual results to differ from current expectations. So now let me review the agenda with you and introduce our speakers.

Today, we're going to spend a fair amount of time talking about the promise of T cell engagers in autoimmune diseases and how we're generating data that underpins that promise. So I'm going to start talking about our T cell engager strategy and why we believe this modality holds such promise to address unmet needs in immunology and also why we have selected 2 clinically validated and complementary targets with CD19 and BCMA.

I'm then going to ask Dr. Jeff Jones, our Chief Medical Officer, to talk about the emerging clinical data for CLN-978. And then Jeff is going to come back to talk about next steps in development for the program and also discuss the initial data that we've seen for velinotamig. We're very pleased to be joined by Dr. Ricardo Grieshaber-Bouyer, who's going to talk about the science of B cell depletion and immune reset and how the emerging data positions CLN-978 as one of the first T cell engagers indicating immune reset. We're also joined by Dr. John Tesser, who is going to provide his expert perspective on how CLN-978 could be incorporated into routine rheumatology practice in the community, importantly, where patients live and work. And Dr. Tesser is also going to share his personal experience of treating patients with CLN-978. I'll then come back, summarize our strategic perspectives and discuss next steps. And then, of course, we'll open up a panel Q&A session to address your questions.

So let me talk about why and where CLN sees -- where Cullinan sees itself in the T cell engager space. We're very excited about T cell engagers. We believe that this modality can really change the game across immunology and oncology. And that's why we now have developed a unique leadership position with clinical stage T cell engager programs that span immunology and oncology. At the same time, we're advancing a pipeline of T cell engagers that are addressing high-impact, clinically validated targets, ultimately with the goal of delivering best-in-class disease-modifying medicines.

Now I will say in immunology, T cell engagers offer a unique therapeutic proposition, if you think about it, rapid and deep B cell or plasma cell depletion to reset the immune system and ultimately deliver durable treatment-free remissions with a short course of therapy administered in the community outpatient setting. And that's really important for patients who are often on lifelong chronic medications, rarely experience treatment-free remissions, and have to deal with the ongoing accumulating burden of their disease, risk of infections, and often organ damage. The way we're addressing that challenge is through our own immunology portfolio, which is anchored by 2 cornerstone therapeutics, CLN-978 for CD19 and velinotamig addressing BCMA. And both of these programs now are in Phase I/II development.

At the same time, in oncology, we're continuing to advance CLN-049, our FLT3 T cell engager, which is currently in Phase I for relapsed/refractory AML. And as many of you know, we presented highly promising data for that molecule at this past ASH, where the unmet need remains profound. And look, the broader point here is that we've now built deep T cell engager expertise across targets and across diseases, which we're now applying to immunology with a portfolio that is differentiated and highly complementary. And so now I'm going to discuss how CLN-978 and velinotamig complement each other in the space.

This slide reflects the core of our immunology strategy. And I'm going to walk through in detail how CLN-978 and velinotamig complement each other scientifically before turning to the indications that we now have access to with these complementary mechanisms. CLN-978 targets CD19, an optimal target for rheumatic diseases where broad lineage depletion of pathogenic B cells is often important to induce clinical remission. Velinotamig, on the other hand, addresses BCMA on plasma cells, an optimal target for those diseases where the pathophysiology is driven by pathogenic autoantibodies that are produced by long-lived plasma cells. And with both of these molecules in terms of differentiation, they've been designed for high affinity for the target, whether it's CD19 or BCMA to enable rapid and deep immune cell depletion. And you'll see that reflected in the clinical data today.

And so as you think about it, we now have a very broad portfolio. And autoimmune diseases, the issue there is that it's a very complex heterogeneous set of diseases. And so we have a portfolio that's designed to address both BCMA and CD19 targeting to address distinct disease drivers that allows us access to the broadest set of autoimmune diseases. And so with that, I'm now going to talk about the rheumatology opportunity with CLN-978.

CLN-978 is our lead immunology program, and we're positioning it as an anchor drug in rheumatology, where there's very strong rationale for deep B cell depletion and where current treatments still leave significant unmet need. Our initial indications under development include SLE, RA and Sjogren's disease. But at the same time, we're looking to expand into additional high-value indications where there still remains significant unmet need, as you can see in this slide. Also, this slide shows you the commercial opportunity for the first 3 indications that we're pursuing for CLN-978.

So I'll start with lupus. If you look at the approved biologics in the space last year, they generated global revenue of greater than $3 billion, despite modest efficacy and relatively limited market uptake, which indicates a much larger opportunity in the future, especially for disease-modifying treatment. RA clearly is a very large market, lots of commercially successful drugs, but there remains a significant and persisting unmet need for those patients whose disease has become refractory to current treatments.

Sjogren's disease affects hundreds of thousands of patients. And this is a market that's very underdeveloped, very limited competition, but again, indicates a much larger opportunity in the future, especially for a treatment that can be efficacious and address the key driver of the disease versus addressing the symptoms. So taken together, the rheumatic diseases represent very large market opportunities for CLN-978 and for Cullinan. So now I'm going to explain to you why we need a second T cell engager in autoimmune diseases.

Velinotamig is the second cornerstone therapeutic of our immunology pipeline and allows us access to plasma cell-driven diseases. You'll know now that there's a growing body of evidence supporting BCMA as an important target. And as you'll see from the emerging clinical profile, we believe that velinotamig can be a highly differentiated molecule in this space. You can see on the slide, there are multiple expansion opportunities for velinotamig across autoimmune diseases and beyond, for example, organ transplant rejection. Many of these indications represent substantial commercial opportunities with significant unmet need. But importantly, they're clinically distinct from the rheumatology indications we're pursuing for CLN-978.

So our near-term development focus for velinotamig is nonmalignant hematology, where we see an expedited pathway to establish proof of concept. And in parallel, we look to expand into other plasma cell-driven diseases. So taken together, CLN-978 and velinotamig provide Cullinan with a differentiated and broad portfolio that spans both B cell and plasma cell biology, which allows us to address multiple large market indications in the autoimmune disease space.

So now I'm going to conclude my opening remarks by talking about where we are today and what the path forward looks like. Over the past 2 years, we've made significant progress across our immunology strategy. We've gone from concept to clinical execution. We have a very disciplined approach, including rigorous dose escalation, generating data across multiple indications, and you'll see the results of that work today. As I mentioned earlier, at EULAR, CLN-978 was the first CD19 T cell engager with company-sponsored data where we saw compelling efficacy with just a single target dose of treatment. We've now treated over 40 patients across rheumatic diseases. And at the same time, we're continuing to develop multi-dose regimens for lupus, RA and ultimately Sjogren's disease. Our goal for CLN-978 is for it to become the first CD19 T cell engager approved in autoimmune diseases.

With velinotamig, our partner, Genrix Bio, has established and initiated a Phase I/II study, which allows for rapid data generation. And you're going to see the promising product profile that we're seeing with the data that Jeff presents later. And now how do T cell engagers fit into the clinical treatment algorithm? Our view is in the near term, our T cell engagers have the opportunity to deliver unprecedented treatment-free remissions in later lines of therapy. But we're thinking way beyond that to a future where CLN-978 and velinotamig become the first-line disease-modifying treatments of choice across autoimmune diseases.

However, to get there from here, we really need to disrupt the pathway, and we need to move from chronic disease management to resetting the immune system and ultimately deliver durable treatment-free remissions with a short course of therapy administered in the outpatient setting.

So now let me turn the agenda over to Jeff, who's going to cover the emerging clinical profile for CLN-978. Thank you.

Walking up, thank you, Nadim. And you've really outlined the strategic vision for the program, but it's my job over the next several moments to really dive into the data to show why we believe that, that strategic vision can be realized and increased confidence that we have in the potential of CLN-978.

So to begin, I really want to focus on what has been over the last 6 months, remarkable execution by the team that I'm fortunate to lead. Many of the key members of the team are in the back of the room, and the data we're presenting is their collective effort, and I couldn't be prouder than I am today to share this data with you and to tell you that we've now treated 42 patients across the program, including patients with Sjogren's disease, where we expect to wrap up the single ascending dose component of the trial here over the next several -- here in the near future. Our focus today will not be on the Sjogren's patients. We'll be focused on the SLE and RA patients as we continue to advance the program with momentum.

So to provide an overview of the data, I just want to remind everyone listening here in the room and online about some key features of both the RA and SLE studies. So first and foremost, the majority of the data that you're going to see, the data that we presented at EULAR over the weekend is from the single ascending dose part of the trial. So patients there receive a first dose of 10 milligrams. And then in subsequent dose cohorts, they receive an additional potentially therapeutic dose. We've always called it potentially therapeutic dose on day 8. That ranges from 20 to 30 micrograms. And we've always anchored on the 30-microgram dose as being the dose where we expected to see efficacy since that's the dose at which we saw 1 of 3 patients with non-Hodgkin's lymphoma develop a complete response to therapy with CLN-978.

Another important feature of this trial is that all patients are removed from chronic immune suppression. This is not a combination study. This is a study of CLN-978 monotherapy. All patients have discontinued background immune suppressants at least 2 weeks prior to study entry. And so the efficacy parameters that we'll share today are patients who are experiencing clinical benefit from CLN-978 monotherapy. New in this data set, and I'll review the denominators so that you can all follow along on the next slide. But in today's data set, we will share additional data not only for patients with RA, the initial patients treated with the multi-dose regimen in Cohort 5 of that study, but an initial set of patients for safety observations from the SLE study who have received treatment with a multi-dose regimen.

On the left hand of the slide, you'll see the study population for both slides. Just a few things to note here. The SLE patients all have moderate to severe disease and should have failed not only therapies like prednisone and Plaquenil, but also an immunosuppressant or a biologic. In the case of RA, these are difficult-to-treat patients. These are patients who have active disease, at least one swollen joint, evidence of B cell-driven disease by positive autoantibody titers or a biopsy showing a lymphoid infiltrate and have received treatment with at least 2 disease-modifying therapies. 2 makes -- failure makes you difficult to treat. Keep that in mind as we look at who we really enrolled.

So I'll start first with the RA patients. The denominator here is the same as we presented at EULAR, 11 patients, including the first 4 patients treated with a multi-dose regimen. And as I said, difficult-to-treat RA is failure of 2 prior disease-modifying therapies. The median in this group was 6, and some patients had failed as many as 12, including some patients who achieved a remission after treatment with CLN-978. This is a group of patients who are older. Many of them have a several decade history of rheumatoid arthritis. These are difficult-to-treat patients indeed.

In the case of the SLE patients, they're younger. Most of them have received extensive prior therapy, median of 3 prior therapies. The majority treated with immunosuppressants and a minority with biologics. This really reflects the patient population here in the U.S. and globally treated for SLE. Dr. Tesser will provide his observations regarding the unmet need in patients with SLE. And I think we have enrolled a very representative patient population. A comment on the SLE denominator. Here, you'll see it has increased from 18 patients in our EULAR presentation to include 3 additional patients treated at the initial -- with the initial multi-dose regimen of 10 and then 20 micrograms on days 8, 15 and 22 of a weekly schedule.

So this is ultimately a safety study. So I'll summarize here safety. And in general, CLN-978 is a very well-tolerated drug. If you look at the column of Grade 3 and higher adverse events, there are a very limited number of Grade 3 adverse events. And the safety profile overall and looking at the column in the middle for the most common adverse events are generally mild events, many of them not clearly attributable to CLN-978, but potentially to the patient's underlying disease. The exception, of course, is CRS that was observed in 40% of patients. And on the next slide, we summarize the CRS experience. And I just want to make a couple of general comments about our observations.

So overall, the CRS profile is very reassuring and very favorable, particularly for patients treated at the 10, 20 and 30 microgram dose levels where the drug was very well tolerated with respect to CRS, mostly Grade 1, including the patients who received the 20-microgram dose in a multi-dose regimen. Only 2 cases of higher-grade CRS were observed. The remainder were Grade 1, the majority occurring following administration of the first 10-microgram step-up dose. So overall, like the general safety profile, we believe that the safety profile with respect to CRS remains favorable, particularly for the 20 and 30 microgram doses, which are the focus as we move into multi-dose regimens in the next phase of the program.

So you might have expected that the next slide would be B cell depletion curves. That's how we arranged it initially. But as we stepped back and we looked at what we had achieved, it was efficacy in excess of what we had expected. We've talked over the last several years about what to expect from the initial data set. And we truly, as Nadim shared, didn't believe that we would see this degree of efficacy. More than 70% of patients treated in this part of the study achieved some significant measure of disease activity.

At a minimum, the SRI, a 4-point improvement in hSLEDAI scores, which is a significant component of the regulatory endpoints of interest, the SRI-4 response. That hardly seems compelling in 2026. And that's why we're gratified to see that a significant number of patients achieved a deeper response. LLDAS, as well as DORIS remission, in 5 patients in the data set. Remarkable, remarkable, particularly after a single target dose of CLN-978, remarkable.

So I want to provide a bit more color about the patients to help your interpretation. So many of the patients enrolled at the lower dose levels at the top of the plot had primarily musculoskeletal and dermatologic manifestations of their disease. Many of those manifestations wax and wane over time, which explains some of the fluctuation that you observe in the swim lane plots. As we continue the trial, as confidence built in the drug and in our investigators, we began enrolling patients who had more objective measures of disease, including patients who had prior existing lupus nephritis, prior pericarditis, as we'll hear. And there, we have laboratory parameters that help us understand the dose response for CLN-978.

So on the next slide, we provide the plots for patients with objective laboratory parameters that help us again understand the dose response relationship for CLN-978 response. In general, you'll see as with clinical response here in the RA study, we see transient impact on laboratory parameters, double-stranded DNA and proteinuria at the 20-microgram dose, but we see deeper, more rapidly achieved and sustained impact on these important laboratory parameters, including restoration of normal serum complement levels on the right, when patients are treated at the dose of 30 micrograms, again, helping establish what we believe is the evidence for a dose proportional response.

Finally, the B cell depletion plots. So we know that the drug works, and now we know why it works because as we increase the dose escalation, we saw that the depth of B cell depletion increased. It's hard to tell differences between the 20 and 30-microgram dose with respect to B cell depletion in the plots on the left. But on the right, you see the time to recovery increases as we increase the dose. And that time to recovery is an indirect assessment of the depth of B cell depletion, clearly showing a dose response for CLN-978.

Right. Let's turn to rheumatoid arthritis. And at the start, I'll make comments about the additional data beyond our EULAR presentation. Here, you can see that the last 2 patients on the swim lane plot are patients who were treated at the 10/20 multi-dose regimen. These are the only 2 patients among the ones we had yet treated that had at least 4 weeks of follow-up beyond the completion of therapy, for which reason these are the 2 patients we are reporting today.

In general, we saw that CLN-978 was able to achieve a DAS28 response after a single dose of 30 micrograms. So a threshold dose at 30 micrograms for a single dose effect, but now as we drop the dose back and administered it in a repeat dosing schedule of 20 micrograms, we saw that we could likewise have meaningful impact on disease parameters in this heavily pretreated group of RA patients with 1 of the 2 patients achieving a DAS28 response -- remission, not response, remission. This patient, 11 prior disease-modifying therapies, prior rituximab refractory disease. This is remarkable after 40 years of RA, as we'll talk about.

So here, we also have laboratory evidence that conforms with the observations in the clinic. Here, a trend towards dose response and autoantibody titer reduction. But importantly, vaccine titers on the right remain stable beyond treatment with CLN-978. Memory humoral immune responses are maintained, which helps establish additional therapeutic index for CLN-978 in this disease area. As Nadim said, we believe CD19 is the best target for rheumatic diseases. And this is part of the reason why, because these patients who are already at increased risk of infection maintain their memory humoral responses.

All right. B cell depletion here. And you'll see, again, a similar trend to a depth of B cell depletion increased at the 20 and then 30-microgram dose levels. And then on the right, similar kinetics for recovery with patients in the 30-microgram cohort as yet unrecovering their B cell -- peripheral blood B cell complements at 12 weeks beyond starting treatment. So in clinical medicine, from the time you're in medical school, you really learn medicine by understanding individual cases and it is no different in clinical investigation and particularly in early phase clinical investigation, where as we dive into the data, we look at every individual patient to learn as much as we can.

So I want to share some of those individual cases to help you understand how they have created our understanding of the kinetics of CLN-978 response as well as the dose response that we believe we're observing. So the first patient I'll talk about is patient 007. This patient with 26 years of continuous rheumatoid arthritis, their prior therapies in the upper right corner on the panel, you can see 2 JAK inhibitors, 2 prior attempts at TNF as well as IL-6. And this patient came on to the study with highly active disease and had achieved a DAS28 remission at 8 weeks beyond starting treatment, sustained at week 12. This is remarkable. This is remarkable. This is a patient that before starting the study, I wouldn't necessarily have expected to have any meaningful clinical activity with CLN-978, a remission, remarkable.

I will make one comment on adverse events in this patient. This patient did experience CRS. She had Grade 1 CRS following the 10-microgram dose and Grade 2 CRS following the 30-microgram dose that was a transient decline in her blood pressure that responded to IV fluids. She also received tocilizumab and recovered quite well. But remarkable, the clinical impact for this patient with nearly a 30-year history of RA.

And what else did we see in this patient? Well, we saw that in the peripheral blood, the peripheral blood B cell count dropped precipitously and that B cell depletion is sustained through 12 weeks of follow-up, and there was a concomitant impact on autoimmune titers. When Dr. Grieshaber-Bouyer speaks shortly about the biomarker assessments, he'll dive into additional detail and show that we do know why we saw this response in this patient. We did something really remarkable at the tissue level in this patient that's achievable with CLN-978, something CAR T-like as we'll see.

Now in our first multi-dose experience, so that patient's single dose, 30 micrograms achieving a remission. Now we're moving back to 20 micrograms. And now we're treating the patient with a repeat dose of 20 micrograms on days 8, 15 and 22. And this patient, now a 40-plus year history of rheumatoid arthritis. And I remember from my medical school days just 5 years ago that there's a long history of therapies in development for rheumatoid arthritis. And this patient's treatment history reads like a textbook of rheumatoid arthritis drug development. This patient received treatment with sulfasalazine and auranofin in an era before methotrexate was approved in 1988. And yet this patient achieved a remission at week 4 following therapy with a multi-dose regimen of 20 micrograms of CLN-978, sustained at week 8 at the last time point for which we had data available.

This is really remarkable. It's even more remarkable when you consider that this patient had been previously treated twice with rituximab. The first time, a transient response of only 8 weeks, the second time refractory. But here, a remission. And so we understand why. So this patient was still from prior rituximab exposure completely B cell depleted in the peripheral blood. So we can't call it B cell kinetics. It's B cell statics, I guess. And here, that implies that the patient has achieved a response to CLN-978 solely for B cell depletion beyond what is achieved in the peripheral blood. This is the effect of tissue level B cell depletion with a repeat dose of 20 micrograms of CLN-978 in the absence of any concomitant medications. This is the potency of CLN-978.

I hope you understand how enthusiastic we are and completely convicted that in CLN-978, we have the potential to develop a drug, not a compound, a drug for the treatment of patients with a broad group of rheumatic diseases. These observations are compelling. They are similar in SLE and RA and they 100% give us conviction to accelerate this program into the next phases of development, as we'll talk about later this morning. We've seen the ability of the drug to achieve a remission in patients after a single target dose, not in 1 indication, but 2, both SLE and RA. We've seen that we understand why it works because of profound B cell depletion, not just in the peripheral blood, but also in the tissue. And that's achievable with a safety profile that is amenable to further development and ultimately, we believe, administration in the clinic. We'll have an opportunity to talk more about that experience shortly.

So the biomarker data for which this program is really enriched, is one of the aspects that makes this the most comprehensive data set yet presented for a T cell engager. And we are very fortunate to have collaborating with us colleagues from the University Hospital at Erlangen and Dr. Ricardo Grieshaber-Bouyer, who's joining us this morning. Ricardo really pioneered the development of T cell engagers in autoimmune development. Working in isolation. We both had -- both Cullinan and Ricardo and his colleagues had a similar good idea. Ricardo got there first as he has wanted to do, and he will talk a little bit more about the biomarker data and its implications for development of CLN-978. And then we'll follow that with a conversation with Dr. John Tesser, a community-based clinician and clinical trialist, who can share his perspectives on the unmet need in SLE as well as his experience in administering CLN-978.

So Ricardo, I'll turn it over to you.

Good morning, everyone. It's very exciting to be here today to present the idea of immune reset and B cell depletion for autoimmune diseases. So to give you a little bit of context for the 2 diseases that we talk about a lot today, rheumatoid arthritis and systemic lupus, I brought a chart to show you how B cell depletion, B cell aplasia and the length of B cell depletion, which also relates to the tissue depletion is linked to clinical responses and why you will hear several people today speak about the depth of depletion, the durability and the dose response that is being observed.

So this is a study that came from using rituximab, the first approved CD20 antibody in rheumatoid arthritis and looking at the link between the time of B cell recovery in the blood and the first flares or the relapse of rheumatoid arthritis. And what you can see here is that in the left chart, if you have no B cell reappearance, the dark blue line, that is the patient group that has the lowest rate of relapses and the longest durability of response, whereas if B cells come back less than 4 months after being fully depleted, then the patients have a much higher rate of relapsing.

And the similar thing is observed in lupus. So this comes from a different CD20 antibody, obinutuzumab, that was recently approved for lupus nephritis. And you can see here that compared to the placebo response of 18% of patients achieving a complete renal response. If B cells were detectable at least one time point after giving the B cell-directed antibody, then the complete renal response was 35%. But if the B cells were undetectable at weeks 24 and 52, then the complete renal response was even stronger. So this clearly establishes that there is a dose response from depleting B cells for a longer period of time in the blood and getting better clinical responses.

Now the problem with this approach is that for it to work, you have to deplete B cells constantly, and you're still not getting all B cells in the tissue. And the idea of immune reset is to shorten that amount of time, but to get a deeper depletion in the tissue to do a wipe out once and then get a B cell recovery with naive non-autoreactive B cells. And so this idea here is that with the conventional antibodies, you are depleting superficially and potentially even for a longer time period than with other emerging reset approaches like a T cell engager, but you're critically never getting below that threshold that would allow you to discontinue treatment and still maintain durable responses.

In contrast, the idea for a deep B cell depletion is that there is a certain threshold below which you have to deplete B cells and that in the tissue will lead to certain remodeling effect such as, for instance, the collapse of lymphoid structures in the lymph nodes. And then when B cells come back, the recovery can even be faster than this year or multiyear depletion with conventional antibodies, but nevertheless, you will have achieved reset. And needless to say, in the past few years, the world has essentially been standing upside down after seeing that deep B cell depletion can really revolutionize the treatment of many patients with refractory and life-threatening autoimmune diseases. These initial responses came from using autologous CAR T-cell therapy, which were a great proof of concept and pioneering work, but that have, of course, logistical challenges. And as we've seen now more than 5 years after the first treatment, this treatment approach still has the challenge of reaching the community setting.

So I became very interested in understanding what it was that deep B cell depletion accomplished and where rituximab failed and why it was the case that using T cell redirecting therapy such as a CAR T cell can disrupt the disease course in a more durable way. And I think the tissue here is really important to put things into perspective. As you can see here from a biopsy study of the inguinal lymph node, the B cells are not fully depleted after giving rituximab therapy, so the normal antibody. In contrast, using a T cell redirecting therapy, you can see a complete depletion of B cells in the tissue. And not only the depletion of B cells, but also the structures that surround the B cells, such as the lymphoid follicles, which collapse and probably play a key role in securing immune reset.

So in early clinical development, it's -- things can be very nuanced. But I think here, it's even better than being a bit nuanced because it's really exciting to see that there is a clear dose response of what we put in and what we get out as a result, as Jeff already mentioned in the morning. So you can see in the first cohort of the RA patient that the B cells were not fully depleted in the blood. In the second cohort going higher with a 10-microgram priming dose and the 20-microgram target dose, you can see complete B cell depletion in blood and then a very, very slow recovery with B cell reappearance at between 8 and 12 weeks. But then, in the next higher cohort of 10 and 30 micrograms, you can see extended durability of B cell depletion. So this shows you very clearly that we have entered the phase essentially of active doses and of potentially therapeutic and promising doses.

And then let's look again a little bit at what we can learn from the tissue and why it supports this idea that the higher dose regimens and the higher exposure gets us in the tissue to what we want to see. So you can look at the counts of CD19 B cells and CD20-positive B cells, which are somewhat interchangeable essentially in the tissue. And you can see in the 10-microgram dosing cohort that the patient started with a small amount, but then there was even a measurable increase. That's essentially a little bit, the uncertainty from the assay. But you can see in the 20-microgram cohort and in the 30-microgram where the patient clearly started with B cells in the synovium that they were depleted and that they were depleted in a dose-dependent way.

And then in the 30-microgram target dose, when you look at the effects on the lymph node, you can also see strong depletions, both in the 20 and in the 30-microgram cohort showing that there is depletion not just in the blood, but really also in the tissues. And that's something when we started using low-dose BLINCYTO off-label in RA that we did not see actually in the lymph node. So we saw the ability of a T cell engager to deplete in synovial membrane, but we always knew that the lymph node was quite hard to get B cell depletion. And that had, until that date, only been reported for CAR T-cell therapy.

So at the target dose of 30 microgram, we were -- I was a bit surprised actually to see this, but to see the ability to deplete the follicular architecture, which had been something that, as you can see here from the comparison of rituximab, BLINCYTO, obinutuzumab, and CAR T, had only been accomplished in the CAR T group and not in the other groups, whereas at the 10 and 30 microgram, it was also observed for CLN-978.

And again, if you look at the nuances a little bit between the data, it all starts to make sense because in the 10/20 microgram lymph node, you see a B cell depletion of actually a pretty strong B cell depletion of about minus 85% for the CD19 positive B cells, but you don't see the full collapse of the follicular architecture. And that is -- these types of small things are not noise, but they actually guide us in dose selection. And in this program, they line up very well with what has been seen clinically because that patient has had a longer and stronger response to CLN-978 in RA.

So based on what we've seen so far in this program, CLN-978 has demonstrated the potential to achieve clinical remissions in patients that were heavily pretreated and in the case of RA, exposed to up to 11 biologics or targeted synthetic therapies. So everything that is available with a median of 6, which is a highly refractory RA patient. Typically, for RA, patients are considered refractory if they have failed 2 different mechanisms of action. So this was a very, very strongly pretreated cohort that also had already joint damage.

Then both in blood and in tissue, there's a clear dose-dependent B cell depletion and the dose response is associated with better and more durable clinical responses. The depletion in synovium and in lymph node was seen after a single target dose. And so that establishes CLN-978 as the first TCE to show a complete disruption of the follicular architecture, which is comparable to autologous CAR T and is associated with immune reset. And overall, that has been accomplished with a favorable safety profile with really a CRS in the lower range if you look across different programs that are currently in the clinic.

So thinking a bit beyond RA and lupus, this is a perspective that we have recently published. We're also thinking about other indications where deep B cell depletion and plasma cell depletion might play a key role. And since this came out, there was the first proof of principle also for desensitizing highly sensitized patients before organ transplant and allowing them essentially to receive a solid organ transplant that before they could not get because they had alloantibodies.

So with that, I pass it on to John.

Thank you. Your experience as both a clinical and translational researcher is very helpful in contextualizing our observations in the trial, and we're really glad you could join us this morning. We're going to turn to the next part of our conversation, and we're very fortunate to have with us Dr. John Tesser. Dr. Tesser is a clinician and clinical investigator, practicing now in Phoenix, Arizona. And maybe as we just sort of start the discussion this morning, John, if you could -- well, first and foremost, me, many in the room, we often think we understand what the situation is in community practice where the majority of patients are seen. But I think you can really help us by talking a little bit more about your practice, a little bit about the patients you see, how they come to find their way into your clinic.

Sure. And I appreciate the opportunity to come and speak here. It's been a remarkable journey working with the Cullinan team and seeing how this molecule is developing. I think it's fair to tell you, first of all, that I'm a little bit older than I look. I'm a rheumatologist for 45 years. And so I was one of those guys who used one of those ancient and now extinct molecules, gold and auranofin and the penicillamine, these poisons that we only had available. And to give a mindset for everybody in the room, rheumatologists have been pretty much the opposite of oncologists in terms of thinking about how to treat disease. And way back when I was starting as a fellow up to a number of years after that, the approach was to continue to give people nonsteroidal anti-inflammatory drugs until they developed erosions and damage and then give them these other poisons that didn't work so well either.

So with that being said, I've been on staff at a teaching hospital in Maricopa County for 10 years before I went into practice. And in practice, my group, Arizona Arthritis and Rheumatology Associates, is now 25 rheumatologists strong and 50 advanced practice clinicians. And we have sites all over Arizona, 14 sites, and we have 3 sites in the Fort Worth/Dallas area, 60,000 patients combined that we see. And as you can tell, we have about 3,500 lupus patients in our practice. So that gives you a brief outline of where I've come from, where we are.

Also, we have a very strong research division. I've been doing clinical research and trials since the 1980s, hundreds of trials I've been an investigator primary or a sub-investigator on in all the disciplines of rheumatology. So it gives you an idea where we are.

No, that's certainly a wealth of experience that we've benefited from and will continue to benefit from as our research partnership continues. And I think maybe before we talk about what's new in SLE, maybe you could talk a little bit about the typical patient journey. So what do you do for patients with SLE? How do you characterize the unmet need? Because if we're going to solve a problem, we actually need to know what the problem is. So how do you see it from your standpoint?

People are sent to rheumatologists for everything from hair loss to ingrown toenails. I'm not kidding. We see it all. So if a patient is sent for a positive ANA, which oftentimes happens because the patient has back pain or because they have rash and swollen joints, which is quite evident to a primary care clinician, that patient who walks in with a malar rash, swollen joints, sores in their mouth, you don't even need a test to really understand what they have.

But the patient that's sent for a positive ANA and joint pain, that's much trickier. And that requires a delve into doing multiple studies of autoantibodies, trying to build up an understanding of their autoreactive profile, if you will. And then the difficult part is marrying what the patient's symptoms and physical findings are to those tests. We don't diagnose a disease on the basis of a test because 10% to 25% of everybody in this room has a positive ANA or a positive rheumatoid factor. So it's really important that the clinician really understands if the joint pain is from actual disease or maybe from tendonitis or something like that.

So the journey of a patient could be very difficult. It may take a number of years before that patient is bounced between a primary care physician and then maybe to an orthopedist, maybe to a dermatologist before they get to a rheumatologist who can put all those pieces together. And as you saw on the previous slide, there's a lot of arc to that. It takes a lot of experience. And it can be very difficult. But once the patient has been diagnosed with lupus, then the reflex reaction is appropriately to put that patient on the gold standard therapy for lupus, which is hydroxychloroquine, known as Plaquenil. A weird story there about an antimalarial drug that during the late 1940s and '50s was found to help people, particularly military people who had these diseases, RA and lupus and it got better. And so it was adopted into the practice of rheumatology in treating these patients.

But once they don't respond completely to that medicine, which is for most of them, then the idea has been to use prednisone, put the immediate fire out, and that usually means the patient is going to be on long-term prednisone, which we know is not a good thing. And then over the years, what's happened is the utilization and carryover of using disease-modifying antirheumatic drugs, conventional ones such as methotrexate, azathioprine, cyclosporine -- although that's not used anymore and others of that nature to treat lupus on top of the hydroxychloroquine. Mycophenolate is a very popular one now, particularly for lupus nephritis. And then you wind up having a patient on combination therapy almost from the get-go. I mean if the patient is not responding very well within 2 to 3 months with hydroxychloroquine, you're adding one of those medicines and trying to get a response.

The first medicine approved -- advanced medicine approved for SLE in 50 years was in 2011, which was Benlysta, belimumab. And that was a medicine that as typical for rheumatologists because I told you their background, they're very slow to utilize new medicines and advanced medicines, finally began to be utilized a lot more. It took about 7 or 8 years for that to happen. So that's a next step of therapy once you get beyond one of those others. And then finally, the next advanced medicine, which is a medication that interferes with interferon, which is anifrolumab, Saphnelo, that was approved 2022, I think. And that has been used now as well.

So those are the 2 advanced therapies. And the KOLs in the field, of which I'm one of them because I speak for these drugs, I speak for the companies, I'm a consultant, and there's about 150 or 200 of the 5,000 available rheumatologists who meet and do the advisory boards and such. We're on this bandwagon of right after hydroxychloroquine, use one of the advanced medicines because the goal of treating someone is remission. Remission is what we're trying to get at, but the problem is getting patients there.

Yes. And so understanding the challenge in getting patients to a remission, is there an ability to get patients, so they've started first with Plaquenil, steroids, you try to get them off. hopefully, with immunosuppressants or one of these advanced biologics. Do you have the ability today to put a patient into remission such that they stop everything?

In RA, it's very well understood that if you take medications away from patients, there is a 95% to 100% chance that they're going to flare. So that is highly looked at as not being the way to treat someone with RA. With lupus, it's not quite as clear. But at this point, I would say that most rheumatologists would not take medications away from patients unless they had demonstrated clear clinical remission for some time, sometime being at least 1 or 2 years.

Now clinical remission means no rashes, no oral ulcers, no alopecia, no swollen joints, no nephritis, no cytopenias, all of those things. Because if you take medication away, this is -- we don't cure these diseases. We manage them, we control them. You can see from the slide, the graphs on the right, the number of -- the percentage of patients on the 2 advanced medications who are put into remission is not much different of the modern medications we use for RA. It's only about 20% complete remission. And that's something that is a little bit frustrating to say the least because when we say medications are effective, that's in the face of that.

And so effective means you have to figure out, well, how effective and you sort of have to add it, well, low disease activity to remission because low disease activity is an acceptable outcome if you can't get people into remission. And then you have to consider how many patients you get there. So our ability to really get our patients into an excellent state is very limited. And therefore, there's this need for more medicines that work better than what we have and are actually safer than what we have.

And it's very clear, like patients with SLE need remission. And so let's talk now about your experience with CLN-978 and one of your patients is among the group that has shown the potential for CLN-978 to induce the remission. So maybe you could talk more about this young woman's case and your experience with CLN-978.

Yes. This was patient 31, if you remember the other graphs that were shown earlier. And she's a 32-year-old Hispanic lady, very nice lady, who had been through the mill with all kinds of medications, as you can see up there. There's your hydroxychloroquine and mycophenolate and list and methotrexate over those various time periods in the right upper corner there. And her disease was diagnosed in 2019. She had positive serologies, including an anti-Smith, double-stranded DNA, and polyarthritis. She had Class II and V nephritis, low complements, proteinuria, pleuropericarditis, Raynaud's and a history of a seizure disorder, so neuropsychiatric disease as well as though not active at the time that we treated her. But she had active rashes when she was entered into the trial.

And all of those characteristics of the patient's clinical profile belie the underlying fatigue malaise, you know how you feel when you come down with even just a cold or a flu, you just feel weird and you feel out of it and foggy and you kind of hurt all over and actually if people touch you, it hurts. That's a condition known as allodynia. It's actually a physical finding, a non-noxious stimulus that causes pain. So that's how these people feel most of the time when their disease is active. Their body is on fire, and this inflammation is everywhere. And the way it pushes out in an organ system here or there is just a reflection of what's going on inside of it.

So that's how this woman is feeling as well as anxiety and depression, which really are neurologic correlates of inflammation as well. And so her hSLEDAI was very active at the time that she was dosed. She had the active rash and proteinuria, active DNA binding. Her hSLEDAI was 8. At week 4, it was 6 after the initial dose. Her rash was already fading by then. At week 8, she was in remission and through week 12.

So that's -- it's an amazing outcome for your patient. And like you said, a relatively short history of SLE, but checked a lot of the more sort of calamitous complications of SLE. So we're very pleased to sort of see this. I know you were. Now there were adverse events. This patient experienced CRS. So maybe talk a little bit about your experience with grade CRS. You're in a community setting. This is not an academic practice. So what was that like?

We elected as a Phase I trial to utilize a vendor in town at a Phase I unit, actually run by a hepatologist group. And so this patient, her name is Cynthia. She was in that unit while she was dosed 24-hour observation. And she experienced some fever, but she also had a lot of nausea and vomiting. Her blood pressure remained stable. Hemodynamically, she was not compromised, but the clinical nurse practitioner who was overseeing this was reporting that she had a rough night through the 24 hours that this was going on. She was treated with acetaminophen for the fever. She didn't really require tocilizumab, and she got through it. So I mean, the grade of CRS was only 1, but it was rough for her just at that lower dose.

And then CRS on the second dose, how did that fare?

I don't think she had any.

No.

No. I think she really tolerated it very well.

Amazing. Amazing. So from your standpoint, when you think about that kind of safety profile, how do you view that as amenable in the future for utilization in a practice like yours?

Yes. That's -- I think that's a great question because rheumatologists are not used to thinking of adverse events in terms of CRS and ICANS. Oncologists certainly are. Rheumatologists are more concerned with hypersensitivity reactions, particularly infusible drugs, intravenous drugs, biologics, hypersensitivity reactions in anaphylaxis. As a matter of fact, when Rituxan was approved for rheumatoid arthritis in 2005, the rheumatology community was absolutely scared s-less, if you know what I mean, because we heard all these horror stories of what happens with the lymphoma patients when they were getting rituximab.

But it turns out that those reactions are actually relatively few and far between even with Rituxan for rheumatoid arthritis and even when it's used for lupus. So with CRS, this will be somewhat of an educational process for rheumatologists in terms of understanding what it is, what the grades mean because we don't use them. I'm familiar with them because I'm an investigator and how to manage them. But I think in terms of utilizing a new drug in the clinic, we're going to have to see how that plays out in terms of the hemodynamic issues that may occur in relationship to this. And I think as the development of program comes out more and more, and we see the frequency and the severity of these things, hopefully very low, that will give more confidence that this is utilizable.

But for a Grade 1 experience, if we could resolve it to Grade 1 or higher?

Yes, I don't think that people will accept that. I think that's manageable, as we say.

So with an acceptable, understandable side effect profile, what on the efficacy side, what now as an investigator and experience with TCEs, what most captivates sort of your aspiration for what a TCE could mean for the patients you care for?

Well, it's an amazing potential game changer. I think what we've seen with the patients so far in the study has been an unusual look at these very refractory patients who otherwise would be suffering ongoing with us playing around with the available agents. But something like this would definitely be highly advantageous. As an investigator, obviously, I'm an early adopter. I think the way it may be taken up by the community of rheumatologists remains to be seen. But I think that as younger people are coming out and they're seeing these more advanced therapies, I think that their utilization may be quicker than what some of my old cronies were able to wrap their hands and their heads around.

It was a changing world in oncology, too. And I can -- it was before I started practice, but rituximab even in oncology settings was often administered in the hospital and the initial launch there were nurses and things dispatched to the community to help onboarding clinicians and their nurses and advanced practitioners to adopt. So I expect it to be similar. But now it's as routine as administering IV fluid in most centers.

So John, thank you very much for your contribution to the program. As clinical drug developers, you are our eyes and ears. We can't do what we do without your assistance. We rely on you. And we thank you for your trust and contribution to the program, and we're really gratified to see this remarkable outcome for your patient and hope it's the first of many more to come. So thank you for joining us today.

You too. Thank you. Thank you for the opportunity.

And we'll have you back to answer questions. I want to shift the focus now for the last part of the conversation here about CLN-978 to really focus on how we see the next steps of development. So we have, again, in the life of anyone who's developed drugs for any difficult-to-treat disease, you find unique opportunities. There are some people who spend an entire career without landing on the drug that really works, that does exactly what it's supposed to do, and you have an opportunity to make it work in a way that could transform the lives of patients. That's the aspiration, but it's seldom achieved for the majority of people in our industry.

And we have that opportunity now for CLN-978. This is a drug that's shown capacity to induce deep responses and remission after a single dose. And we have every reason to believe that at those well-tolerated doses now administered and repeat dosing schedules, we can repeat that kind of clinical activity in a larger group of patients. That's matched by an understanding of the fundamental mechanism of action of the drug enriched with a really strong biomarker program, the most comprehensive clinical and biomarker data yet demonstrated for any T cell engager here for CLN-978. And with the network of investigators and sites, patient advocacy groups that we have seen, we have an opportunity to take this remarkable drug into the next phase of development.

And so as we think about the opportunity to move beyond chronic disease management that Dr. Tesser outlined and really think about the potential to achieve remission and immune reset, we're going to do it in what is already a Phase II-ready clinical trial footprint. Across the program in 3 separate indications, we have active clinical trial applications, INDs variously named in the United States, Europe and Australia. And we're doing this in collaboration with key patient advocacy groups who provide support and guidance as we try to advance this program, not to develop proof-of-concept data in a handful of patients, but really to bring this forward as a medicine for patients through the systematic collection of data and robustly designed clinical and biomarker enriched trials across indications.

So for SLE, we've completed the single ascending dose experience. We'll soon complete it for Sjogren's that started only in Q4 of last year. And now we're in the phase of multi-dosing cohorts. And the goal here is to take doses that are deeply B cell depleting, employ them in multi-dose regimens to identify the dose and schedule that we will carry forward into Phase II, which we expect to begin no later than early 2027. The focus in the SLE program will be similar to where it has been, which is in patients with general SLE, but we will also be interested to further explore the patient population with lupus nephritis. And I showed you, while the experience thus far has been relatively limited, the findings are notable with prompt declines in urine protein, stabilization of creatinine and resolution of other active markers of inflammation in those patients, which, if replicated, provides a very unique opportunity as we'll discuss.

We do think there's some interest to further conduct some dose selection work that would be conducted as part of the study in general SLE patients. And I would emphasize that this will be conducted in our already open ongoing clinical trial open at global sites in Europe, Australia and the U.S.

So we talked about the opportunity. Dr. Tesser was speaking about the incredible unmet need despite existing standard of care and clear monotherapy efficacy for CLN-978 opens up incredible opportunity against standard of care in general SLE. But there's an even more unique opportunity in lupus nephritis. We know from some CAR T developers that there's regulatory latitude to consider single-arm trials for accelerated approval in this indication in CAR T. And if we replicate monotherapy efficacy with CLN-978, there's no reason that, that same pathway is not available to us.

And we expect that as we continue to move the program forward through Phase II, replication of this compelling observation with additional measures of durability, we could take that data to regulators to seek special designations and look for opportunities to accelerate development in a high unmet need patient population. That's the remarkable opportunity for a drug like CLN-978. And that opportunity extends to the patient population with rheumatoid arthritis. We'll continue to think about schedule and dose in the next phase of the study. We're continuing to do that as we've shown you. And then we'll carry those doses forward into Phase IIa for dose selection, again, expected to begin in early 2027.

So one amazing drug in autoimmune disease. But what if we had 2 amazing drugs in autoimmune disease at Cullinan? And Nadim has outlined a strategic vision for how multiple targeted therapies in autoimmune disease, CD19 and BCMA could be complementarily developed. And that opportunity extends to BCMA at Cullinan. And so when we in-licensed velinotamig from Genrix Bio last year, we talked about a potential for differential development in indications beyond rheumatology. We'll talk more about that shortly. But Genrix Bio had already commenced a Phase Ib/IIa study in autoimmune indications, rheumatology, starting with SLE.

And I can tell you and we'll show you that the initial experience with the drug is remarkable in that disease space. And that data showing potency of the drug as an antibody depleting agent will allow us to power our global development outside of China. We'll leverage our leadership position in T cell engager development for autoimmune disease to accelerate a global development plan, continuing to work with our partners at Genrix Bio.

So let's talk about the study that Genrix is conducting. So again, the study was almost in flight when we signed the deal with Genrix Bio. And so given the stage of development, while SLE was not our initial target indication for development, it has provided and will continue to provide very important information to guide development in indications beyond SLE. But here, the patients are defined by moderate to severe activity by hSLEDAI score. They will have had a failure of standard therapies as defined there on the right. And this study is now enrolling patients at 5 sites in China.

I want to comment a bit on the dose at which the patients were treated and a little bit about the dosing schedule. So first, in this initial experience, velinotamig is being administered as an IV agent, although in the future, we expect at Cullinan to deliver the drug through subcutaneous administration. The second point I'll make is that the dose for multiple myeloma, the dose that's expected to be approved later this year is 180 micrograms per kilogram. The data that I'll show you is for patients treated at 5% of the multiple myeloma dose. 10 micrograms per kilogram, the target dose, the schedule there, days 1, 4, 8 and then an additional dose on day 29.

I'm going to start with efficacy again. So I'm showing you data for only 2 patients, but the findings are remarkably consistent and profound. So the patient here on the left, the hSLEDAI scores dropping dramatically after the first 3 doses. So by the time the patients came in to receive the day 29 dose, they had already achieved a remarkable clinical response to therapy before they've even gotten the second target dose. The same was true for proteinuria. The patient there at the top, both of these were general SLE patients with significant nephritis. The one patient had more than 2 grams of protein in their urine a day. By the time they came in for day 29 dosing, they already met criteria for complete renal response. Ultimately, both of these patients achieved a complete renal response to therapy, remarkable.

And it worked, and we know how it worked. It worked through really rapid depletion of antibodies, pathologic antibodies in the left lower quadrant, double-stranded DNA autoantibodies below the upper limits of normal in both patients within 2 months following therapy. Immunoglobulins as expected for a plasma cell depleting agent to drop below the limits of normal over the same range, complement typically low in patients with active disease normalizing and of course, the expected peripheral blood B cell depletion reaching nadir at 8 weeks beyond dosing.

So those results are phenomenal, but they're even more phenomenal because they were achieved with a very exceptional safety profile. Neither of these 2 patients experienced CRS, neither patients experienced ICANS and SAE or a Grade 3 infection. Both patients did develop lymphopenia. This is an expected pharmacodynamic effect of the drug, owing both to B cell depletion as well as transient T cell redistribution. And we will note that both patients did experience viral infections. These were reactivation of chronic DNA virus infections, CMV in both cases, EBV in one, and these can be prevented. So with drugs where this has been shown, safe antiviral prophylaxis is standard of care in many areas of practice, it has been implemented in this trial going forward to keep patients safe.

So we've been granted another exceptional opportunity with velinotamig. And one thought you may be thinking is that we're -- Cullinan is -- this is great, but Cullinan is behind. But we're not behind if we're seeing efficacy like this with this kind of therapeutic index at the first dose level to be assessed. We're not going to be another year in dose and schedule finding, somewhat by serendipity, somewhat by good planning, we landed on a therapeutic regimen very likely very early in development. There'll still be a little bit of work to do, but we're very happy with where we are, understanding that there is meaningful efficacy here at a dose that is more than safe enough to carry forward for further development.

So what will we do? So for Cullinan, initial aspirations for velinotamig are beyond rheumatology. And leveraging our internal expertise in hematology, existing relationships with investigators in hematology, we'll begin Cullinan-sponsored development in autoimmune cytopenias, both ITP and autoimmune hemolytic anemia. These are physicians who treat -- hematologists treat these diseases. They know TCEs. The endpoints are very objective and the readout is very quick. This is a rapid path to proof-of-concept data in a hematologic indication, but that data is very portable for development in other autoimmune diseases outside of rheumatology, important high-value, high unmet need indications in neurology, nephrology as well as endocrinology, things like Graves' disease and thyroid eye disease that affect many thousands of patients globally.

So where we start, but with opportunities to finish very broadly. So this is a global development plan. So Genrix Bio will continue to execute its Phase I study starting with SLE, expecting to move into Phase II by the end of this year. We're not behind. We have an opportunity to be at the lead of the pack for BCMA as well as CD19. And here, we also have an opportunity within our relationship with Genrix Bio to add additional indications in Phase II to more fully explore the potential for velinotamig in autoimmune disease. More on that to come in the future. We'll provide an update on data from the Genrix Bio study in Q4 of this year, consistent with our prior guidance.

So Cullinan, we're moving very quickly to initiate our own program, and we expect to have our autoimmune cytopenia Phase I/II study, again, enrolling patients in 2 indications in a basket study, inclusive of autoimmune hemolytic anemia and ITP. That study to commence no later than Q1 of 2027. We're on track, and we look forward to an opportunity to move it as quickly as possible into Phase II, understanding that the first part of the study may be less dose escalation and dose finding than dose confirmation based on an expected maturity of data from the Genrix Bio study.

I'll just finish there. Thank you for your attention. Again, the excitement and the data that Nadim conveyed that we've heard about from our investigators and collaborators, and Nadim will take us through the rest of the program.

All right. So you've seen a lot of data, heard a lot of expert opinion, reviewed a lot of development plans. So now I have the enviable task of summarizing all of that together in terms of key takeaways and also next steps. So let me start there first.

The first thing I'll reiterate is that Cullinan is one of the only companies with a clinical stage T cell engager program that spans immunology and oncology. In immunology specifically, we're addressing the most promising targets with CD19 and BCMA to design a portfolio that will allow us to address multiple large market indications in autoimmune diseases. From the data that Jeff presented, you have seen already that CLN-978 could become a breakthrough therapeutic option for patients with autoimmune diseases.

Across studies with just a single target dose of CLN-978 without background chronic immunosuppressive medications, we're seeing compelling efficacy, including DORIS and DAS28 remission in lupus and in RA. We have seen clear indicators of immune reset and disease modification through complete B cell depletion in tissue and also significant autoantibody reduction, combined with a favorable safety profile that we believe supports outpatient administration in the community setting.

The initial multi-dose data confirms our thesis that a short course of CLN-978 treatment can completely deplete B cells and deliver disease remission. At the same time, as you just heard from Jeff, our CLN-978 our ace global program has significant momentum now. We have built a robust immunology infrastructure that can rapidly execute clinical trials, and we see an expedited regulatory pathway here, including the potential for accelerated approval based on the clear and compelling monotherapy efficacy signal that we've now seen.

I go back to our target for CD19 is for it to be the first CD19 T cell engager approved in autoimmune diseases. With velinotamig, we've clearly seen very promising data, and our belief is we've already established proof of concept in autoimmune diseases with that molecule. Importantly, with the data that we have generated, we view that we have significantly derisked the clinical profiles of both of our immunology molecules now ahead of multiple near-term value-driving catalysts over the coming months.

Let me now walk you through those catalysts. This is just the beginning of a series of milestones. And you can see the team is going to be very, very busy over the coming weeks and months. So in Q3, we have guided to additional multi-dose data from our RA study. In Q4, we're now also going to share updated multi-dose data from our SLE study. At the same time, we're going to update the velinotamig data set. By the end of the year, we'll also have initial single target dose data for our Sjogren's disease study. And in terms of next steps for development, you've heard that in early '27, we're going to rapidly expand the CLN-978 program to initiate Phase IIa studies in SLE, lupus nephritis and also RA. At the same time, we're going to initiate a basket Phase I/II study in autoimmune-related cytopenias with velinotamig.

So that cadence should provide you with very clear line of sight to the ongoing significant value creation opportunities over the coming quarters following the very promising data that we have just generated. And now I think it's important sometimes to take a step back. Our conviction doesn't just come from the highly promising data that we've presented, but it's all the progress behind it. The disciplined clinical execution, our extensive global network of investigators and their treatment sites, our close collaboration with patient advocacy organizations, but especially the work of my Cullinan teammates, many of whom are in this room, and we're really looking forward to working alongside multiple investigators treatment sites.

And I'll finish by saying we're really proud of what we're accomplishing alongside leading investigators like Dr. Grieshaber-Bouyer, like Dr. John Tesser to deliver the transformative promise of T cell engagers for patients living with autoimmune diseases.

I'm now going to ask my colleagues and speakers to come and join me on the Q&A panel, but thank you very much for your attention.

So questions. The floor is now open.

Congrats with the update. Alex Thompson from Stifel here. I guess, as we think about the setup for the rest of this year, what should we look for in these updated multi-dose cohorts to sort of get comfortable that you can select doses for the Phase IIas? And then maybe in that context as well, how confident are you in the therapeutic index now for CLN-978? Just in the context of that 45-microgram patient that had the Grade 3 CRS, how much should we worry? Or how are you thinking about safety moving forward?

Sure. Let me start and then Jeff, please feel free to chime in. So let me start with the last part of that question. So look, this is why you do dose escalation, right? You push the dose until you see how patients are tolerating it. We've clearly chosen 20 and 30 micrograms to move forward with. So the 45-microgram dose, that was a dose-limiting toxicity. As it happens, that patient actually did remarkably well from a clinical benefit perspective.

And then going to your first question, how does this set up for the rest of the year? I think what you're seeing from the data is a very clear dose response relationship across lupus and across RA when you put the totality of the data together, not just the swim lane plots, including the biomarker data. And so the reason we're doing the multi-dose experience is to further optimize efficacy so that you can move from a single target dose where you're seeing efficacy to a multi-dose regimen where you can further optimize efficacy and get additional consistency of response. So that's what we're looking for in the multi-dose data.

And I think in terms of what we're looking for, Alex, you and others who follow us, you have made note of some interpatient variability in the clinical outcomes in the patients treated with single dose. That's not unexpected. It's a single dose of drug. What we really do expect in the multi-dose experience is to see more consistency of effect to see more consistency of the ability to achieve deep responses like remission. I think that is what will help us at least on the clinical assessment side of selecting doses for further follow-up -- for further development.

And of course, we'll be triangulating all of that with the important biomarker observations from both studies. We will also be generating data from biopsies in the Sjogren's protocol that we didn't talk about today. And so it's a very rich data set that helps us look at the dose response relationship from a lot of different directions. And I think that will be sufficient to inform our selection for Phase II by early 2027.

Maybe Dr. Grieshaber-Bouyer, I could ask you about your observation on the data so far and dose response relationship.

Yes. I mean I think based on what we've seen so far, the dose response is very clear. And essentially, with the 20 microgram then crossing into the 30 and now with the 20 multi-dosing, we're clearly in the territory where we have active doses and where we are seeing clinically what we want to see. We are seeing depletion-wise, what we want to see. So it's all very well connected and panning out.

Marc Frahm from TD Cowen. Maybe for the company, just can you kind of walk through the process that went into kind of dividing the indications between the BCMA asset and the CD19 and kind of why BCMA for some of those where some of them we do have proof of concept for BCMA targeting agents of a couple of patients a case series and things. But others, we also have that for CD19 or CD20 targeting agents. So why BCMA for those? And then maybe for the physicians, can you -- as we start to run out these patients to longer and start seeing durability of some of these responses or even remissions, just what does that minimum durability need to look like in your mind to kind of justify the overall treatment profile of these patients?

Maybe we start, Nadim, with that question, Ricardo, John talk about what like an expectation for durability would be for T cell engager.

I'll take a swing at that. I think that rheumatologists are used to dosing patients with these advanced medicines usually about monthly to every 6 months when you think about B cell depletion with things on the market now like rituximab. But for example, Benlysta and Saphnelo are both monthly IV-delivered medications and by subcu administration, both of them are weekly. So rheumatologists are quite comfortable with that and patients accept that. But if this -- if a T cell engager came to market that could be given every 3 months or better every 6, that would be particularly advantageous and welcomed by both the clinicians and the patients. What do you think?

Yes. I think that time window that you expressed makes sense. I mean in a refractory setting, the question of how frequent do you have to redose is totally secondary or even tertiary, right? The primary relevance is do you get a patient to respond or not. And then when you're thinking about the optimal treatment schedule, and that will depend on durability of response, but everything from what you said, I think it's what we have available so far and everything longer than that is even better.

Yes. No, I would agree with that. If this wound up giving a response of never flaring to maybe a year or 2, that would be amazing, right.

What would you be -- you obviously at a tertiary referral center, you see a lot of these refractory -- so with the short course of treatment, what would be kind of the -- maybe to Marc's question, the minimum kind of duration of response that you would like to see?

Yes. I mean I think in the refractory setting, even 3 months is transformative because you don't have a drug that induces 3 months of treatment response in a refractory setting. If you're benchmarking it to patients that are responding to rituximab, then we know we are retreating every 6 months. So if you cross the 6-month mark, that's an improvement. But also if you stay at a 6-month mark and you get better clinical responses, that's also the improvement. So I think the bar actually in RA is not yet so high because we have the ceiling effect of the available drugs already. And then especially as patients become more refractory, it's very, very hard.

And then maybe, Marc, coming back to your question of BCMA versus CD19. And I think the reason we landed on rheumatology as a target for CLN-978 is both strategic and biologic. And so biologically, we know those diseases are very often driven by dysfunctional B cell pathways. And if we use the example of RA, if you're a patient, the risk benefit for CLN-978 versus BCMA that's going to wipe out your plasma cells is clearly in favor of CLN-978.

So our view still is that CD19 is the cleanest target, but there are some diseases that are driven by these plasma cell produced pathogenic autoantibodies where it makes much more sense to address them with something that's targeting BCMA specifically. And that's why our view is, and that's why we did the deal in the first place is that having both in our pipeline will allow us to address more diseases than either of those targets alone.

Can we get the mic up turned on, please, at the front.

Kaveri Pohlman from Clear Street. Congratulations on the excellent data and thanks for the insightful event. For the KOLs, I would like to know, as a potent drug like CLN-978, where do you think this could really fit in the treatment landscape? What types of patients particularly will be eligible? And how much convenience like you previously mentioned, can play a role there?

And how do you think about its positioning relative to options like rituximab? And I believe there was a comment that was made earlier, the adoption of newer drugs is relatively slower. So just thinking about that, how do you view adoption if it gets approved, let's say, today? So how do you view adoption immediately versus 5 years from now? I have a question later for the management.

Yes. I'm happy to start with that because we actually also had an interesting conversation around that this morning. And I think when you think about oncology, typically, you have clinical development that starts in very late lines and then patients that get treated initially are refractory to like 2, 3, 4 lines of therapy. For autoimmune diseases, that's not really the case.

So I can remember multiple patients that have not received immunosuppression yet, but the diagnosis is clear, and they come asking for the strongest available treatment because they do not want to wait and jump through multiple hoops to get what clearly has demonstrated to work better. So I think clinical development as it's being done, starts in refractory patients where you are starting to do dose finding and you are defining the risk-benefit profile. But then once available, you see very rapid, I think, uptake also in first and second lines of treatment. What's your expertise?

I'm not so sure that's relevant in the United States, and one of the big challenges here is the adoption by the payers. So we're always fighting against the payers, particularly in the first year as they develop slowly more and more acceptance of bringing on new therapies into their armamentarium as they have contractual deals for better monetary purposes on their end as opposed to what's newly coming out. And also, there'll be a little bit of a slow process in the beginning and then it will catch on. But something that works as well as what we've seen, I think that remains to be seen because the data from -- particularly if Phase III trials is consistent with what we've seen so far is going to be a game changer. I think it will be transformative.

Maybe I'll pick up that question, especially for the U.S. health care system, having done a lot of launches in that space. So I think what Dr. Tesser is referring to is, certainly, in some of these rheumatology, where you have to deal with these step approaches that payers induce. Now the one thing I will say that is prepare clinically at least is you're not adding on top of background chronic immunosuppressive therapy. So from that perspective, if you have a clean monotherapy efficacy signal, I think you approach the payers and you have that discussion around the clinical benefit of them being able to come off these other therapies, the quality of life implications that come with that and how this can be a very, very different treatment.

The second thing I'll point out is these are very, very large markets. If you take the RA market alone, and if, obviously, this isn't our aspiration. But let's say, for argument's sake, you could only get a refractory disease, poly-refractory, the worst of the worst. In the U.S., that's 60,000 patients. That's more than all of lymphoma combined. So again, I think that's where we start, but that's not where we finish. And I think that's where you have to make the compelling clinical argument. And as Dr. Tesser said, as long as the data hold up, I think we feel very good about where we are today.

That's very helpful. And maybe for the management team. Just wondering if you, by chance, have any timeline for how fast the Phase II trials can be completed and how -- any time line you can provide for the Phase III study initiation? And also in terms of manufacturing, how you're thinking about scaling and localizing manufacturing, specifically for the BCMA?

Yes. So manufacturing, let me start there first. So I think T cell engagers are definitely not like CAR T when it comes to complex manufacturing of somebody who's been involved in 2 CAR T launches in the U.S. It's much more antibody-like. And in terms of timelines, we've certainly told you when things are going to start. We'll keep you updated on when things finish.

Yes. I'll just make one sort of qualitative comment that you're asking about time lines for Phase III and you're asking about profile for adoption, how amazing? We've just completed a single ascending dose trial, and we've shown enough data to shift the conversation to thinking about efficacy assessments, pathways to registration. That's really remarkable and really encouraging to hear that reception.

Matt Phipps, William Blair. A question for Dr. Grieshaber-Bouyer. You have personal experience with both CD19 T cell engagers and BCMA T cell engagers. You published on some of this. I'm interested to hear your perspective on the efficacy and safety of both targets. Would you want to study velinotamig in your patients? And then for the company, you obviously have done a single ascending dose single target dose and now SLE and Sjogren's. If you do continue to expand CLN-978, will you have enough data at that point to be able to just go right into kind of multi-dose here's a target, maybe 1 or 2 doses, but not have to start over?

The last one is really easy, Matt. Yes. So as we start additional indications, the plan would be with sort of a common Phase II dose and schedule, ideally executed at that point in basket studies that could allow us to explore multiple indications in parallel. So I think we will have that data in hand as we expand in Phase II. But the BCMA CD19 question, Ricardo?

Yes, sure. I mean the velinotamig data what was shown today looks amazing, right? That's a very strong clinical response in a short amount of time. So absolutely, we would like to study that. I think coming from the -- do you deplete plasma cells versus do you spare them angle, it probably makes sense for many patients to start with a B cell targeting approach that leaves the plasma cell pool intact so that you do not have to give IVIGs. However, there might be patient populations where the response to CD19 is so mixed that it makes sense to go to a BCMA first line. And separately of that, just at EULAR, we have seen several cases now of patients that became refractory to CAR T-cell therapy, and most of those ended up being treated with a BCMA-targeting therapy.

So I think the field is right now really appreciating BCMA as a rescue therapy after failing a CD19. And in addition, there are indications where we have seen a differentiated benefit from BCMA over CD19, and that will just be this balance between improving for the safety versus maximizing for efficacy from the get-go. And I think that will also continue to evolve as the entire field sees how comfortable physicians are with managing hypogammaglobulinemia, how much you can optimize regarding the dosing to maybe low dose versus high dose, how much depletion do you get. And that's going to be an ongoing assessment.

Yes. I would add to that, Matt, is things aren't really binary. So there's probably some diseases in the middle that are more gray and having both available to us gives us the opportunity to even think about sequential or combinatorial approaches. Like if we take the example of autoimmune-related cytopenias, there's now data from the New England Journal where there were patients that got the CD19 CAR T, relatively short remission, but were very well salvaged by a BCMA T cell engager. These guys have done a lot of that work. So I think it gives us tremendous flexibility and optionality to have both in our own pipeline.

Sam Semenkow from Citi. I wanted to ask about the patients that had the lymph node follicular disruption and that also achieved that pretty rapid remission. You did a good job of outlining how this is the first time we've seen this in a T cell engager, but we do have experience in CAR T. So I'm wondering, based on that experience, what is the correlation between seeing follicular disruption and durable remission in CAR T patients? And what does that tell you about how to think about that happening more with CLN-978? How repeatable is it? And how does that inform how you're thinking about durability for this drug?

You've done a lot of work in that space.

So essentially, when for the CAR T work because the dosing had already been established from oncology, almost all patients started at the efficacious dose. And then it was rather consistent to see this lymphoid structure disruption. For antibody-derived therapies, it's really not defined yet at all, and it hasn't been observed in the field before. So I think we will continue to look at that with lots of excitement, especially at these now active dose levels. But my hunch is that because it lines up with the length of B cell aplasia and the time to recovery, the remission that we saw that we will see more of that.

Turn the mic up, please.

Great. Brad Canino, Guggenheim. Kind of a similar question because I really see this as a presentation of a lot of anecdotes that are showing you're inducing the remissions and anecdotes to support that those remissions will be durable as well. And I guess I want to double-click on Slide 23, where you have the multi-dose RA patient going into remission. You do see some of the scores around joints and patient assessment kind of have some volatility. And I want to know is that common even in chronic treatments where you have a patient that you consider to be in remission? Or is that telling you anything about the durability of the drug or previewing what that might be?

Yes. For refractory RA, I mean, also feel free to jump in, but the disease activity fluctuates. And so I think it's rather normal to not see one straight line, but rather disease activity hovering and it's essentially about the long-term trend that you observe.

Yes, that's very true. And one of the things to keep in mind is the way that we measure disease activity. It's usually a composite score of one type or another, but it includes joint counts of tender and swollen joints plus a patient global assessment of their disease activity and the physicians and for an ACR response, you have to add in a HAQ disability index and acute phase reactant and pain score. But when you look at patient-reported outcomes of pain and global assessments, it's always a combination for the patient.

Everything that is hurting them, it could be from their neck, it could be from their ankle that's not related to their disease and their fatigue and their overall pain and global assessments may drive that score up or down because it contributes to the composite score at any given point in time. So that's a longer explanation why that can happen. But absolutely, Ricardo is right. You will see these fluctuations, but it's always like a regression to the mean when you're looking at a durability and a consistency of response.

Boris Peaker, JonesTrading. I have 2 questions, one on lupus and one on SLE. So maybe let's start with SLE first. Ricardo, if we look at the CAR T space and Georg Schett from Erlangen, I believe they had B cell depletion about 3 to 4 months, something in that order on detectable level. Here, if we look at the data, we see B cell recovering after 4 weeks. Do you think there is kind of an optimal time for that B cell suppression? And where would that be based on what we know from all the modalities tested?

And maybe a question on the RA side. I believe there was a 2-week washout period before patients were started on CLN-978 treatment. I'm just curious, would the expectation -- obviously, we don't have a control arm here, but would the expectation be that if there'd be no treatment, if there'd be a placebo arm that there would be kind of a unanimous relapse in these advanced patients with a 2-week washout stopping all their treatments. And so can we then make an argument that even not seeing a substantial relapse is suggestive of efficacy here given how advanced these patients are?

Yes, I'll start with the second question. The washout is at minimum 2 weeks, right? So depending on the prior treatment in the case of biologics, it's multiple half-life and it can be 3 months of washout period overall. So yes, if you do the same thing to a patient that has refractory RA and you wash out the baseline DMARD, whether it's a biologic or a targeted synthetic, you will see more flares. And I think that would apply also to such a placebo-controlled study. And then for the lupus question...

B cell duration.

The B cell aplasia, yes. So I think here, we saw 4 weeks, but we also saw more than 12 weeks. So it's -- again, it's an evolving dose response that shows if you get higher exposure to CLN-978, you have more than 4 weeks of B cell aplasia. Which matches essentially then the 3 months plus or so that have been seen with cell therapies.

And again, remember, this is a single target dose, not repeat dosing as well.

Julian Harrison, BTIG. A few for me. First, I'm just wondering for management, can you talk about your confidence of activity in rituximab failures in indications going forward? I understand you have some examples already, but just wondering to what do you think is driving that? Is it the deeper tissue residing depletion versus maybe targeting CD19 versus CD20?

So I do think it's a combination of both modality and target. That's an argument we've made from the beginning. I think modality is central to this. So the potency of the T cell redirecting therapy is an order of magnitude greater than a monoclonal antibody, T cell-mediated cell killing versus ADCC. So that's the difference between CAR T and any NK cell-derived product of whatever provenance. So I think T cell immune responses are just going to be more potent. And I think it is more potent in the place where it matters, which is in a depth of tissue level B cell depletion that has thus far not been consistently achievable with a monoclonal antibody, whether the target CD19, CD20, it hasn't really mattered.

In terms of the target itself, CD19 covers much broader territory. And in a period where we don't have exquisite precision in knowing exactly which cell we are trying to deplete in depleting all of them, although we're getting closer in some instances. I think that CD19 provides a better target versus CD20 in particular. But I think a lot of the effect is really modality-mediated. I don't know, Ricardo, you have maybe some thoughts on that as well.

Yes. I mean I think it's mostly the modality because T cell redirecting therapies have a much higher potency in terms of fully eliminating target cells. So if you think about the Blina studies that were done in MRD-negative B-ALL and you still had in an RCT, clear survival benefit from patients getting a CD19 TCE plus chemotherapy standard of care versus the ones that did not get the TCE. What that tells you is that the sensitivity of the T cell engager and in depleting remaining malignant cells was higher than the assays used to determine minimal residual disease. So it's pretty sensitive to be able to get down to complete depletion even in a malignant setting. similar to what is seen in lymphomas where you can see complete responses, right? And that's, of course, stronger than with conventional antibodies.

Yes. I mean I would add, interestingly, for those of you who follow the EULAR data, there was the presentation of CAR T in RA, CD19 CAR T. And interestingly, of the 6 patients, there were 4 that responded well, the 2 that didn't respond so well were rituximab refractory. So these data are very contextual in that context, if you think about it.

Excellent. And then a follow-up, if I may. On velinotamig, it's been discussed the potential safety differences versus a CD19 T cell engager. Maybe in a setting like ITP, can you walk us through the expected comfort level among physicians in a safety profile for BCMA targeted T cell engager?

Yes. So I'm a hematologist. I treated ITP both with and without concurrent malignancy. I'd be perfectly comfortable with that safety profile. IVIG is therapeutic for ITP. It's a part of the sort of not stepwise treatment, but it's often employed as one of the therapies to achieve remission in patients with idiopathic ITP. So there are many situations in hematology where patients are receiving chronic administration of immunoglobulin supplementation either because of their disease like in diseases like CLL, where they become naturally deplete in immunoglobulins with the course of the disease. And there are plenty of other immune conditions where patients receive chronic supplementation with IVIG, which can be administered outside of a facility, can be administered intramuscularly. There are other methods. I think that level of supportive care is fine.

There will still be a potential risk for infection. That is something that we contend with in a lot of other clinical settings, and that can be prevented. We talked about how reactivation of viral infections, that's an easy fix. Antivirals, prophylaxis is a part of treatments in a lot of situations and can prevent potentially severe infections from viral causes. So I think perfect comfort, particularly in hematology. That's one of the reasons we selected this as our place to go. We don't have to go out and try to figure out how to coordinate care with ophthalmologists, endocrinologists and hematologists, oncologists in administering a TCE to a patient with TED. Like that -- we can get there, but that's not where we're going to get there the fastest. And we know we're in a race. And so we've got an opportunity now to move really fast, and that's why we picked what we picked.

Excellent. And then a final one for me. Development now clearly focused on highly refractory patients across indications. A comment was made earlier in this event about a long-term potential to move up in the treatment sequencing across many indications. Maybe for the physicians on the panel, I'd love to hear from you how you think that happens in practice.

Yes. I mean moving up, I mean, we kind of had this question already, right? I think that for development, again, you start in the refractory setting. I think as the safety data builds, there will be less and less requirements to really perform studies in a refractory setting. That's also very clear. And the interactions with the agencies, both in Europe, but also here in the U.S. have been getting better over time as they see more data from TCEs in autoimmune diseases.

And for the uptake, I'm pretty optimistic that patients will want transformative therapies first and as closely to the first line or to the first line as possible, depending on what the payers ultimately will reimburse. But then again, I think it becomes a question of showing differential benefit to the patient and durability of response compared to standard of care.

Yes. I do think one thing that's still a little bit underappreciated is that, as Jeff showed earlier, if you can show clear monotherapy efficacy signal, you don't get stuck into that whole placebo-controlled world that current therapies do. So I think that also allows, Jeff, right, for efficient development.

It allows for efficient development, and it allows for us to think about an entirely different way of approaching disease. When a lot of situations, if the therapy is not particularly efficacious, you wait till the time where the risk-benefit balance is correct. But if you have a well-tolerated therapy with disease-modifying potential, it's an opportunity to intervene early to prevent patients from becoming sick instead of rescuing people from exceptional end organ toxicity and sort of narrowly avert the need for dialysis, you prevent the whole set of downstream immunologic consequences that lead you there. And so that's the aspiration.

I mean, what you're hearing from John and Ricardo is that for us to succeed at that, we've got to develop the data to support that. But we've also heard from them that if we develop that data, that will help them as early adopters as clinical trialists lead the way and convince their colleagues over time that, that's a better way of taking care of patients.

And you can cost that out to payers, too.

There's a catch-22 with all of this. So -- and it depends on the developmental program, particularly of the Phase III aspects of it. If the population that you choose for the program is a somewhat refractory population, whether it's 1 advanced therapy failure or 2 advanced therapy failures, what happens is you kind of box yourself into getting a label from the FDA for patients to get this new therapy who actually had a failure or 2. And that's the problem because with all these better therapies working at earlier time points, you kind of like -- you roll the dice or you just set it up for less efficacy than you potentially could get. And also, you also put the patients at risk for having multiple and a prolonged time frame whereby these other therapies don't work so well and they're developing organ damage.

I will tell you that in rheumatologists' minds, a main goal of treating a patient with lupus is to prevent organ damage, getting to a remission and by doing that, you prevent organ damage. And that's what the focus has and is developing in the whole community. And that will be something for the company to keep in mind and to do the damage assessments during the clinical trials. But I do bring this catch-22 out, and it's -- I'm not sure how you really solve that.

Yes. I think that's a great point, Dr. Tesser. I think the other thing when Jeff laid out the plan, for example, in lupus, right? So lupus nephritis could be an accelerated approval path. We know complete renal response is well accepted by the agency. We know at least one CAR T company has already agreed an approach for that group of patients. But at the same time, to your point, Dr. Tesser, it allows you to have an SLE general Phase III study that can give you the patient population that you really want as well.

Absolutely.

Great. This is Dave Dai from UBS. A couple of questions. One, just on the CLN-978. The initial data suggests potential for immune reset and disruption of follicular structure architecture. So moving to repeat dose, what additional longitudinal evidence do you want to see the different sets of B cells or different follicular architecture that will give you the confidence that the immune reset is durable instead of a transient remission suppression here.

And then for velinotamig, given the data come out of China-based study, how comparable are the patient population background therapies also trial design to the planned global studies?

Let's take the first one. So I think as we move into multi-dosing, what we're looking to do is to increase the consistency with which that effect is achieved, first and foremost. So as Ricardo said, there's a dose response exposure sort of response emerged in our experience to date. And the point of the multi-dosing regimen is to achieve that in a larger number of patients. So that's probably one of the single most important objectives. That's sort of the impact at the tissue level in the lymph node is just one of the factors we're looking at.

There are other features of immune reset is characterized by the population of B cells like their phenotype at time of recovery. For the patients who've achieved these deep B cell depleting results, we don't yet have that data. We can't phenotype a B cell that hasn't recovered if it hasn't recovered, and that's kind of where we're at. We'll have that data in the future. And that will also be really important in understanding whether we've achieved an effect that is likely to be durable based on the CAR T precedent.

In terms of velinotamig and the comparability of the patients in the trial, for us, we're less interested in terms of the efficacy observations here and how we port those into global development, then we are these very important PK/PD relationships and safety associated with those data because that's what really informs global development. And that data is globally transportable you raised a question about comparability of patient populations. If our aspiration were to take this data to the FDA and say, look, this supports doing a Phase III trial in SLE, then there are issues with patient comparability. But in terms of the data that we're deriving from the study, it will be solid for our regulatory aims.

Yes. I would add to what Jeff said. Look, when we did this deal, speed of execution across our programs is critical. And that's why we chose for our partner to run the first study. If you look at all the deals that are currently done by large pharma in the space, they grab a drug from China and then they throw it into their old playbook of this stodgy EU, U.S. clinical operations playbook. We took a much more creative approach. We're very comfortable with the development capabilities of Genrix Bio and said, look, why don't you guys carry on doing the first study so we can generate data as quickly as possible because ultimately, that will accelerate our ex-China plans as well.

We're very pleased with where we are. And I think going back to your question, David, about confidence. As I said before, we're very confident that we have significantly derisked the profiles of both of these agents now. Now obviously, we want more and more data. But again, we blew away our own internal expectations.

Katherine Sun from Morgan Stanley for Sean Laaman. Just 2 quick questions. One for Dr. Tesser, in your experience treating patients, I think we saw for patient 031, we tapered down prednisone from chronic use down to less than 5 mg. Can you just talk more about like decisions that drove that in your experience treating patients? And do you foresee this going down to none with long-term mycophenolate usage?

And then just quickly for management, as we look to evaluate velinotamig from the Genrix study to your evaluation plans going forward, do you foresee any differences in PK/PD or safety tolerability when it comes to switching from the IV to the subcu dosing?

When you taper the steroids down in the patient, what were the decisions?

Yes, along with the mantra about lupus in terms of not only getting patients to a clinical remission to prevent organ damage is the understanding that that's a 2-sided coin, and it's done with an understanding you need to use advanced strategic medications to control the disease. But if you don't get the patient off prednisone, the most commonly used steroid, then the patient still is at risk for organ damage. And in fact, corticosteroids toxicity is one of the major drivers of long-term organ damage in lupus. So even though a DORIS remission winds up allowing for 5 milligrams or less of prednisone, among the KOLs in the U.S. about lupus, the mantra is to get the patients completely off.

Because there is even a little bit of toxicity that has been seen with evidence for every 1 milligram of prednisone extra the patient is taking. So to get at your question, we're always trying to drive the prednisone dose down consistently, constantly to the lowest dose possible to get the patient off. So that's the answer to that part.

Jeff, do you want to take the IV subcu question?

In the IV subcu. So Genrix is introducing IV -- pardon me, subcutaneous administration into their multiple myeloma program imminently. And we do have some initial bioequivalence of sort studies and animal studies that Genrix conducted that suggest relatively similar exposures, ultimately IV and subcu. So we think that the transition will be based on what we currently know, relatively seamless.

Okay. Look, I'm going to thank you, closing out the session by saying that we're still very excited about delivering the promise of T cell engagers in immunology to build a portfolio that can deliver immune reset and durable treatment-free remissions across multiple autoimmune disease settings. The other thing I'll point out is that as a company, we're uniquely positioned at the intersection of deep T cell engager expertise, multiple autoimmune markets as well as a catalyst-rich development plan. And so we look forward to keeping you updated as we continue to execute multiple [Technical Difficulty].

Good morning, and thank you for joining our session of Citi's Virtual Oncology Leadership Summit. I'm Sam Semenkow, one of the senior biotech analysts here at Citi. And it's my pleasure today to be hosting Cullinan Therapeutics' CEO, Nadim Ahmed; and CFO (sic) [ CMO ], Jeff Jones.

Nadim, Jeff, thank you very much for joining us today.

Great to be here, Sam.

Thank you.

And so for those listening live, if you have any questions during the session, please feel free to e-mail them to me directly at [email protected] or you can put them into the portal, and those go to my e-mail as well, and I'd be happy to ask those questions on your behalf.

So I think we can just get started then. So Nadim, maybe you can kick us off a little bit and talk about the evolution of Cullinan's oncology pipeline, a little bit about what assets you've prioritized recently, the company's overall strategy when it comes to developing assets for oncology in particular.

Sure. Happy to do that, Sam. Look, the first thing I'd say is 2026 is a very exciting year for Cullinan Therapeutics. We've got multiple catalysts across our whole program and pipeline and especially for our 2 high-priority T cell engagers, CLN-978 and CLN-049.

If I may divert slightly away from oncology for a second or 2, Sam. So starting with CLN-978, which is our CD19xCD3 T cell engager we're developing across autoimmune diseases. There, we have a best-in-class potential opportunity with a global development program across multiple large market indications in autoimmune diseases. And thinking about the molecule itself, we believe we have a very highly differentiated molecule relative to other CD19 T cell engagers, especially since we have very high binding affinity for CD19, we have a very small molecular size, and all of that combined with subcutaneous administration, which obviously was convenient for patients.

Also, I think our only aim or goal for the program ultimately is to move up early in the treatment sequence so that we can also displace monoclonal antibodies that are often used across these autoimmune diseases, which are very safe, but with marginal efficacy. So I think we have a potent molecule that can do that.

I would add, thanks to the work that Jeff and his team are doing, we have great momentum across our global development program for autoimmune diseases. We have 3 high-value indications, so lupus, RA and Sjogren's disease. And we plan to present the first company-sponsored data for CD19 T cell engager throughout 2026. So very exciting for that program.

And then the last thing I'll add is there's still significant strategic interest in the B-cell depletion space. You probably saw last week Lilly acquired Orna Therapeutics. So it remains an area that's actually very hot.

So now, let me get back to oncology to your original question. So I think the first molecule I'd point out is CLN-049, which is our FLT3xCD3 T cell engager, which we're developing in AML. So this one here, we have a potential first-in-class opportunity to bring forward an immunotherapeutic approach to address a broad group of AML patients and unlock significant commercial value. I would say AML is probably one of the last large heme malignancies where we haven't seen an immunotherapeutic approach to be successful. So obviously, this is very exciting for us.

We presented dose escalation data at ASH in December 2025, where we presented compelling monotherapy efficacy data, which we believe is within the regulatory benchmark for success, and we can certainly come back to that. And in 2026, we're really focusing on going from dose escalation to dose expansion, dose optimization and really using the Fast Track designation status we recently got from the FDA to then select the recommended Phase II dose so that we can move towards a single-arm pivotal study for relapsed/refractory disease.

At the same time, in parallel, we're also moving the program in the frontline setting. So we're planning a Phase I/II combination study with ven/aza towards the end of this year. And so we're making sure we're working both in relapsed/refractory disease and also taking the frontline opportunity in parallel.

With zipalertinib, the program that's been here since I joined the company and has come full circle. So that's our EGFR exon20 tyrosine kinase inhibitor, which addresses non-small cell lung cancer. Here, we have, I would say, both a clinically and financially derisked molecule with best-in-class potential. And I say financially derisked because of our partnership with Taiho, where we managed to strike a great deal back in 2022.

So our partner, Taiho, is planning to complete the rolling NDA, which was started towards the end of last year. That's, again, for relapsed EGFR exon20 non-small cell lung cancer and to complete that rolling NDA submission this quarter, and at the same time, also complete enrollment in the frontline study in the first half of this year.

And so I think with zipalertinib, clearly, we see this as a molecule that can address important unmet need. But with the deal we have with Taiho, it also represents an opportunity to bring in significant nondilutive capital through regulatory milestones and a 50-50 profit share with Taiho. So that molecule is on its way to NDA submission and an important milestone for the company to have our first NDA. So that's another exciting opportunity for the company.

And then going back to your question, Sam, about how we approach pipeline and pipeline strategy, we really focus on molecules that we believe have the potential to either be first-in-class or best-in-class before we actually put them in the clinic and molecules that can really have a transformative impact for patients with cancer, and also, of course, autoimmune diseases.

And so the pipeline that I went through, I didn't mention poziotinib yet. But if you think about oncology, we're addressing both clinically and commercially validated targets with exon20 and FLT3. On the autoimmune disease side, we're addressing, again, clinically validated targets with both CD19 and BCMA. So I'd say we have a relatively derisked pipeline also.

All of these molecules have demonstrated monotherapy efficacy in the clinic, and all of these programs are addressing substantive market opportunities. So I think both on the autoimmune side and on the oncology side, we're looking forward to a really exciting 2026.

And then, the last thing I'll say, which is very important, is we have a very robust balance sheet. So as of the end of December last year, we reported over $430 million in cash, giving us a runway into 2029, which allows us to execute on all our programs, but especially CLN-978 and CLN-049 so that we can deliver shareholder value quickly. Hopefully, that worked.

I think that was a wonderful intro. It gives us a lot to work off of. And I would -- let me just say before you go back to oncology, I'm very excited for the 978 data that's going to start rolling out in the second quarter. So looking forward to that. But why don't we -- going back to oncology, start with 049. Can you just share a little bit about this molecule design? How it binds to FLT3? And what about this molecule is perhaps differentiated from some of the prior attempts we've seen to target FLT3?

Yes. So maybe, Sam, I'd just start by emphasizing that in this case, we're thinking about FLT3 as a target for immunotherapy rather than as a target for kinase inhibition. So FLT3 is a receptor tyrosine kinase that in about 30% of patients has kinase domain mutations that lead to constitutive activation. But it's actually an oncogenic driver and present on the surface of AML blasts in at least 80% of cases regardless of a kinase domain mutation. So it really does access the broad patient population of AML.

And it is -- you ask how our molecule is distinct within prior molecules previously developed for FLT3. There's actually been relatively limited development of FLT3-directed immunotherapies. Ours is built on an IgG backbone. It has 2 arms binding to FLT3. And as the C-terminus has 2 single-chain variable fragments that bind to CD3, although only one of them is functionally active, preclinically, very high affinity for FLT3 with a favorable cytokine window, which has now been demonstrated in the clinic.

In terms of prior FLT3, the program that made the furthest was a BiTE-like structure in the Amgen portfolio. That molecule was on a half-life extended BiTE format that has largely been discontinued at Amgen. So I think the failure of that program, ultimately, we have heard for intolerable cytokine release syndrome, may be more of a format liability than a target liability. And we think that the data that we've generated to date for FLT3 really validates that the approach we're taking is a good one.

Well, so then maybe let's dive into that data that you presented at ASH. What can -- or maybe just give an overview of the efficacy and safety data that you've seen so far? And what's really stood out to you as impactful for this disease?

Yes. So I think there are 2 ways. This is primarily a safety study, but in this dose escalation phase, we actually saw really compelling efficacy. And once we had reached a dose of 6 micrograms per kilogram, again, emphasizing the potency of the drug, we began to see complete responses emerge, and complete responses in AML are really what matters. You want all of the AML to be eradicated, and you want normal blood-forming elements, normal hematopoiesis to recover. And that's what we began to see at 6 micrograms.

At the time of ASH, we had further dose escalated up to 12 micrograms per kilogram. And in this group, we saw 8 patients achieve a form of CR, either a complete response or a complete response with incomplete hematologic recovery, which also tend to be quite durable.

In that group, at least 5 of the patients had responses that were durable in excess of 4 weeks. So a reasonably high rate of complete response, composite complete response, about 30% and the majority of those patients durable for at least 4 months. So a measure of clinical benefit in terms of durability. So that's only half the equation, of course. If those responses are achieved, you want to know in which kind of patients.

And here, we saw that the responses appear to be achievable no matter the patient's underlying genetic risk, which often is the key prognostic factor in AML as well as a predictive factor for treatment. There, the most profound observation was in p53-mutated patients, probably the worst prognostic subtype of AML, where the drug seemed to work equally as well with or without p53 abnormalities.

Finally, this was achieved with a favorable safety profile. If you compare the overall rate of CRS, which was about 1/3 of patients, that compares favorably to any T cell engager yet approved in hematology. And we saw only 1 Grade 3 CRS case that in a patient who received only a single step-up prior to the therapeutic dose. Once we instituted a 2-step-up dose regimen, we did not see further Grade 3 CRS and saw a general trend to lower rates overall and sort of a shift to lower-grade CRS on the whole.

And that step-up, that double-step-up that you found, I mean, is that just let's drug a little bit to get the patients sort of acclimated to the therapy? Is that proving out as you continue to expand in those double step-up cohorts?

Yes, it's a great question. There are a lot of theories why it works, but some -- it has become the standard approach to mitigating CRS and initiating therapy with T cell engagers, and all of the approved T cell engagers utilize some form of step-up dosing. It appears that by delivering pharmacologically active doses, that is doses that activate T cells, but are still associated with relatively low levels of cytokine production, you preclude the risk, you limit the risk for higher-grade CRS when you deliver higher therapeutic doses. This was first established with the first approved T cell engager, blinatumomab, going back to the 2000s and now has become sort of standard practice.

And when you look at the safety profile that you've generated thus far, is this something that you think could be an outpatient dosing setting for -- in the actual community?

Yes. So for AML docs, the distinction between inpatient and outpatient is a little less important since they are very used to giving therapy inpatient. Because of the inherent risk of treating an AML patient with a T cell redirecting therapy, I tend to think that therapy might always be started in the hospital. But even now, once patients are established on therapy, treatment can be safely given in the outpatient. And Nadim and I both have experience with commercializing -- developing and commercializing drugs in AML where initiation of treatment in hospital is not uncommon.

Okay. All right. So there's definitely a path for a bit of outpatient dosing down the road.

That's correct.

We have a few client questions actually that have come in. So one of them is asking, where do you intend to go one dose from here and for the data later this year, including the higher doses and the 12-microgram step-up? So I guess, once you have that, I think, final cohort, I think what they're asking, where do you intend to go from there?

Yes. So the next -- Nadim?

No, no. I was saying, Jeff.

Okay, sure. So the next phase of the study that we outlined around the time of ASH is to complete the dose escalation, and we stated our intentions to dose escalate up through a target dose of 24 and that is still the plan. And then, after completion of dose escalation and potentially some backfill within the dose escalation phase to generate additional PK/PD data, we anticipate initiating expansion cohorts in the second quarter of this year, and we're still on track to do that. That's important to not only confirm the clinical observations from the dose escalation phase, but it is also important to support selection of a recommended Phase II dose for future development. And we have stated that our current timeline has us on a trajectory to initiate a registration-enabling study in relapsed/refractory AML by the end of 2027. The other thing that what...

And when will we -- just in, when will we see that next tranche of data? And are you enrolling more patients at the 12-microgram step-up that we've seen initial data for? And will that be included in the next tranche of data?

Okay. Good question. So we stated our intention to provide a data update in the second half of this year, and we provide greater specificity as the year goes on. We have continued to enroll some patients in backfill cohorts at doses of interest, including 12 micrograms, again, to support additional PK/PD observations that help us support a dose for further development with regulators.

Sam, I would add to what Jeff said. The reason we've also said second half of this year is because we want to make sure, as Jeff said, we enroll the cohorts, but we also want to have enough follow-up to assess durability accurately as well, which is very important for the next data release.

That makes sense. And Jeff, I think I might have cut you off mid-response. I don't know if you...

No, I think we chop up or thought out. No worries.

And then, they're asking one more question, actually. So -- and I think this goes into those higher doses that you're enrolling now. What is the goal here relative to the CR and CRh rates that you've already seen that are quite encouraging as you continue to dose escalate higher?

Yes. Another way of ask -- sometimes people ask a different question, and they say, aren't you concerned that the response rates will fall off when you move into expansion or Phase II development? So short answer is we want to make sure that we don't leave any efficacy on the table. At the time of ASH, we showed that we clearly had a therapeutic index to continue dose escalation. And so we want to make sure in this very difficult-to-treat disease that there isn't an opportunity to further improve efficacy with greater exposure. So that was the intention of continuing the dose exploration. But we don't believe, based on our current understanding of the molecule and modeling that we need to dose escalate much above the current levels. So we do plan to truncate it at 24, but that's the reason. If we could get to a 40% response rate, we'd be overjoyed, right? So as long as we feel like there is still a margin of safety, that's a worthy goal.

Got it. That makes sense. And then, Jeff, you alluded to this a little bit, but you're seeing responses in patients that have TP53 mutations. These patients are responding, and they even have some durability as well. Can you just talk about how these patients are currently managed? And how -- what the KOL response has been to seeing responses in this population?

Yes. So p53-mutated patients have a dismal prognosis. So median life expectancy beyond the time of diagnosis is 6 months. So that's the worst of the worst in cancer diagnosis. And when you lose your p53, you sort of become insensitive to the effects of cytotoxic chemotherapy, which have always been the cornerstones of treatment for AML. So therapeutic options for that group are not well established. There's no existing standard of care. Many patients receive ven/aza, but the response rates are woefully inadequate and survival has not significantly improved.

Current treatment guidelines state that the first best therapy for a patient with p53 at any line of therapy is participation in the clinical trial. And so to be able to see that similar rate of 30% composite CR, actually, it was a bit higher in the p53 group, it was 50% in that group. If you see that rate, physicians are really impressed because if you can treat the hardest of a lot, it speaks a lot about the potential for the development of your drug.

It's also an alternative development pathway. While we still think our first approach will be development in the broad group of relapsed/refractory AML patients, this is another area of particular development and regulatory interest. And there have been companies that have sought development in p53-mutated AML as their primary development strategy. So that does present a fallback strategy as well. And there, the threshold for success is likely significantly lower than in a broader group of patients.

Got it. But the planned single-arm trial that could be pivotal for accelerated approval in relapsed/refractory that would include TP53 mutated. It would be an all-comers sort of relapsed/refractory or no?

Yes. So I think the data from our initial expansion will help us take a final decision there. There, we are pulling those patients out into a separate cohort for 2 reasons. The first is sometimes the results in that group have been different than in our broader group. And then secondarily, it's also an opportunity to treat patients with previously untreated p53-mutated AML.

As I stated, standard of care is participation in the clinical trial at all lines of therapy. So it also presents this unique opportunity to give the drug to previously untreated patients where there is some expectation it may work better potentially in patients who haven't been somewhat beaten up by exposure to prior therapy. Once we see that, if we were to see that those response rates continue to hold up as largely similar, there wouldn't be a whole lot of reason to continue to exclude them.

Got it. Okay. So 2 separate expansion cohorts that you're planning to initiate, I think you said, next quarter, that's still on track?

Q2. That's on track.

Right. Perfect. And so then you'll take one dose into both of those expansion cohorts. And then that was -- what you see there will inform that single-arm pivotal design?

Actually, Sam, in at least one of those cohorts, the all-comer non-p53 cohort, we will likely expand it more than 1 dose. Standard recommendations or direction, I should say, from the FDA is to expand in more than 1 dose to support selection of the recommended Phase II dose for further development. The earlier you dispense with that dose optimization exercise, the fewer patients, the faster it can be settled with the agency and allow you to move more rapidly into real registration-enabling development. So we'll try to get that done as well this year.

And then, Nadim, you mentioned this in your intro, how you believe you've already sort of met the regulatory bar that you would need for the single-arm study. Can you just talk a little bit more about that and maybe what gives you confidence in pursuing that accelerated approval pathway?

Sure. Yes, happy to do that, Sam. I think the fact that we've seen this very promising monotherapy efficacy, as Jeff outlined, including in the p53 patients, I think that got us really excited. It gives you then, in this disease, especially, a very, very clear development and regulatory pathway. So you can get relapsed/refractory approval potentially with a single-arm Phase II study and then use a frontline study to service both the confirmatory study as well as the expansion study to get you in the frontline setting.

And so sticking with relapsed/refractory disease, if you look at the recent precedent over the last few years, you see that companies have generally got registered on a single-arm study of about 100 patients, typically accelerated approval, but sometimes full approval. And all of these molecules have been targeting a specific biomarker-driven subset of patients.

So the treatment of relapsed/refractory disease is highly fragmented. The fact that we have a treatment that could be broadly applicable, it really gives us an opportunity to both disrupt and defragment the current treatment of AML. That's why we're super excited about it. And so if you look at those approvals, you see a CR/CRh rate of around 20% to 30% with duration of 4 to 6 months. And I think that's why we feel very good about where our data are.

And as Jeff said, obviously, we need to reproduce it. We need to get more patients. But what we've seen so far is extremely encouraging for both the broad all-comer patient population, but also the p53 patients.

The one -- the other thing I would add, and Jeff kind of alluded it before, is that within the company, we also have very, very strong hematology expertise, including Jeff, by the way. And so I think between the 2 of us, we've either developed, commercialized or launched 5 drugs in MDS, AML. We have deep hematology expertise in the company. So clear regulatory pathway, clear development pathway with very strong expertise in the company in this space.

Got it. Yes. No, that should serve you very well as you continue to push 049 forward. What about the frontline setting? I guess, what do you need to establish from the dose escalation -- the dose expansion cohorts that you're planning in order to move into that setting? And when would you consider starting that study?

Yes. So I don't think -- I think we've seen what we need to see from the program to begin planning a Phase Ib/II combination study in the front line. And we stated our intention to commence that study by the end of the year. But what's the backbone there? Our -- we are planning a study built around venetoclax and azacitidine, so hypomethylating-based therapy.

And while that is currently approved and largely has been thought of as therapy for elderly or infirm patients with comorbid medical illnesses, emerging data is suggesting that it may be as good or even better than traditional 7+3 induction chemotherapy, which has been the mainstay of treatment in younger fitter patients since the mid-1970s with very little modification.

And the data to support that comes from a number of places, but probably the most prominent is a study called the PARADIGM study, a randomized Phase II study presented at ASH this year that showed equivalent or in some cases better outcomes in patients treated with ven/aza over cytotoxic induction and much favorable safety. And so those were in younger, fitter patients. And so it seems that that's like the backbone for the future, and that's where we're built.

We do need to do some dose finding as experience with other drugs being added to ven/aza has shown, you sometimes need to think about the way to introduce your drug into combination and you need to ensure that you are still maximizing treatment intensity of the backbone regimen. And so we're working through those design considerations, seeking external input, but we'll ultimately share a study design in time, but are on track still to have that started by the end of this year.

Got it. So you could have maybe, I guess, a part of the study that does that dose exploration, and then, you move into the pivotal cohort with the selected doses for all 3 assets?

At least the Phase II cohort. I mean, I think the anticipation is that we -- because this can be powered for survival in the front line, it would require a randomized study in order to satisfy regulatory expectations. But this study would be a label expanding study, but also make a future Phase III, but also be a confirmatory study for a potential accelerated approval in second line and beyond.

Got it. Okay. Perfect. That makes sense. So then, maybe we go back to the upcoming data update in the second half. We're going to see more durability, obviously, that higher cohort, some backfill patients. Is there a chance we also see some early expansion cohort data? Or -- and let me just ask another question then, when could we see that expansion cohort data considering it will be informing the design of both of your studies?

Sure. Yes. So definitely one step at a time, Sam. So I think as we mentioned, for the current dose escalation study, the next update will be in the second half of this year. That's the plan. And as Jeff alluded to, this is to make sure we can capture all cohorts to assess both response and durability. So that's going to be very important.

I think the other aspect of that study update is we anticipate that we'll have a follow-up period of at least 6 months for most patients. So again, it allow us to inform durability as we move forward. We haven't yet guided to the expansion study data readout. I think we're going to take the time to start the study first. And of course, we'll keep everyone updated in the future.

Got it. Okay. That makes sense. So then just a last question on 049 before I spend some time on zipalertinib. Just what does the addressable market look like as you move into the relapsed/refractory patient population first, and then, down the road, potentially expand the label to frontline? How should we think about the market opportunity there?

Sure. Yes. So in the U.S., every year, approximately 20,000 patients are diagnosed with AML. And unfortunately, most of those patients relapse. So that does create quite a large relapsed/refractory pool of patients. And the fact that we're addressing an all-comer patient population, for example, unlike menin inhibitors, which address 30% to 35% patients. So when you have the whole pool of patients to work, we have a large relapsed/refractory pool.

And the way we think about it, yes, we anticipate that the relapsed/refractory segment could be a $1 billion segment on its own. And then, when you move up into the frontline setting where you have more patients, obviously, longer treatment duration, that can potentially unlock a multibillion-dollar opportunity, again, with a very clear regulatory development pathway, one Phase II study for relapsed/refractory approval, one Phase III study for frontline approval. So from a capital allocation ROI perspective, it's a very attractive value proposition.

Got it. Makes sense. So I want to spend a little bit of time on zipalertinib. So you mentioned that Taiho is completing the rolling NDA submission. Now, if we assume that, that does gain approval, I'm wondering just how we should think about the market opportunity for that drug? And maybe you could take us through a little bit about the profit share agreement? And how to think about the cadence of revenue generation there given your 50-50 profit share?

Yes. So I think the first thing I would say is our estimate and the publication literature varies, but exon20 non-small cell lung cancer in the U.S. is probably 3,000 to 5,000-plus patients diagnosed annually. And it's one of the largest subsets of the EGFR-mutated patient population. So I think for us, it reports an attractive opportunity.

In terms of the agreement with Taiho, so when we first did the deal, we had an upfront cash injection into the company of $275 million, which quite frankly, has really helped to kind of advance the pipeline and talk about some of the other molecules we spoke about today. So for us, that was a great deal.

Taiho owns ex U.S. development and commercial rights. So we have a 50-50 profit share in the U.S. We also owed $130 million in regulatory milestones for U.S. approvals in both the second line plus the frontline setting. So that's what I refer to as a near-term source of non-dilutive capital. And I think the way we think about kind of commercialization here because we do have a co-commercialization option is that Taiho is -- they're very well equipped to address these kind of precision medicine approaches with the current portfolio they have in the U.S., where they're addressing very unique subsets of patients.

So they have a strong commercial capability in the space. They run a very lean organization. And so the way we're seeing this deal evolve, it's going from a cost share arrangement to a revenue/profit share arrangement. And with that kind of focused commercialized effort that Taiho has, it becomes accretive very, very quickly based on the opportunity that I outlined. And so, again, it allows us to use those proceeds to continue to advance our programs built into our cash runway, et cetera. So I think this is a very clear opportunity, but it also allows us to continue to bring non-dilutive capital into the company.

Got it. That's helpful. And can we expect maybe like -- as if it were to be approved in the initial quarters of launch, you'll provide more guidance over time on when you shift to profitability down the road once you have a better visibility there?

Yes, most definitely. The thing I can say today is that it will become accretive very quickly based on the very tight organization that Taiho runs in the commercialization space.

Got it. Okay. That's helpful. Looking forward to that. And then, you're also running -- or Taiho is running a first-line study as well. I guess, just briefly, what gives you confidence that zipalertinib can be successful in that first-line setting as well?

Yes. So if we just look at the data that we've generated in relapsed/refractory patients, so patients who would have failed frontline therapy with platinum, we see that the duration of response and the 40% of patients who respond in that setting is beyond 9 months and the PFS similarly. That compares favorably to the PFS achievable in the front line with platinum-based standards of care, which is roughly 6 to 7 months depending on the series. So we already had some good data sort of suggesting the potential for durability of clinical benefit, which is really important in moving things into the front line.

The design of our Phase III study with Taiho is a randomized comparison of standard of care platinum versus platinum plus zipalertinib. This is a strategy successfully executed by J&J in getting RYBREVANT approved in the front line. So we think that in part derisks this design. Further, we understand that in some cases, TKIs can add toxicity to the chemotherapy backbone. But the favorable toxicity profile of zipalertinib and nonoverlapping toxicities with chemotherapy gives us confidence that, that won't be a problem. But the additive clinical benefit seems to be significant.

And there, despite the ability of TKI to beat chemo in the case of osimertinib, when osimertinib was added to chemotherapy in the FLAURA2 trial, it not only improved progression-free, but overall survival as well. And survival always trumps. So our belief is that chemotherapy, and our KOLs tell us the same thing, is still a backbone of frontline therapy for exon20 and that we will maximize the clinical benefit and their meaning survival in combination, TKI plus chemo. So a number of lines of thought to sort of build confidence there.

Got it. Well, looking forward to that data. I think they've guided to completing enrollment this first half. Is that correct in that study?

That is correct.

Perfect. Okay. Looking forward to that. Well, I think we've been pretty efficient with our time, and this has been wonderful. I wanted to give you both an opportunity maybe just to recap what we have looked forward to because I know there's a lot of catalysts in '26 across both the oncology and autoimmune pipeline as well as any other closing remarks you wanted to share.

Sure. Yes. Happy to do that, Sam. So summarizing where we are with CLN-049 based on what we discussed, so update from the dose escalation study second half of 2026, initiating dose expansion cohorts in the second quarter of 2026, and then, completing enrollment of that dose expansion by the end of the year so that we can identify a recommended Phase II dose for a single-arm pivotal registrational trial, as we discussed.

And then, in Q4 '26, obviously, in parallel, we're continuing to develop the frontline opportunity. So as Jeff mentioned, we would plan to initiate a Phase I/II combination study on top of the ven/aza backbone, which will then inform a future frontline randomized study, which will serve both as label expansion confirmatory study. So lots of milestones for CLN-049.

And for zipalertinib, we want to get this NDA submission in. And so our partners are guided to finishing that this quarter, which is coming up very soon. And as you mentioned, enrollment of the frontline study in the first half of 2026, so we can fully maximize the opportunity with zipalertinib. And so I'd say with these updates from both CLN-049 and zipalertinib plus the multiple milestones throughout the year for CLN-978. I think 2026 is going to be a real defining year for Cullinan Therapeutics and a great opportunity to value create for shareholders.

Absolutely. Looking forward to all of those updates throughout the year.

Thank you so much for the time. This has been wonderful. I really appreciate it.

Thanks, Sam.

Thanks, Sam.

And with that, operator, we can go ahead and close the call.

All right. Good evening, everyone. Thanks for coming as we look forward to discussing the compelling initial results for CLN-049 that were presented at ASH today and also look forward to the promise of CLN-049 for patients with AML.

So our disclosure slide. So as outlined in the slide, during this event, management will be making certain forward-looking statements. Please consult the risk factors discussed in our SEC filings for additional uncertainties that may cause the actual results to differ.

All right. Glad to get that one out of the way. Okay. So turning to this evening. I'm very pleased to welcome Dr. Jeff Jones, our Chief Medical Officer, and we're especially pleased to welcome Dr. David Sallman from the Moffitt Cancer Center, where he's associate member, a myeloid section head, also the research institute. And now not only is Dr. Sallman, a leading investigator in our study, he's also a leading researcher in the field of p53 mutated AML and MDS, which you'll see is very, very important for the content today.

So I'm going to start out by outlining our broad pipeline strategy as a company. Jeff will then recap the results for 049 that were presented today and also talk about immediate next steps for development. Dr. Sallman is going to cover the current treatment of AML, including the need for more broadly applicable treatments and especially new treatment options for patients with p53 mutated AML, which is a very poor prognosis disease. And then I'll conclude by outlining our development and regulatory strategy for CLN-049 and also frame the potential commercial opportunity. And then we'll open up the session for Q&A.

I will say Cullinan Therapeutics, we're very excited to be entering a rich catalyst period in 2026, starting from today and enabled by our pipeline strategy. And so now we have a derisked pipeline of 4 clinical programs that are either first or best in class. And the reason I say derisked is because each molecule is addressing a high-impact clinically validated target. Each molecule has already demonstrated monotherapy efficacy in the clinic, and each program is addressing large market opportunities. And so for the purposes of this talk, I'm going to be focusing on 2 of our T cell engager programs that we consider higher priority. And if you look at our pipeline, the majority of our programs now are T cell engagers, which is a core capability of our company and of course, a highly promising treatment identity, not only for oncology, but also for autoimmune diseases.

And so let me start with the immunology side of the business. With CLN-978, our CD19xCD3 bispecific T cell engager, we have the opportunity to generate multiple value-creating milestones in the first half of the upcoming year. So we're very excited about that. And if we dive deeper into the program, with CLN-978, we clearly have a highly differentiated molecule and a best-in-class potential for the treatment of autoimmune diseases as a disease-modifying treatment.

From a development perspective, we're leading global studies across multiple automate diseases in RA, lupus and Sjogren's disease, and we also plan to present the first company-sponsored data with a CD19 T-cell engager as we share our initial data from our RA lupus studies next year.

The other thing I'll add, if you've been attending immunology conferences, is that we now have clear external validation of our approach. Data from both ACR more recently and ULAR this year clearly underscores the importance of T cell engagers for the treatment of autoimmune diseases as does the persistent interest by large pharma demonstrated by multiple M&A opportunities and transactions in the space.

On the oncology side of the house, with CLN-049, FLT3xCD3 bispecific T-cell engager, obviously, the focus of the program this evening. And there, we have a first-in-class opportunity to treat a broad all-comer population of AML patients, which we're very excited about. As we discussed this evening, we've already generated compelling clinical data as monotherapy in the relapsed refractory AML setting. We also have external validation now from the hematology community with an oral presentation at ASH. We've also been selected for inclusion in the upcoming 2026 highlights of ASH meeting, so very pleased about that. And the other thing that was very important for us was that we secured Fast track Designation from FDA just last week for 049 for the treatment of relapsed/refractory AML. So again, underscoring the clinical promise of CLN-049 for the treatment of AML.

Finally, we have, and we're fortunate to have a very robust cash position, we have approximately $475 million as of the end of September this year, which gives us runway to 2029 and ample resources to continue to execute our programs and generate multiple near-term and longer-term milestones with our immediate focus on quickly delivering the highly anticipated data from our CLN-978 program in the first half of 2026.

So hopefully, I gave you an outline of our overall pipeline strategy and what we've got going on, especially in the space of T cell engagers. I'm now going to turn the program over to Jeff, who's going to cover and recap the CLN-049 results presented at ASH.

Thanks, Nadim. And before we talk about the clinical results that were presented this morning, I'll take a moment to just talk about the CLN-049 itself since this program has been percolating on stealth for a number of years, and it's an opportunity for us to share a little bit more detail.

So CLN-049 is a T cell engager, very familiar modality in hematologic malignancies, but AML has been one of the largest indications for which a T cell engager has not yet been successful. And we think that's what gives us a first-in-class opportunity for an immunotherapy for AML, but also a first-in-class potential to use the FLT3 target as antigen for the immune therapy. And so in this case, CLN-049 is a FLT3-directed T cell engager, and FLT3 presents several features that give it potential both on the safety side as well as on efficacy.

For the safety argument, FLT3 expression is nearly uniform on patients with AML. In the blast, more than 80% will express FLT3, which is an oncogenic driver in this disease. On the other hand, normal hematopoietic precursors, only small subsets of those express FLT3 as well as small subsets of dendritic cells. So there's an inherent therapeutic index compared to other targets that have been pursued for T-cell engagers like CD33 and CD123.

With respect to efficacy, as I mentioned, FLT3 is expressed as an oncogenic driver on AML cells and thus, is less likely to be lost as a target antigen. And FLT3 is also expressed on AML stem cells, which are important in -- are important to eradicate in order to achieve deep and lasting responses in this disease.

Finally, FLT3 is, of course, a well-validated target. But there, we're considering the 30% of patients who have intracellular mutations leading to constitutive activation of the kinase domain. But here, by looking at FLT3 and binding to the extracellular domain, we are able to address a very broad population of AML patients as Nadim shared more than 80%, we believe.

So now I'll dive into what is, as Nadim said, very compelling initial data. And I would just remind you that this data comes from a dose escalation study. Now expectations for Phase I studies continue to increase in oncology, and we're always looking for meaningful efficacy from the first patient treated. So it's very gratifying to know that it was only several dose levels in from where we started at a target dose of 1.5 micrograms that we were able to see compelling efficacy as well as we'll share.

So the dose escalation is depicted on the left-hand of this. And as you'll see, we started at a target dose of 1.5 and ultimately escalated in this data set at the time of the cutoff in August to a dose of 12 micrograms per kilogram. So there was dose escalation, but there was also step-up dosing iteration. So we began with a one step-up dose scheme and ultimately added a second step-up dose to further mitigate class-related adverse events as we'll discuss. But importantly, we iterated on that 2 step-up dose scheme to further improve the rates of cytokine release syndrome, allowing us to continue the dose escalation beyond as I've mentioned as we close. So the step-up doses were given on days 1 and 4 in the case of a 2-step up dose scheme with the first target dose given on day 8 and continued weekly thereafter. Now this study enrolled a total of 45 patients by the time of the data cutoff in August, but efficacy data was only available for the first 41. The last 4 patients treated at the 3, 6, 12 cohort did not yet have efficacy assessments at the time of the data cutoff. So the denominator for all of the efficacy data will be 41 patients in total.

Just again, as we said, FLT3 is uniformly expressed on the majority of patients with AML. So there was no requirement for FLT3 testing, and we think that's an important aspect of this program that there is no need for testing as our data suggested.

So in understanding the implications of efficacy, you're always interested to understand the nature of the patients who are enrolled in the trial. And there have been questions on whether the patients we enrolled were cherry picked. Well, you wouldn't pick these cherries. So these are pretty representative set of patients with relatively adverse risk AML. So you can see there by the ELN classification, more than 2/3 of the patients fell into the adverse category. And there in the blue box on the bottom, you can see the higher risk cytogenetic abnormalities that characterize these patients, particularly TP53 mutations, as we'll talk about, when Dr. Sallman speaks shortly, that we're present in the majority of the patients who were treated at the highest dose that we tested. These were also patients who were very treatment-experienced with a median of 2 lines of prior therapy. And another question that came up this morning is whether or not these patients had a significant burden of disease. And you can see that there were a substantial number of patients who did have in excess of 50% blast in their marrow.

So this is a dose escalation trial, and the first thing that we're always interested in is to characterize safety and in general, this is a very favorable safety profile for a therapy in AML, it is likewise a very favorable safety profile for a T cell engager. And I think it compares favorably with any of the T cell engagers that are currently approved in non-Hodgkin's lymphoma, ALL and multiple myeloma with respect to the most commonly reported adverse event here, which was cytokine release syndrome in just over 1/3 of patients and then another 1/3 of patients who experienced an infusion-related reaction. Many of these other adverse events are things that are commonly encountered in patients with refractory AML and are as much attributable to their disease as to how it's treated.

So let's dive in a little bit more to the CRS since it's of great interest for this modality. So I would begin by saying that nearly all of the CRS events, that is all but one, or grade 1 or grade 2, and we're not treatment limiting in any instance. The onset as expected for a T cell engager with early in treatment, typically after a step-up dose or a first target dose. And there was only one grade 3 events. You'll see it there, the one in green in a patient who was treated with only 1 step-up dose. Once we initiated the 2 step-up dosing scheme, the rates declined and they also decreased in grade. So you can see that in general, there was something of a lift and shift with respect to the likelihood and severity of CRS.

Now what about other cytokine-related adverse events. ICANS is another one that is particularly concerning in T cell-redirecting therapies. And in this case, we saw only 2 cases of low grade, grade 1 ICANS that occurred coincident with cytokine release syndrome.

Likewise, transaminitis. We saw elevations of hepatic transaminases in 3 patients that met criteria for dose-limiting toxicity. But once we initiated a 2 step-up dosing scheme, we saw no further significant elevation of liver transaminases. I will mention that in the cases that we did see, all of the transaminase elevations were reversible. And again, this phenomenon could be mitigated through a second step-up dose.

And finally, what has been the most gratifying part of this trial to date are the response data. And again, for a dose escalation trial, this is a very robust set of data. You can see that in the group of 32 patients who were treated at doses of 6 micrograms and above, which appears to be the threshold dose for robust efficacy in AML, 8 of those patients have responded. And at the highest dose that we assessed, 12 micrograms per kilogram, among those 16 patients, 5 patients achieved a complete response or a complete response with a complete hematologic recovery or positive CR rate of 31%, which is an endpoint of regulatory importance as you're aware.

But a response is only clinically meaningful if it's durable, and this is data that was not available at the time of the abstract and is new in the presentation. Among those 8 patients who achieved a CR or CRH at target doses greater than 6 micrograms per kilogram, we saw that 5 of those patients had a response that it extended beyond 4 months, 16 weeks, and 3 of those patients had an MRD-negative response, all of which was durable beyond 16 weeks, including the one patient at the top of the plot whose response was ongoing beyond 36 weeks. So clinically meaningful rates of response as well as initial data for durability, and this therapy also allowed 2 patients to go on to potentially curative therapy before with hematopoietic stem cell transplant.

So that's where we've been. Where are we going? Well, we have further dose escalated since the time of the data cut off in August and have completed enrollment to a cohort of patients who are receiving a target dose of 18 and anticipate completing the dose escalation later this year with planned enrollment at a 24-microgram dose level. At this point, 53 patients have been enrolled to date. So a pretty substantial group of patients enrolled since we began this phase of the trial a year ago summer. So very, very exciting to see the way that our investigators are interested in helping us explore this exciting new drug.

But we've got more work to do beyond completing the dose escalation, and that's outlined on the rights. So here, we are planning initial expansion to initiate in Q1 of 2026 with a target completion by the end of the year. And here, we will be expanding in 2 separate patient populations. The first is a group of all-comer patients with the exception of patients with TP53 mutations, and here, we will be exploring the efficacy of the drug in an all-comer population and also be checking the box necessary to satisfy requirements for dose optimization by expanding at more than one dose in that patient population.

In parallel is another important patient population with an exceptionally high unmet need, patients with TP53-mutated AML. And here, not only are we enrolling patients with relapsed refractory disease, but also patients who have not received prior therapy, so frontline patients, where the recommendation for most treatment guidelines is to pursue clinical trial. So this will be an opportunity to assess a broader population of patients with TP53-mutated AML.

So just to summarize the key points from the presentation and again, to emphasize why we are particularly excited about what we have already been able to demonstrate and that is, again, compelling clinical activity, particularly in the patients who were treated at the highest dose we had assessed 12 micrograms where the composite CR rate was 31%. The majority of those responses durable beyond 16 weeks.

Again, in this relatively older patient population, heavily pretreated, safety is also of great importance. And there, it's gratifying as well to see that grade 3 CRS and other dose-limiting adverse events could be mitigated at the highest target doses when the dose step-up scheme was optimized. And as Nadim shared, we will be proceeding under FDA Fast Track Designation for further development and are excited that the expansion phase of this trial will be initiated very shortly.

And with that, I'll ask Dr. Sallman to share his point of view. Thank you so much for joining us today.

Perfect. Perfect. Thanks for that beautiful overview. So it's a really exciting time. I actually should have searched in my Outlook, it's my first conversations, I would call it, is probably 4 or 5 years ago. So it just takes such an amount of time, and we're now at the really pivotal time. I'm begging for a slot on a weekly basis. And for being here tonight, I think I was promised an additional one spot on the record from the...

[indiscernible]

Exactly, exactly from that perspective. So -- and Dr. Chan, who is in our group, she's actually the PI from the study. She has a lot of experience. I would also look to reach out to her as well. But we're very, very excited by this program, and we really hope that this is going to be the first really immune therapy in acute myeloid leukemia, and I think there's some far-reaching implications from that perspective.

So acute myeloid leukemia is obviously a very, very challenging disease. I'd argue this is the most challenging disease in hematology. And again, we'll talk about P53 mutation in a moment. The majority of patients are older, and the majority of patients are not necessarily able to go for curative therapies. And even with that, even good and younger patients, still a lot of -- over 50% of the patients are not alive long term. And again, if you take all of AML 5-year survival, can be as low as 10%. And even despite a lot of novel therapies outside of really the very good molecular subsets of patients are still such an emergent need. Even the patients that have good risk disease, once you relapse or often even have some other factors, you're really not good risk from that perspective.

I think at the same time, because we've had such a lack of agents for a long time in AML, actually, our MRD technologies and a lot of the translational studies is actually very rapidly advanced. So I really think, over the course of even just the next couple of years, MRD is going to be dramatically incorporated more and more. I kind of look at it as sort of your emergent 911 SME, you need to do something. And again, having a therapy that you can utilize immediately in order to eradicate it is quite critical. And actually, I think that's going to be a really exciting phase of this program going forward.

So for -- just broadly, and I know the room is actually very expert on all the therapies that are out there. I think in newly diagnosed acute myeloid leukemia, where we have really done great core binding factor with gemtuzumab on an intensive chemotherapy backbone, we're curing a vast majority of those patients. But I really argue that a lot of the other subsets, we still have a ways to go. Of course, we have targeted FLT3 agents, particularly gilteritinib, quizartinib, frontline IC is doing quite well from that perspective. NPM1, of course, the conversations. I'm very happy to not talk about tonight. But I do think we're going to increasingly cure more and more of those patients with frontline combination strategies.

p53, and again, we're going to talk a little bit in more detail in a moment, is its own disease. And although we are talking tonight about acute myeloid leukemia, I very strongly argue there is a 0% difference between p53-mutant MDS and AML. This is a singular entity actually already recognized by one classification system. We've had a lot of editorial into the sort of harmonization between ICC and WHO criteria, where as soon as you just have 5% blast or you're a multi-hit p53 patient, this is a singular disease. So although, yes, study is focused on AML, if our p53 signal continues to show, this is going to have, in the United States, instant adoption across MDS independent of what the label will show.

Again, targeted mutations are really exciting, but at the very most, including even IDH and FLT3, NPM1, KMT2A, at the very most, we're talking about half of patients, so that still have that have essentially nothing in the salvage setting. And of course, all these patients with targeted mutations once you fail a venetoclax-based therapy, which was a majority, as Jeff presented just a moment ago, these patients do dismal independent if they have something to target or not.

Again, in relapse/refractory, we essentially have targeted agents that are now here. Again, we're still talking about composite CR/CRh rates that have led to approval around that 20%, 23%. So far, we're seeing close to 1/3 and actually a much worse subgroup of patients. And again, a lot of this is really optimizing now into the front line. That's really the pharmaceutical race across these good subsets, but again, what are we doing for the adverse subsets is obviously a critical question.

Now as far as what is risk, this is obviously continuing to be updated. I think the ELN 2022, which is here, is quite nice. I would just caveat that this is really specific to intensive chemotherapy. So we now have also ELN 2024, which is actually quite simplistic. Essentially, if you don't have NPM1 or IDH mutations, you're essentially intermediate or adverse from that perspective.

Again, you can see the survival. Even in favorable, I don't know if we necessarily say it's so great if, unfortunately, 2 -- half of patients are still not having long-term survival. Of course, part of this is enriched in the fact that a lot of these patients are older, elderly from that perspective.

Just to highlight poor and adverse. Again, the most important category, and I like the bold here is p53-mutant disease. A lot of the other things, for example, monosomalcariotype complex, cariotype minus 5,717. This is just P53. It could essentially all be rolled up in that singular one. Most of the other ones are extremely rare changes with the exception of the secondary type mutations, which although as adverse is really sort of a hybrid, I would consider between intermediate and adverse.

Just one thing to say at p53. If you look at every academic center in the U.S. right now, about 1/3 of patients coming in our doors are p53 muted. So we can overnight accrue these cohorts. The world is sort of desperate. And this is with a population incidence of p53 probably somewhere closer to 8% and 10%. But because of this, and if you look at every trial presented at this congress across elderly AML, why are there so many p53 mutants because these are the patients that we're seeing and why we so urgently need a change in the paradigm. And the world has come together to university, we've now run with a pivotal frontline Phase III, a pivotal frontline in both AML and MDS. So we can do this actually quite easily from that perspective.

So I've talked a little bit about this. Again, 12 to 13, I'd probably say 8 to 10, but again, in real life and across every center across the world, again, we're often talking up to 30% of patients. There are some subgroups that are in rich, particularly therapy related, where this can be up to 40% of patients. And with the increasing of all of these novel therapies in solid tumors as well as IO therapies, actually, this is going to probably continue to increase where actually the incidents of p53 may start to be, let's say, closer to 15%. A big, big challenge, actually one of the plenaries here, how can we prevent maybe p53 clonal hematopoiesis from progressing the sort of CD46 plenary that was given yesterday from that perspective.

The challenge with p53 is not -- response rates are often okay in the frontline setting, but the survival is dismal. And what's nice about the signal for p53 mutant disease, I mean for good or for bad, is if you have p53 and AML as frontline, independent, if you are 18-age, marathon runner, the survival is 6 months. That is the median survival; doesn't matter how old you are, how fit you are from that perspective, which is why, again, even in front line, which I think is really an exciting and bold move by the company, I think is a really interesting consideration. Unfortunately, once these patients relapse, we're often talking survival more weeks to months, and that's why when I highlight the case in a moment, I think you really have to put that into context. Again, this is in a salvage setting where, again, we're talking weeks to months for a majority of these patients.

So this is just a singular case. Actually had a number of personal patients on the trial that have really done beautifully. And as Jeff really nicely highlighted, this is not cherry-picked population. This is the very worst group in salvage setting with severe cytopenias, infectious risk bleeding, et cetera. So this is a 70-year-old patients with p53 mutant AML. You could see just by complex carrier type, this is automatically your multi-hit or biallelic, I know there's a lot of discussion is that rare low risk. So complex carrier type equals bad independent of any other feature from a p53 perspective.

Again, this patient was treated actually pretty aggressively. What I have -- this is not my personal patient, but what I have treated exactly this way, I don't know, but essentially got a novel combination. Actually, the way I treat p53 is at every step from day 1 through out their course of therapy is to try to do something different than normal. So this was a novel combination of [indiscernible] plus venetoclax, got sort of a partial remission, which is a sort of unicorn in the state of AML response criteria, but nonetheless was ultimately bridged to stem cell transplants in January of 2023.

Now what we do and actually, we had a nice abstract here at ASH si we do universal essentially HMA maintenance. Actually, we pitched a pivotal trial. We'll see if this happens within CIB FDR. But this patient actually did really quite well. I mean this is actually a quite good survival for a multi-hit p53 patient that's bridged to transplant, but ultimately, unfortunately, did relapse.

So this patient enrolled on the trial. What's nice with this therapy is responses, almost always are quite rapid. So you can see the patient did achieve blast clearance. It was actually MRD negative by flow cytometry. I think we've learned and we're still learning actually a lot kind of the kinetics of response. So a lot of times, we kind of see this emptying of the bone marrow, but fortunately a relatively rapid recovery. So we only had MLFS and that was all the response that we that we see. I would not be excited at all in this patient because patients, particularly with p53 need count recovery, you can see relatively rapidly within 2 months, had CRH. CRH is an amazing response for any relapsed AML patient. This patient further improved to a full CR, which is a very rare event in p53 mutant patients that relapsed and had a 6-month optimal response and complete remission before the patient ultimately relapse. Again, some of us can count on one hand across studies in a number of patients that achieve this type of response.

This just shows the bone marrow biopsy. I'm not a pathologist, but maybe I can pull some people in the room, essentially looking at the top. So these things that have a very large purple nucleus that looks a little bit more pale or blast, which is what the arrows are helping us out for bone marrow is essentially relatively hypercellular for this patient's age. And you can see at just 1 month, essentially, all of these blasts are gone. The bottom left picture is really just peripheral blood, which if the bone marrow gets more empty, you see -- you could see all the circle white globules essentially is fat, and there's really no blast or just kind of some endothelials and a little bit of other cells. And again, these blasts are eradicated again quite rapidly. Another way to look at is for CD34, which in general stains the majority of blast. So essentially, anything that's brown is positive. And you can see clearly that at the 1-month mark, all of these blasts are gone, there's no brown. The little ground that you see again are staining endothelials which do express CD34.

So again, we've actually enrolled a decent number of patients, not like this is a singular example. And again, a 50% CR CRH has never ever been seen in the setting of P53 mutant salvage therapy, and this is with monotherapy with IO. And again, these -- we have several patients that are having very durable responses. Actually, I would take an CR CRh CRI as extremely meaningful. And I wouldn't say MLFS is never valuable, particularly in younger patients. And remember, I have 18 year olds in a p53 mutant disease. If we can achieve this and give them a chance for a curative therapy with stem cell transplant, I think, is extremely meaningful. Again, there is nothing really competitive on Earth as far in this disease, particularly when we're talking about the salvage setting. And again, we're really, really excited for this next phase. I think what I really, really like is the fact that we're rightly looking at p53 cohort. We're looking at the other cohort. I think we're going to hear about the developmental strategies in a moment. And I'm so excited once he releases all of the expansion slots because I have about a list of 20 patients at any one time. And actually, up to half of those patients are p53. But I'm excited about both cohorts. I don't think we should solely be thinking about p53. Again, any relapse refractory patient has very poor outcomes independent of baseline molecular fashion. And again, I really hope that this can be the first approved T cell engaging type therapy that we'll have in the field of AML. It's been desperately looked at and worked hard by many in the field across multiple technologies.

So thank you, and I'll be happy to answer questions a little later.

Thank you so much, Dr. Sallman. And before Nadim takes over, I'll just state tonight, I had reason to reminisce that during this week, 19 years ago, I began my career as a hematologist attending on a hematology service. That was all acute leukemia during -- while the whole faculty evacuated, which is the short straw of academic medicine. And so it's very gratifying to see the progress in AML. And it's a reminder that we really rely on people like Dr. Sallman, the patients and their families in order to execute these studies and learn important things to help patients. So thank you very much for your point of view, for your participation in the trial. And then, Nadim, I think you'll share a bit of the strategic context.

Yes. Thanks, Jeff. Thanks for Dr. Sallman. I appreciate. Great talk. Look, one of the things about drug development is when you've got investigators that are fighting for slots on your study, that's a really, really good sign that you have something special. And I think we feel that we have something really special here.

So look, let me put our results in some framework around context. You heard a little bit from someone about the current targeted therapies. And so this table shows in recent years all the approvals for these targeted agents in relapsed/refractory AML. And I'll point out -- sorry, I'll point out 3 key observations. The first thing, all of these drugs received accelerated approval with single-arm studies of approximately 100 patients. All of these drugs were approved for a relatively small biomarker-driven subset of patients, including the recently approved [indiscernible] inhibitors. And third, these approvals have really kind of set the reference benchmark for approval in the relapsed/refractory AML setting, which we believe to be a CRh rate of around 20% to 30%, as Dr. Sallman mentioned, and response duration of 4 to 6 months; a fairly modest hurdle or benchmark for success.

You heard from both Jeff and Dr. Sallman, we've delivered promising clinical data in a broad range of AML patients, including patients with p53 AML. And so in many ways, we've actually already met the bar for regulatory success. So that's one thing. And secondly, I think our data now have really opened up the opportunity for a very clear development and regulatory pathway for CLN-049.

Now let me talk a little bit about the commercial opportunity. So if you look at the table I just presented, all of these recently approved therapies are addressing relatively small subsets of patients. So in other words, we have a very fragmented relapsed/refractory AML patient population. In contrast of CLN-049, we have a therapy that can be applied to a broad group of general AML patients. And so with CLN-049, we really have the opportunity to both disrupt and defragment the treatment of AML patients, which opens up a sizable patient population.

Dr. Sallman presented the intimates of AML. So just again to remind you, every year in the U.S., 22,000 patients are diagnosed with AML. And unfortunately, many of those patients, the vast majority will relapse following initial therapy. Now that does create a relatively large relapsed/refractory pool of patients, which is representative of about a $1 billion-plus opportunity. When you then expand into the frontline setting with a larger patient pool increased treatment duration, the commercial value significantly increases and opens up a multibillion-dollar opportunity for CLN-049.

The other thing I'll mention, the combination of the unmet need, the opportunity for CLN-049 to address a broad group of AML patients. And our internal hematology expertise, which more specifically includes deep experience in the development and commercialization of AML drugs means we have the opportunity to really rapidly execute the development plan for CLN-049.

Jeff alluded to the development plan earlier. And as I mentioned again, in this disease, we have a very clear development and regulatory pathway for success. We have a two-pronged approach. So for relapsed refractory AML, it's a monotherapy approach. Starting in 2026, we plan to complete the execution of both dose expansion dose optimization cohorts which will give us a recommended Phase II dose to then initiate a pivotal single-arm study for accelerated approval. At the same time and in parallel, we're also developing CLN-049 in the frontline setting with a combinatorial approach. So in 2026, we plan to initiate a Phase I/II study of CLN-049 in combination of standard frontline treatments. And the data from that study will allow us to initiate a complementary Phase III study which will also expand the label to the frontline setting. And so I will tell you, we're very excited to execute this program so that we can deliver a new treatment option for patients with AML.

Let me now summarize and bring home the kind of key messages, right? So for CLN-049, we've clearly seen compelling efficacy as a monotherapy in relapsed/refractory disease. We've also seen promising initial durability data and very encouraging efficacy in the p53 mutated patients, combined with a favorable safety profile. I spoke earlier about why context matters. And in this case, to see this remarkable clinical profile, while we're still dose escalating is really something special. Based on this mechanism of action, all 3 of us highlighted that CLN-049 can address a broad all-comer patient population of AML patients without the need for biomarker testing, another key point of differentiation versus current therapies. And as I said earlier, the efficacy data we have generated to date already meets the benchmark for regulatory approval and also opens up a very clear development and regulatory pathway for CLN-049, including accelerated approval of the single arm study. The combination of our Fast Track status and our internal deep expertise in hematology will allow us to rapidly developed CLN-049. And in terms of the commercial opportunity with CLN-049, with the relapsed/refractory AML segment alone, we have an opportunity north of $1 billion. Expanding into the frontline setting opens up a multibillion-dollar opportunity for CLN 049.

So now let me open up the session for Q&A, and thank you very much for your attention.

Questions?

Mark Frahm from TD Cowen. Maybe for Dr. Sallman, you really elegantly talked about the true unmet need in the P53 positive. But can you maybe just talk through a little bit of the unmet need on the other side of the bar on the p53 negatives? And where what you would be encouraged by -- as the experience gets bigger on that side of the setting as well?

And then maybe for the company as well, just in AML, I mean certainly relapsed/refractory first line like you laid out, but another big opportunity often is the maintenance setting. Just what's the -- is there a plan there at all?

And maybe this is also a little bit for Dr. Sallman, just the AE profile you're seeing, how amenable that may or may not be to that setting?

Maybe I'll start off with the company part of the question. So I think for us, we really want to focus right now on the very clean development strategy that will rapidly get us accelerated approval. And I think there, it includes the relapsed/refractory setting from monotherapy approach, the combinatorial approach frontline setting. I think in between that, Marc, there's lots of different opportunities. And [indiscernible] someone answer your question about the targeted patients. But one way we are thinking about the product profile here is in the very worst case, you would pick up the nontargeted therapy patient population, but that's not how we're thinking about this. So one way you can look at it is we have seen approximately 30% CR/CRh rate. In the targeted patient populations with the targeted agents, we're not seeing a 60% CR/CRh rate, right? And so if you're a conservative treater, the provocative question would be why would you need the biomarker test if you're getting the same results of a general treatment. However, I think the more provocative question is what can you do with combination therapy? So can you push that 30% in a IDH2 or an NPM1 patient to 40% to 50%? And there, I think that's a very intriguing opportunity, but I'd love to get your clinical perspective.

Yes. Yes. I would say maybe just briefly about the tolerability of the agent. I think it's sometimes difficult looking at AE tables and what do things mean from that perspective. We, unfortunately, actually, this hasn't been just specific to this program, but like neurotoxicity is extremely rare for whatever reason across the myeloid portfolio. Really, it only occurs in the setting of high fever and sort of like delusional issues in that setting. So you could have a grade 1 CRS, but with some neurotox as again that we've seen. What we incorporated and with dexamethasone premed, essentially eliminates I've had 0 recurrence issues from that perspective. And again, these are very well tolerated. Also the duration of the CRS is often very short-lived. So this is not like they're in the ICU refractory. Again, there was only a singular grade 3 throughout the event. It's actually been very easy to get. Again, multiple patients, clearly, elderly and frail staying outpatients from that perspective and doing very well. So the tolerability has been very clean from that perspective.

I think one thing I'd say in the development of relapsed/refractory AML, one big challenge with 1 out of 3 patients coming into all the big centers at p53 is like what do you do with that approach. We have all these patients, everybody is eager. Again, sometimes, again, up to 50% of patients. What's nice is it's not that there's something necessarily unique about p53 mutant versus wild type. Although I think translationally, there's a lot of work to be done. It's that these patients are doing just as well as the wild type, which we actually rarely see across studies.

I think to your point, there's still a huge patient population. All of the secondary type patients have nothing that is targetable. So again, these are splicing epigenetic factors from that perspective. And again, status post HMA venetoclax or other therapy, they really don't have anything else. And even in the good risk, again, there is still a lot of patients. I already talked about the expansion of the MBS. In the U.S., this will happen instantaneously in the p53 perspective. And I think what's nice with the sort of ICC. Usually, it's MDS hoping for some AML therapies. But I think in this setting, like what's the difference between a 10% to 19% blast secondary type MDS patients. There's not. If anything, these are the very best patients to think about novel IO therapy. So I think there's going to -- there will be a lot of extrapolation across the relevant last barrier.

I think frontline combination approaches, I completely agree. It's the right direction to go. They're very complicated, right? Even with response rates of near 100% across menin portfolio, people are betting are these trials going to be positive. A very interesting question. This is where the response rate is up to 100% because there's just a lot of challenges. Where I see this type of therapy being really exciting is, again, response rates are high, but a lot of patients still will have some level of MRD. So as soon as I had this agent, if I had an HMA then IC chemo, whatever from that perspective, they have any level of MRD, this is exactly when I want to apply it. One, the tox risk is essentially 0% in that setting. And again, this is the whole goal of therapy. Whether or not they bridge to transplant or not, I think this could be independent of fitness from that perspective. But there's a -- if we can get this over the line with this, again, a very relatively easy single-arm perspective, the expansion, at least in U.S. markets, would be great.

Agree. And I think, Marc, probably I think what you're alluding to Dr. Sallman is that for the MRD patients are more of a consolidation sort of approach it the necessary maintenance.

Yes, exactly. Whether or not you need to put all the drugs, as Mark Levis likes to say, and mix it or again, we can have a little bit more of a strategic approach, which may help from a toxicity perspective. Again, I love running the front line trial from that perspective. But I think there'll be a lot of art to how to expand it once we have -- the science really starts once a drug is approved.

Matt Phipps, William Blair. For the company, when you're thinking about this dose and step up and everything, how much do you think the first dose matters for trying to really get early control of the blast? You really only tested kind of 1 and 1/2 of are just moving up. So do you think that can get you more efficacy? Or is it trying to get to that higher target dose? I'm not sure how much are you really able to look at changes in between these doses as you're doing some of this initial step upwards?

There are certainly many instances where you sort of experience a kinetic failure where the kinetics of the disease outpace your ability to escalate. I think this is what you're referring to. It's like to escalate to a therapeutic dose. That's why we did some of the iterations that we did. It's important that the first dose actually be sufficient to have a pharmacodynamic effect with respect to T cell activation that you can assess through modest but not clinically significant cytokine production. If you haven't achieved that, then you or step-up dose is probably not effective. I think what we've seen is that the 3 16 scheme is allowing us to escalate beyond where we saw really compelling efficacy. So I'm not concerned that we were at risk for the kind of kinetic issue with this step-up scheme.

And then sorry if I missed it. On the potential pivotal accelerated approval, is that just in p53 mutant as a first step? Or that's all comer?

No, that would be -- the going-in approach will be all comers. Now it will be great to see activity in the p53 patient. I think that opens up a whole another opportunity to it.

Robert Driscoll from Wedbush. Maybe just -- did you guys see a correlation with FLT3 expression at all? Or is that something...

We didn't talk about that tonight. But in the presentation, you'll have seen that there is no correlation with FLT3 expression. T cell engagers are particularly efficient, somewhat differentiated from CAR T and being efficient at very low levels of antigen expression. So here, using conventional flow methods, we didn't detect any difference between responders and nonresponders, which is a great thing. If it does open up a very broad opportunity as we've discussed.

And maybe I missed it on the -- some of the swim pass. But did you guys treat after transplant in any of the patients that did go...

There were patients who were included who had relapsed after transplant, but we did not continue the drug beyond transplant. No.

And I think just to comment on that, it's an interesting group because a lot of patients will have mixed kind risk actually the functionality of the T cells may be better. Actually, if you look across CAR T programs, which we have done a lot with not necessarily amazing success. Actually, a majority of the responses in CAR-T and AML have been in the post-transplant relapse, at least with autologous products. So I think it's a huge unmet need that has nothing. And again, because we have a great technology an interesting trial, I would love to pitch, let's say, post approval is for p53. Like -- because we're already essentially doing maintenance again, that was our abstract, but like why not at day 42 or something do this. There's already discussions around prophylactic DLI. We need to be very aggressive with anything to augment GL. That would actually be something I would love to pitch will mark tonight at the first night, it was mentioned from that perspective.

I think you just pitched it.

Justin Zelin on for Julian. BTIG. My first question is, what do you attribute your beneficial CRS profile to relative to other approaches here? Is it something with the dose schema or the modality itself? And I'll ask a follow-up.

Yes. So it's a good question. I mean, certainly, preclinically, this molecular format performed the best. There were attempts to try the same binders using different formats and this one empirically. So I think there is something that we are still looking to understand about structure, function, relationships with respect to toxicity and it probably depends on the specific antigen that's being targeted.

I also think that there's something unique about FLT3. Its expression is relatively low as compared to something like CD19 on lineate cells or BCMA on plasma cells, and that may also be beneficial.

I think to piggyback because we've done a lot, both with CD33 and 123. And I think the fact that there's such broad expression throughout hematopoiesis has been a major issue 123, and again, excited about some of the data here at ASH from that perspective. Also, endothelial expression in the sort of whatever you want to call it, capillary leak syndrome versus edema tox has been an issue across multiple technologies. So I think that is a unique difference with FLT3 as far as not broad expression across all of hematopoiesis and even antigen think, et cetera, are some challenges from that perspective.

Great. And I was just curious on how you'd expect the data to evolve in earlier lines where you might have higher immune cell fitness in patients? And is the goal here to be a bridge for transplant? Or do you think that this can ultimately have durable activity in patients?

David, you take that one.

That's kind of a soft ball. But yes, I mean, yes, I think anytime we can move things in earlier lines of therapy. I think exactly right, from T cell fitness it should definitely be better. I would be shocked if we're not moving metrics between the sort of 10% to 20% as we move into earlier lines of therapy. Again, that sort of consolidated MRD eradication approach is something that I think would also be very exciting from that perspective.

We actually do have -- do you want to describe the ongoing study we have?

Yes. So we didn't talk about it tonight. But in parallel with the study, we have a second study ongoing in Europe where we are utilizing CLN-049 as consolidation therapy to eradicate MRD in patients who are in CR with persisting MRD after induction or reinduction, and that study is ongoing in parallel. So we are interested in this. MRD is still a challenging endpoint from a regulatory standpoint, but from a clinical standpoint, it's very meaningful. Without it, you're not going to have a durable response.

Even in the next [ 5 years, 2 tiers, ] collaborate with Stephen UT Southwestern and he does actually a very cheap CD34 selection, and we're getting up to like 90% MRD calling from that perspective although the paper will be out shortly, but it's been presented [indiscernible]

There was a time when MRD was not accepted in myeloma, right? But it is now by the agency. So I think these things evolve for time if you can show the data.

This is David Dai from UBS. A couple of questions from me. One is, is there any correlation between the onset of CRS and complete response.

There's no apparent association that we've identified in the data to date. That's the short answer.

Great. And then just on the 3 Grade 4 transaminitis, just curious what's the reason behind this? And how confident -- now that you have gone through mitigation strategies, those company are you that you want to see a adjustments happening again?

Yes. So I think our hypothesis that it's cytokine-related only occurred in the context of higher grade CRS. And in all instances, there was no hepatic dysfunction. This was clearly just -- it looked more like a cytokine-driven acute liver injury sort of pattern. And so when we have better managed CRS, we haven't seen it recur.

Yes, I would say across -- like we have a very large CAR T service as well as actually a bispecific service at our group. We see this not infrequently across approved -- fortunately, I don't think I've ever seen across any technology like the fatal liver event afterwards, but especially early, you can get this significant transamanitis in a rare subset of patients that is rapidly reversible. I have a patient currently screening for a trial and he went to Grade 3 without actual therapy. So some of these AML patients, in general, whether or not it's extramedullary disease or et cetera, and a lot of CONMED issues with azoles and other medications, we see these LFT things. But again, without the actual liver failure events, it's clinically irrelevant.

Brett Canino with Guggenheim. Kind of difficult to ask a hard question on the data because as you've shown the dose installation, you're already meeting the bar. So maybe let me try a regulatory one. Because the precedents that you put up there, they're all targeted therapies, right? They've gotten full approvals on single-arm trials really based on palliative care thinking from the FDA. And I'm wondering, is there a chance that the FDA looks at an immunotherapy and ask for a higher bar on OS. And I know between Nadim and Jeff, you've sat through a lot of AML regulatory discussions, what would you say about that potential risk?

Yes. Let me ask, let's see if we say the same thing -- so the first thing I would say is when we're thinking about accelerated approval, then it isn't the longer-term outcomes like EFS, PFS or overall survival rates really focused in on the kind of some form of composite CR rate, whether it's CRC, CRh. And I think there, the fact that we're seeing so far -- and again, remember, we're still in dose escalation. So we've got room to go. The fact that we're seeing -- and that was a comment I made earlier. The fact that we're seeing approximately 30%, but we're not seeing 60% of the targeted therapies, our view is that reference benchmark should still apply it to a broader group of patients, and that's kind of how we're thinking about it.

Yes. I mean, I think the reference benchmark is a measure of clinical benefits. And so I think if you -- we started -- Dr. Sallman emphasized that roughly 50% of the AML patients, particularly if they've relapsed, they don't have anything, and they don't have a targetable mutation. So there, I think the unmet need is just as high. And I think the benchmark for clinically relevant outcomes is the same, which is a meaningful rate of response that is durable, and there isn't an expectation of demonstrating and technically, outside of a randomized controlled trial, you can't demonstrate a survival advantage. So the agency isn't different to survival at least in terms of making label claims. I still think it's influential and sometimes in your thinking but it's not something that enters into the specific regulatory discussion.

Yes. Usually, when it becomes challenging, Brad, is when you're seeing something kind of spectacular in that targeted group of patients, right? So if you think of lung cancer, and you think about ALQ 1 and those other things, right, checkpoint inhibitors contraindicated. But here, we're kind of seeing similar activity across the broad group. And I think what we would want to do in our expansion cohort is to be able to report out on patients who buy the H1 IDH2 and show the same results. So I think, unfortunately, because of the poor prognosis of the disease, the bar is quite modest, and I think we're excited about the opportunity to bring this forward.

Yes. And I think regardless of modality, I mean, historically, there are instances where the agency has shown great latitude where companies have demonstrated robust relapsed/refractory data and it's led to frontline approvals. And that's in other types of leukemia but in a very highly high unmet need population, if the efficacy is compelling, it's difficult to say that patients should have failed some sort of inferior therapy before progressing to something that's more efficacious than a frontline therapy.

Okay. Times up. I'm getting -- So very subtle thing we have. I still wasn't getting -- so look, in closing, the thing I would say is with CLN-049, we're at the very beginning of transforming outcomes in patients with AML, with a therapy that's broadly applicable to a broad segment of AML patients as we just discussed, independent of the cytogenetic risk factors and mutational status. So that's why we're super excited about this. And when you think about the promise of CLN-049 for AML patients, together with the promise of CLN-978 for patients with autoimmune diseases, I would say Cullinan Therapeutics is really poised to deliver very exciting and catalyst-rich period in 2026.

So thanks again for coming. We look forward to updating you in the future. Thanks, everyone.

Thank you.