Good morning everyone, 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. 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. 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 two. 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. 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. 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.
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. Also why we've selected two clinically validated and complementary targets with CD19 and BCMA. I'm going to ask Dr. Jeff Jones, our Chief Medical Officer, to talk about the emerging clinical data for CLN-978. Jeff's going to come back to talk about next steps in development for the program, and also discuss the initial data that we're seeing 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. Dr. Tesser is also going to share his personal experience of treating patients with CLN-978. I'll come back to summarize our strategic perspectives and discuss next steps. Of course, we'll open up a panel Q&A session to address your questions. Let me talk about why and 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. 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. I will say in immunology, T-cell engagers offer a unique therapeutic proposition if you think about it. Rapid 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. 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 two cornerstone therapeutics. CLN-978 for CD19 and velinotamig addressing BCMA. 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 relapse refractory AML. As many of you know, we presented highly promising data for that molecule at this past ASH, where the unmet need remains profound. 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. 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. 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. 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. You'll see that reflected in the clinical data today. As you think about it, we now have a very broad portfolio in autoimmune diseases, the issue there is that it's a very complex heterogeneous set of diseases.
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. 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 B-cell depletion and where current treatments still leave significant unmet need. Our initial indications under development include SLE, RA, Sjögren'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. This slide shows you the commercial opportunity for the first three indications that we're pursuing for CLN-978. I'll start with lupus.
If you look at the approved biologics in this 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. Sjögren'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 treatment that can be efficacious and address the key driver of the disease versus addressing the symptoms. Taken together, the rheumatic diseases represent very large market opportunities for CLN-978 and for Cullinan.
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. Our near-term development focus for velinotamig is non-malignant 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. 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. 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 two years, we've made significant progress across our immunology strategy. We've gone from concept to clinical execution with 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 Sjögren'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. Now, how does 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.
To get there from here, we really need to disrupt the pathway. We need to move from chronic disease management to resetting the immune system, ultimately deliver durable treatment-free remissions with a short course of therapy administered in the outpatient setting. 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. You've really outlined the strategic vision for the program, 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, increase confidence that we should have in the potential of CLN- 978. To begin, I really want to focus on what has been, over the last six 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, the data we're presenting is their collective effort.
I couldn't be prouder than I am today to share this data with you, to tell you that we've now treated 42 patients across the program, including patients with Sjögren's disease, where we expect to wrap up the single ascending- dose component of the trial here in the near future. Our focus today will not be on the Sjögren's patients. We'll be focused on the SLE and RA patients as we continue to advance the program with momentum. 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. First and foremost, the majority of the data that you're going to see, the data that we've presented at EULAR over the weekend, is from the single ascending dose part of the trial.
Patients there receive a first dose of 10 mg, then in subsequent dose cohorts, they receive an additional potentially therapeutic dose. We've always called it potentially therapeutic dose on day eight. That ranges from 20 mcg- 30 mcg. We've always anchored on the 30-mcg dose as being the dose where we expected to see efficacy, since that's the dose at which we saw one of three 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 two weeks prior to study entry. The efficacy parameters that we'll share today are patients who are experiencing clinical benefit from CLN-978 monotherapy.
New in this data set, I'll review the denominators so that you can all follow along on the next slide. 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 had moderate to severe disease and should have failed not only therapies like prednisone and PLAQUENIL, but also an immune suppressant 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 two disease-modifying therapies. Two failure makes you difficult- to- treat. Keep that in mind as we look at who we really enrolled. I'll start first with the RA patients. The denominator here is the same as we presented at EULAR, 11 patients, including the first four patients treated with a multi-dose regimen. As I said, difficult-to-treat RA is failure of two prior disease-modifying therapies. The median in this group was six, 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 three prior therapies, the majority treated with immune suppressants 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, 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 three additional patients treated with the initial multi-dose regimen of 10 and then 20 mcg on days eight, 15, and 22 of a weekly schedule. This is ultimately a safety study. I'll summarize here safety. 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. The safety profile overall, in 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. On the next slide, we summarize the CRS experience, and I just want to make a couple of general comments about our observations. Overall, the CRS profile is very reassuring and very favorable, particularly for patients treated at the 10 mcg , 20 mcg , and 30 mcg- dose levels, where the drug was very well-tolerated with respect to CRS, mostly grade 1, including the patients who received the 20- mcg dose in a multi-dose regimen.
Only two cases of higher grade CRS were observed. The remainder were grade 1, the majority occurring following administration of the first 10- mcg step-up dose. Overall, like the general safety profile, we believe that the safety profile with respect to CRS remains favorable, particularly for the 20 mcg and 30 mcg doses, which are the focus as we move into multi-dose regimens in the next phase of the program. You might have expected that the next slide would be B-cell depletion curves. That's how we arranged it initially. 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 SLEDAI scores, which is a significant component of the regulatory endpoint of interest, the SRI for response. That hardly seems compelling in 2026, and that's why we're gratified to see that a significant number of patients achieve a deeper response. LDAS as well as DORIS remission in five patients in the data set. Remarkable. Remarkable, particularly after a single target dose of CLN-978. Remarkable. I want to provide a bit more color about the patients to help your interpretation. 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 continued 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. 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 and in the RA study, we see transient impact on laboratory parameters, double-stranded DNA and proteinuria at the 20- mcg dose.
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 mcg . Again, helping establish what we believe is the evidence for a dose-proportional response. Finally, the B-cell depletion plots. We know that the drug works, and now we know why it works, because as we increased the dose escalation, we saw that the depth of B-cell depletion increased. It's hard to tell differences between the 20 mcg and 30 mcg dose with respect to B-cell depletion in the plots on the left. On the right, you see the time to recovery increases as we increase the dose. 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. At the start, I'll make comment about the additional data beyond our EULAR presentation. Here you can see that the last two patients on the swimlane plot are patients who were treated at the 10, 20 multi-dose regimen. These are the only two patients among the ones we had yet treated that had at least four weeks of follow-up beyond the completion of therapy, for which reason these are the two 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 mcg . A threshold dose of 30 mcg or a single-dose effect.
Now as we drop the dose back and administered it in a repeat dosing schedule of 20 mcg , we saw that we could likewise have meaningful impact on disease parameters in this heavily pretreated group of RA patients with one of the two 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. Here we also have laboratory evidence that conforms with the observations in the clinic. Here, a trend towards dose response in 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. You'll see again a similar trend to a depth of B-cell depletion increased at the 20 mcg and then 30- mcg- dose levels. Then on the right, similar kinetics for recovery with patients in the 30 mcg cohort as yet un-recovering their peripheral blood B-cell complements at 12 weeks beyond starting treatment. 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. 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.
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. 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 two JAK inhibitors, two prior attempts at TNF inhibitors as well as IL-6 inhibitors. This patient came onto the study with highly active disease and had achieved a DAS28 remission at eight 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-mcg dose and a grade 2 CRS following the 30- mcg 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 impacts for this patient with nearly a 30-year history of RA. What else did we see in this patient? 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. 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 mcg achieving a remission. Now we're moving back to 20 mcg , and now we're treating the patient with a repeat dose of 20 mcg on days eight, 15, and 22. This patient now a 40+ year history of rheumatoid arthritis.
I remember from my medical school days, just five years ago, that there's a long history of therapies in development for rheumatoid arthritis. This patient's treatment history reads like a textbook of rheumatoid arthritis drug development. This patient received treatments with sulfasalazine and auranofin in an era before methotrexate was approved in 1988. This patient achieved a remission at week four following therapy with a multi-dose regimen of 20 mcg of CLN-978, sustained at week eight 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 eight weeks, the second time, refractory. Here, a remission. We understand why. This patient was still, from prior rituximab exposure, completely B-cell deplete in the peripheral blood.
We can't call it B-cell kinetics, it's B-cell statics, I guess. 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 mcg of CLN-978 in the absence of any concomitant medications. This is a 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. 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 one indication, but two, 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. 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. 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. We are very fortunate to have collaborating with us, colleagues from University Hospital 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 is want to do, he will talk a little bit more about the biomarker data and its implications for development of CLN- 978. 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. 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. To give you a little bit of context for the two 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. 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.
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 four months after being fully depleted, the patients have a much higher rate of relapsing. The similar thing is observed in lupus. This comes from a different CD20 antibody, obinutuzumab, that was recently approved for lupus nephritis. You can see here that compared to the placebo response of 18% of patients achieving complete renal response, if B cells were detectable at at least one time point after giving the B-cell-directed antibody, the complete renal response was 35%.
If the B cells were undetectable at weeks 24 and 52, the complete renal response was even stronger. 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. 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. 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.
This idea here is that with the conventional antibodies, you're depleting superficially and potentially even for longer time periods 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 effects, such as, for instance, the collapse of lymphoid structures in the lymph nodes. Then when B cells come back, the recovery can even be faster than this year or multi-year depletion with conventional antibodies. Nevertheless, you will have achieved reset.
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. As we've seen now more than five years after the first treatment, this treatment approach still has the challenge of reaching the community setting. 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. 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, the normal antibody. In contrast, using a T-cell redirecting therapy, you can see a complete depletion of B cells in the tissue. 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. In early clinical development, things can be very nuanced. 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.
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- mcg priming dose and a 20- mcg target dose, you can see complete B-cell depletion in blood, and then a very, very slow recovery with B-cell reappearance at between eight and 12 weeks. In the next higher cohort of 10 mcg and 30 mcg , you can see extended durability of B-cell depletion. This shows you very clearly that we have entered the phase, essentially, of active doses and of potentially therapeutic and promising doses. 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.
You can look at the count of CD19 B cells and CD20 positive B cells, which are somewhat interchangeable, essentially, in the tissue. You can see in the 10- mcg 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. You can see in the 20- mcg cohort and in the 30 mcg 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. In the 30- mcg target dose, when you look at the effects on the lymph node, you can also see strong depletions, both in the 20 - mcg and in the 30- mcg cohort, showing that there is depletion, not just in the blood, but really also in the tissues.
That's something when we started using low-dose Blincyto off-label in RA that we did not see actually in the lymph node. 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. At the target dose of 30 mcg , I was a bit surprised actually to see this. 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 mcg and 30 mcg , it was also observed for CLN-978.
Again, if you look at the nuances a little bit between the data, it all starts to make sense because in the 10- mcg , 20- mcg lymph node, you see a B-cell depletion of actually a pretty strong B-cell depletion of about -85% for the CD19 positive B-cells. You don't see the full collapse of the follicular architecture. These types of small things are not noise, but they actually guide us in dose selection. 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.
Based on what we have seen so far in this program, CLN-978 has demonstrated the potential to achieve clinical remissions in patients that were heavily pre-treated, and in the case of RA, exposed to up to 11 biologics or targeted synthetic therapies, everything that is available, with a median of six, which is a highly refractory RA patient. Typically for RA, patients are considered refractory if they have failed two different mechanisms of action. This was a very strongly pre-treated cohort that also had already joint damage. Both in blood and in tissue, there is 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.
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 recess. 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. Thinking a bit beyond RA and lupus, this is a perspective that we have recently published. We are also thinking about other indications where deep B-cell depletion and plasma cell depletion might play a key role. 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. With that, I pass it on to John.
Thank you. Your unique experience, as both a clinical and translational researcher is very helpful in contextualizing our observations in the trial, and we are really glad you could join us this morning. We are going to turn to the next part of our conversation, and we are very fortunate to have with us Dr. John Tesser. Dr. Tesser is a clinician and clinical investigator, practicing now in Phoenix, Arizona. Maybe as we just sort of start the discussion this morning, John, first and foremost, many in the room, we often think we understand what the situation is in community practice, where the majority of patients are seen. 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. I appreciate the opportunity to come and speak here. It has been a remarkable journey working with the Cullinan team and seeing how this molecule is developing. I think it is fair to tell you, first of all, that I am a little bit older than I look. I have been a rheumatologist for 45 years, I was one of those guys who used one of those ancient and now extinct molecules. Golds and Aranesp and the penicillamine, these poisons that we only had available. 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.
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 non-steroid and anti-inflammatory drugs until they developed erosions and damage, then give them these other poisons that didn't work so well either. With that being said, I've been on staff at a teaching hospital in Maricopa County for 10 years before I went into practice. In practice, my group, Arizona Arthritis & Rheumatology Associates, is now 25 rheumatologists strong and 50 advanced practice clinicians. We have sites all over Arizona, 14, and we have three 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. That gives you a brief outline of where I've come from, where we are.
Also, we have 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. Gives you an idea where we're at.
No, that's certainly a wealth of experience that we've benefited from and will continue to benefit from as our research partnership continues. I think maybe before we talk about what's new in SLE, maybe you could talk a little bit about the typical patient journey. 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. 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. 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. The patient that's sent for a positive ANA and joint pain, that's much trickier. That requires a delve into doing multiple studies of autoantibodies, trying to build up an understanding of their autoreactive profile, if you will. Then the difficult part of 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%-25% of everybody in this room has a positive ANA or a positive rheumatoid factor. 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. The journey of a patient can be very difficult and may take a number of years before that patient has 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 art to that, and it takes a lot of experience. It can be very difficult.
Once the patient's 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 anti-malarial drug that during the late 1940s and 1950s was found to help people, particularly military people, who had these diseases, RA and lupus, and it got better. It was adopted into the practice of rheumatology in treating these patients.
Once they don't respond completely to that medicine, which is for most of them, then the idea has been to use prednisone to put the immediate fire out, and that usually means the patient's going to be on long-term prednisone, which we know is not a good thing. 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. You wind up having a patient on combination therapy almost from the get-go. If the patient's not responding very well within two to three months with hydroxychloroquine, you're adding one of those medicines and trying to get a response.
The first advanced medicine approved for SLE in 50 years was in 2011, which was BENLYSTA, belimumab. 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 seven or eight years for that to happen. That's a next step of therapy once you get beyond one of those others. Finally, the next advanced medicine, which is a medication that interferes with interferon, which is anifrolumab, SAPHNELO, that was approved 2022, I think. That has been used now as well.
Those are the two advanced therapies, 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 all 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.
Understanding the challenge in getting patients to a remission, is there an ability to get patients, so they started first with PLAQUENIL, steroids. You try to get them off, hopefully with immune suppressants 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's a 95%-100% chance that they're going to flare. That is highly looked at as not being the way to treat someone with RA. With lupus, it's not quite as clear.
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, some time being at least one or two years. Now, clinical remission means no rashes, no oral ulcers, no alopecia, no swollen joints, no nephritis, no cytopenias, all of those things. If you take medication away, we don't cure these diseases. We manage them.
We control them. You can see from the slide, the graph on the right, the percentage of patients on the two advanced medications who are put into remission is not much different of the modern medications we use for RA. It's only about 20% hit 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. Effective means you have to think of, well, how effective? You sort of have to add in, well, low disease activity to remission, because low disease activity is an acceptable outcome if you can't get people into remission.
You have to consider how many patients get there. 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.
It's very clear, patients with SLE need remission. Let's talk now about your experience with CLN-978 and one of your patients, who's among the group that has shown the potential for CLN- 978 to induce a remission. Maybe you could talk more about this young woman's case and your experience with CLN- 978.
Yeah. This was patient 31, if you remember the other graphs that were shown earlier. She's a 32-year-old Hispanic lady, very nice lady, who'd been through the mill with all kinds of medications, as you can see up there. There's your hydroxychloroquine, mycophenolate, BENLYSTA and methotrexate, over those various time periods in the right upper corner there. Her disease was diagnosed in 2019. She had positive serologies, including an anti-Smith and anti-double- stranded DNA, polyarthritis. She had class II and V nephritis, low complement, proteinuria, pleuropericarditis, Raynaud's, and a history of a seizure disorder, so neuropsychiatric disease as well, although not active at the time that we treated her.
She had active rashes when she was entered into the trial, all of those characteristics of the patient's clinical profile belie the underlying fatigue and malaise. You know how you feel when you come down with even just a cold or a flu? You just feel weird, you feel out of it and foggy, you kind of hurt all over, 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. That's how these people feel most of the time when their disease is active. Their body is on fire, this inflammation is everywhere. The way it pushes out at an organ system here or there is just a reflection of what's going on inside of them.
That's how this woman was feeling, as well as anxiety and depression, which really are neurologic correlates of inflammation as well.
Her SLEDAI was very active at the time that she was dosed. She had the active rash and proteinuria, active DNA binding. Her SLEDAI was 8 at week four. It was 6 after the initial dose. Her rash was already fading by then. At week eight, she was in remission.
Yeah
Through week 12.
That's an amazing outcome for your patient. Like you said, a relatively short history of SLE, but checked a lot of the more sort of calamitous complications of SLE. We're very pleased to sort of see this. I know you were. There were adverse events. This patient experienced CRS.
Yes.
Maybe talk a little bit about your experience with grade CRS. You're in a community setting. This is not an academic practice. 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. This patient, her name is Sophia, she was in that unit while she was dosed, 24-hour observation. She experienced some fever. 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.
She got through it. The grade of CRS was only 1, but it was rough for her just at that lower dose.
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.
Yeah.
Amazing. 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?
Yeah, 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 in infusible drugs, intravenous drugs
biologics, hypersensitivity reactions and anaphylaxis. As a matter of fact, when Rituxan was approved for rheumatoid arthritis in 2005, the rheumatology community was absolutely scared essless, if you know what I mean, because we heard all these horror stories of what happened with the lymphoma patients when they were getting rituximab. 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. 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. 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. I think as the developmental 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.
For a grade 1 experience, if we could resolve it to grade 1, no harm.
Oh, yeah. I think that people will accept that. Yeah.
Okay.
I think that's manageable, as we say.
What then, acceptable understanding side effect profile. What's 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. 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 rheumatologists remains to be seen. 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 heads around.
It was a changing world in oncology, too. It was before I started practice, but rituximab, even in oncology settings, was often administered in the hospital. The initial launch, there were nurses and things dispatched to the community to help onboarding clinicians and their nurses and advanced practitioners to adopt. I expect it to be similar.
Yeah.
Now it's as routine as administering IV fluid in most centers.
Yeah.
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. Thank you for joining us today.
Me too. Thank you.
Thank you.
Thank you for the opportunity.
We'll have you back to answer questions.
Sure.
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. 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 a 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.
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 in 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.
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 three separate indications, we have active clinical trial applications, INDs, variously named in the U.S., 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 in robustly designed clinical and biomarker-enriched trials across indications. For SLE, we've completed the single ascending- dose experience.
We'll soon complete it for Sjögren's, that started only in Q4 of last year. 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 on 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. 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, 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. We talked about the opportunity. Dr. Tesser was speaking about the incredible unmet need despite existing standard of care, clear monotherapy efficacy for CLN-978 opens up incredible opportunity against standard of care in general SLE. 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. If we replicate monotherapy efficacy with CLN-978, there's no reason that that same pathway is not available to us.
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. 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. Then we'll carry those doses forward into phase IIa for dose selection, again, expected to begin in early 2027. One amazing drug in autoimmune disease. What if we had two amazing drugs in autoimmune disease at Cullinan?
Nadim has outlined a strategic vision for how multiple targeted therapies in autoimmune disease, CD19 and BCMA, could be complementarily developed, that opportunity extends to BCMA at Cullinan. 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. Genrix Bio had already commenced a phase Ib/IIa study in autoimmune indications rheumatology, starting with SLE. I can tell you, and will show you, that the initial experience with the drug is remarkable in that disease space. 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 developments for autoimmune disease to accelerate a global development plan, continuing to work with our partners at Genrix Bio.
Let's talk about the study that Genrix Bio is conducting. Again, the study was almost in flight when we signed the deal with Genrix Bio, 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 and indications beyond SLE. Here, the patients are defined by moderate- to- severe activity by SLEDAI score. They will have had a failure of standard therapies as defined there on the right, this study is now enrolling patients at five 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. First, in this initial experience, velinotamig is being administered as an IV agent.
Although in the future we expect 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 mcg per kilogram. The data that I'll show you is for patients treated at 5% of the multiple myeloma dose, 10 mcg per kilogram, the target dose, the schedule there, days one, four, eight, and then an additional dose on day 29. I'm going to start with efficacy again. I'm showing you data for only two patients, but the findings are remarkably consistent and profound. The patient here on the left, the SLEDAI scores dropping dramatically after the first three doses.
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'd 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 g 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. 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 two months following therapy, immunoglobulins as expected for a plasma cell-depleting agent to drop below the limits of normal over the same range, complements, typically low in patients with active disease normalizing, and of course, the expected peripheral blood B-cell depletion reaching nadir at eight weeks beyond dosing. Those results are phenomenal, but they're even more phenomenal because they were achieved with a very exceptional safety profile. Neither of these two patients experienced CRS. Neither patient experienced ICANS, an 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. 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, these can be prevented. 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. We've been granted another exceptional opportunity with velinotamig, one thought you may be thinking is that this is great, Cullinan's behind. 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. What will we do? 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 developments in autoimmune cytopenias, both ITP and autoimmune hemolytic anemia. These are physicians who treat the diseases. 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. 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. Where we start, but with opportunities to finish very broadly. This is a global development plan. 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. 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.
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 two 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 in 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. You've seen a lot of data, heard a lot of expert opinion, reviewed a lot of development plans. Now I have the unenviable task of summarizing all of that together in terms of key takeaways and also next steps. 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're seeing 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 outreach global program has significant momentum now. We've 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're significantly de-risk 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's going to be very busy over the coming weeks and months. In Q3, we've 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 dataset. By the end of the year, we'll also have initial single target dose data for our Sjögren's disease study. In terms of next steps for development, you've heard that in early 2027, 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. 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've just generated. 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. We're really looking forward to working alongside multiple investigators' treatment sites. I'll finish by saying we're really proud of what we're accomplishing alongside leading investigators like Dr. Gries, 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 a Q&A panel, but thank you very much for your attention. Questions. The floor is now open.
Great. Hello? Hey. Thanks. 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? 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- mcg patient that had the grade 3 CRS? How much should we worry or how are you thinking about safety moving forward? Thank you.
Sure. Let me start, and then Jeff, please feel free to chime in. Let me start with the last part of that question. 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 mcg and 30 mcg to move forward with. The 45- mcg dose, that was a dose-limiting toxicity. As it happens, that patient actually did remarkably well from a clinical benefit perspective. 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.
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. That's what we're looking for in the multi-dose data.
I think, in terms of what we're looking for, Alex, you and others who follow us, you have made note of some inter-patient 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 effects, 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. 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 Sjögren's protocol that we didn't talk about today.
It's a very rich data set that helps us look at the dose -response relationship from a lot of different directions. 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.
I think based on what we've seen so far, the dose response is very clear. Essentially with the 20 mcg then crossing into the 30 mcg and now with the 20 mcg 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, it's all very well connected and panning out.
Thank you.
Marc Frahm from TD Cowen. Maybe for the company, just walk through the process that went into dividing the indications between the BCMA asset and the CD19 and 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 in case series and things. Others, we also have that for CD19 or CD20- targeting agents. Why BCMA for those? Maybe for the physicians, 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 justify the overall treatment profile of these patients?
Maybe we start, Nadim, with that question. Ricardo, John, talk about what an expectation for durability would be for a T-cell engager.
Sure. 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 six months, when you think about B- cell depletion with things on the market now, like rituximab. For example, BENLYSTA and SAPHNELO are both monthly IV-delivered medications, and by subcutaneous administration, both of them are weekly. Rheumatologists are quite comfortable with that, and patients accept that. If a T-cell engager came to market that could be given every three months or better every six, that would be particularly advantageous and welcomed by both the clinicians and the patients. What do you think?
I think that time window that you expressed makes sense. In a refractory setting, the question of how frequent you have to redose is totally secondary or even tertiary, right? The primary relevance is do you get a patient to respond or not? When you're thinking about the optimal treatment schedule, that will depend on durability of response. Everything from what you said, I think it's what we have available so far, and everything longer than that is even better.
Yeah, no, I would agree with that. If this winds up giving a response of never flaring to maybe a year or two, that would be amazing.
You obviously at a tertiary referral center, you see a lot of these refractory patients. With the short course of treatment, what would be maybe to Marc's question, the minimum duration of response that you would like to see?
Yeah, I think in the refractory setting, even three months is transformative because you don't have a drug that induces three 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 six months. If you cross the six-month mark, that's an improvement. Also, if you stay at a six-month mark and you get better clinical responses, that's also the improvement. I think the bar actually in RA is not yet so high because we have this ceiling effect of the available drugs already. Especially as patients become more refractory, it's very hard.
Yeah. Maybe, Marc, coming back to your question of BCMA versus CD19. I think the reason we landed on rheumatology as a target for CLN-978 is both strategic and biologic. Biologically, we know those diseases are very often driven by dysfunctional B- cell pathways. 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 a CLN- 978. 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.
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. Yep. Kaveri.
Kaveri Pohlman from.
Can we get the mic turned up, please, at the front? There you go.
Okay, great.
There she is.
Hi. Kaveri Pohlman from Clear Street. Congratulations on the excellent data and thanks for the insightful event. For the KOLs, 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? How much convenience, like you previously mentioned, can play a role there? How do you think about its positioning relative to options like rituximab? I believe there was a comment that was made earlier, the adoption of newer drug is relatively slower. Just thinking about that, how do you view adoption if it gets approved, let's say, today? How do you view adoption immediately versus five years from now?
You want to start with that?
I have a question later for the management.
I'm happy to start with that, because we actually also had an interesting conversation around that this morning. I think when you think about oncology, typically you have clinical development that starts in very late lines, then patients that get treated initially are refractory to two, three, four lines of therapy. For autoimmune diseases, that's not really the case. I can remember multiple patients that have not received immunosuppression yet, but the diagnosis is clear, 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. I think clinical development, as it's being done, starts in refractory patients, where you are starting to do the dose finding, you are defining the risk-benefit profile.
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 U.S. One of the big challenges here is the adoption by the payers. 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. There will be a little bit of a slow process in the beginning, then it will catch on. Something that works as well as what we've seen, I think that remains to be seen, because the data, 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, I think it will.
Maybe I'll pick up that question, especially for the U.S. healthcare system, having done a lot of launches in that space. I think what Dr. Tesser's referring to is certainly in some of these rheumatology where you have to deal with these step approaches that payers induce. The one thing I will say that is different here, clinically at least, is you're not adding on top of background chronic immunosuppressive therapy. From that perspective, if you have a clean monotherapy efficacy signal, I think you approach the payers, 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, how this can be a very, very different treatment. The second thing I would point out is these are very, very large markets.
If you take the RA market alone, if obviously, this isn't our aspiration, but let's say for argument's sake, you could only get a refractory disease population, polyrefractory, the worst of the worst. In the U.S., that's 60,000 patients. That's more than all of lymphoma combined. Again, I think that's where we start, but that's not where we finish. I think that's where you have to make the compelling clinical argument. 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. Thank you. Maybe for the management team, just wondering if you by any chance have any timeline for how fast the phase II trials can be completed and any timeline you can provide for the phase III study initiations. Also in terms of manufacturing, how you're thinking about scaling and localizing manufacturing specifically for the BCMA.
Manufacturing, let me start there first. I think T-cell engagers are definitely not like CAR T when it comes to complex manufacturing. As somebody who's been involved in two CAR T launches in the U.S., it's much more antibody-like. In terms of timelines, we've certainly told you when things are going to start. We'll keep you updated on when things finish.
I'll just make one sort of qualitative comment. If you're asking about timelines 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.
Okay. Thanks for all the information, Matt Phipps, William Blair. Question for Dr. Grieshaber-Bouyer. You have personal experience with both CD19 T-cell engagers and BCMA T-cell engagers. You've 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? Then for the company, you obviously have done single ascending target dose in now SLE and Sjögren'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 years of target, maybe one or two doses to not have to start over? Thank you.
The last one's really easy, Matt. Yes. As we start additional indications, the plan would be with a 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. I think we will have that data in hand as we expand in phase II. The BCMA CD19 question, Ricardo.
Yeah, 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. 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. 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. I think the field is right now really appreciating BCMA as a rescue therapy after failing a CD19. In addition, there are indications where we have seen 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.
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. That's going to be an ongoing assessment.
Yeah, I would add to that, Matt, is things are really binary, so there's probably some diseases in the middle that are more gray. 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. I think it gives us tremendous flexibility and optionality to have both in our own pipeline. Sam.
Hi. Can you hear me?
Yes, we can.
Okay, got it. Hi, Sam Semenko 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. I'm wondering, based on that experience, what is the correlation between seeing follicular disruption and durable remission in CAR T patients? 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? Thank you.
Well, you've done a lot of work in that space.
You definitely have.
Essentially, for the CAR T work, because the dosing had already been established from oncology, almost all patients started at the efficacious dose. Then, it was rather consistent to see this lymphoid structure disruption. For antibody-derived therapies, it's really not defined yet at all. It hasn't been observed in the field before. I think we will continue to look at that with lots of excitement, especially at these now active dose levels. My hunch is that because it lines up with the length of T-cell aplasia, the time to recovery, the remission that we saw, that we will see more of that. Is there anything you want to add?
No, I think that's it, Brad.
Hey, Brad.
Can you turn the mic up, please?
There we go now.
There you go.
Okay, great. Brad Pinsky, 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, anecdotes to support that those remissions will be durable as well. 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. I want to know, is that common even in chronic treatments-
Very common
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?
For refractory RA, also feel free to jump in.
Yeah.
The disease activity fluctuates, I think it's rather normal to not see one straight line, rather disease activity hovering. It's essentially about the long-term trend that you observe.
That's very true. 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. It includes joint counts of tender and swollen joints, plus a patient global assessment of their disease activity and the physician's. For an ACR response, you have to add in a HAQ Disability Index and acute phase reactant and a pain score. 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. Their fatigue and their overall pain and global assessments may drive that score up or down because it contributes to a composite score at any given point in time.
That's a longer explanation why that can happen, absolutely, Ricardo is right. You will see these fluctuations, 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 two questions, one on lupus and one on SLE. Maybe let's start with SLE first. Ricardo, if we look at the CAR T space and Georg Schett from Erlangen protocol , I believe they had B-cell depletion around three to four months, something in that order on detectable level. Here, if we look at the data, we see B cell recovering after four weeks. Do you think there's an optimal time for that B-cell suppression? Where would that be based on what we know from all the modalities tested? Maybe a question on the RA side. I believe there was a two-week washout period before patients were started on CLN-978 treatment.
I'm just curious, would the expectations, 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 a unanimous relapse in these advanced patients with a two-week washout stopping all their treatments? Can we then make an argument that even not seeing a substantial relapse is suggestive of efficacy here, given how advanced these patients are?
Yeah. Maybe the second question.
Yes, please.
The washout is at minimum two weeks, right? Depending on the prior treatment, in the case of biologics, it's multiple half-life, and it can be three months of washout period overall. 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. I think that would apply also to such a placebo-controlled study. Then, for the lupus question.
B-cell duration.
The B-cell aplasia, yeah. I think here we saw four weeks, but we also saw more than 12 weeks. Again, it's an evolving dose response that shows if you get higher exposure to CLN-978, you have more than four weeks of B-cell aplasia, which matches essentially then the three months plus or so that have been seen with cell therapies.
Again, remember, this is single target dose, not repeat dosing as well.
Yeah.
Yeah. Hi, Julian Harrison, BTIG. Two 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 too, what do you think is driving that? Is it the deeper tissue residing depletion versus maybe targeting CD19 versus CD20?
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. 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. That's the difference between CAR T and any NK cells- derived product of whatever provenance. I think T-cell immune responses are just going to be more potent. I think it is more potent in the place where it matters, which is in the depth of tissue-level B-cell depletion that has thus far not been consistently achievable with a monoclonal antibody. Whether the target's CD19, CD20, it hasn't really mattered. In terms of the target itself, CD19 covers much broader territory.
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 the better target versus CD20 in particular. 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?
I think it's mostly the modality, because T-cell redirecting therapies have a much higher potency in terms of fully eliminating target cells. If you think about the blinatumomab studies that were done in MRD-negative B-ALL, 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 in depleting remaining malignant cells was higher than the assays used to determine minimal residual disease. It's pretty sensitive to be able to get down to complete depletion, even in malignant setting, similar to what is seen in lymphomas where you can see complete responses, right? That's, of course, stronger than with conventional antibodies.
Yeah. 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. Interestingly, of the six patients, there were four that responded well. The two that didn't respond so well were rituximab refractory. These data are very conceptual in that context, if you think about it.
Excellent. Thank you. 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-
Yeah
a BCMA-targeted T-cell engager?
Yeah. 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 is 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. 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. 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. 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. 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 hematologist oncologists in administering a TCE to a patient with TED. We can get there, but that's not where we're going to get there the fastest. We know we're in a race, we've got an opportunity now to move really fast, and that's why we picked what we picked.
Excellent. Then a final one from 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.
You start.
Moving up, 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. 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. For the uptake, I'm pretty optimistic that patients will want transformative therapies first and as closely to the first line, or through the first line as possible, depending on what the payers ultimately will reimburse. I think it becomes a question of showing differential benefit to the patient and durability of response compared to standard of care.
Yeah, 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. 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. 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. That's the aspiration. 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.
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.
You can cost that out for payers, too.
There is a catch- 22 with all of this, though, and it depends on the developmental program, particularly at the phase III aspects of it. If the population that you choose for the program is a somewhat refractory population, whether it is one advanced therapy failure or two 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 have actually had a failure or two. And that is the problem, because with all these better therapies working at earlier time points, you roll the dice or you just set it up for less efficacy than you potentially could get. You also put the patients at risk for having multiple in a prolonged timeframe 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.
Yeah.
It is getting to a remission, and by doing that, you prevent organ damage. And that is what the focus has been and is developing in the whole community. And that will be something for the companies to keep in mind and to do the damage assessments during the clinical trials. But I do bring this catch- 22 out, and I am not sure how you really solve that.
Yeah, I think that is a great point, Dr. Tesser. I think the other thing, when Jeff laid out the plan, for example, lupus. 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 David Dai from UBS. A couple questions. One, just on the CLN-978, the initial data suggests potential for immune reset and disruption of follicular structure or architecture. Moving to repeat those, what additional longitudinal evidence do you want to see at the different sets of B cells or different follicular architecture that will give you the confidence that immune reset is durable instead of a transient remission suppression here? Then for velinotamig, given the data come out of China-based study, how comparable are the patient population background therapy, the trial design, to the planned global studies?
Let's take the first one. 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. As Ricardo said, there's a dose response, exposure sort of response emerged in our experience to date. The point of the multi-dosing regimen is to achieve that in a larger number of patients. That's probably one of the single most important objectives. 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 as 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 at recovery 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 precedence. 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 than we are these very important PK/PD relationships and safety associated with those data, because that's what really informs global development. That data is globally transportable. You raise 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. In terms of the data that we're deriving from the study, it'll be solid for our regulatory aims.
Yeah, 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 E.U., U.S. clinical operations playbook. We took a much more creative approach. We were 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?" 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've significantly de-risked the profiles of both of these agents now. Now, obviously, we want more and more data, again, we blew away our own internal expectations here.
Hi, Katherine Sun on for Morgan Stanley for Shal Ahmed. Thanks so much for today on the call you presented. Just two quick questions, one for Dr. Tesser. In your experience treating patients, I think we saw for patient 31, we taper down prednisone from chronic use down to less than 5 mg. Can you just talk more about decisions that drove that in your experience treating patients, and do you foresee this going down to none with long-term CLN-978 usage? Just quickly for management, as we look to evaluate velinotamig from the Genrix Bio 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 subcutaneous dosing? Thanks so much.
She was asking about PK/PD.
Yeah, I think I heard that.
When you say taper the steroids down in the patient you have-
Yes.
What were the decisions there?
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 two-sided coin, and it's done with an understanding you need to use advanced strategic medications to control the disease. If you don't get the patient off prednisone, the most commonly used steroid, then the patient still is at risk for organ damage. In fact, corticosteroid toxicity is one of the major drivers of long-term organ damage in lupus. Even though a DORIS remission winds up allowing for 5 mg 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 mg of prednisone extra the patient is taking.
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. That's the answer for that part.
Jeff, do you want to take the IV/ sub-Q?
The IV/ sub-Q. Cullinan is introducing IV, or pardon me, subcutaneous administration into their multiple myeloma program imminently. We do have some initial bioequivalence of sort studies and animal studies that Cullinan conducted that suggest relatively similar exposures, ultimately IV and sub-Q. 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 would 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. We look forward to keeping you updated as we continue to execute multi