Arcellx, Inc. (ACLX) Earnings Call Transcript & Summary

Good evening. I'm Rami Elghandour. I'm the Chairman and CEO of Arcellx, and it is my pleasure to welcome you to our event. Thank you for joining in person and for those of you who are joining virtually. Before we kick things off here, let's review our forward-looking statements. In terms of our agenda for today, I'm going to kick things off with some opening remarks. I'll then have the pleasure of introducing and inviting Dr. Ciara Freeman to the stage to share the results from our iMMagine-1 pivotal study. Dr. Freeman was one of the top enrollers in iMMagine-1 and one of the leaders in that study. So we're really privileged to have her this evening. Following her presentation, Dr. Chris Heery will lead a panel discussion, where he'll be joined by Dr. Freeman, Dr. Frigault and Dr. Bishop. Dr. Frigault actually has the distinction of being the very first physician to ever treat a patient with anito-cel. He was the principal investigator in our Phase I study and also one of the top enrollers and one of the leaders in iMMagine-1 given his collective experience. And Dr. Bishop, we have the honor of inviting Dr. Bishop as well. He actually opened the second site in our Phase I study, was one of the top enrollers in that study and certainly provided a lot of expertise for iMMagine-1 as well. So we're really privileged to have this group of physicians. They have the longest and most experience with anito-cel. They also happen to be leaders in the field. They represent 3 of the top centers in the world. And collectively, they have incredible experience with CAR-T. So we're really fortunate to have you all. Following that, we'll open up the Q&A for your questions. It is truly a privilege to represent Arcellx, our team, our Board, the patients and the physicians we serve and the investors who've supported us along the way. It is really a rare opportunity to be able to share these results, and they're truly a reflection of the incredible work and effort that you've all contributed to. I especially want to thank the physicians who trusted us with their patients and the patients who volunteered to be part of our studies. Neither of those is easy task, and it's a trust that we certainly don't take for granted. I also want to recognize our teams, particularly the clinical and operations, clinical -- CMC teams. You met a really incredible moment. We had this incredible therapy. It's not easy to run these studies, particularly at the scale, and the results that we're sharing tonight are certainly a reflection of your work. Lastly, I do want to share some special recognition. So most of you probably don't know, but we're coming up on the 10th anniversary of Arcellx in about 2 weeks here. And we're actually really fortunate to have this evening with us the first 6 team members that initially joined Arcellx about 10 years ago, who collectively, with the founder of Arcellx, David Hilbert, we affectionately refer to as the Super 7. They have done an incredible job of developing this technology and really setting the tone for the culture that helps us continue to succeed today. So we're really fortunate to have you here and appreciate everything that you guys have done, the risk that you took to help build this company into what it is today. And that foundation is really for a different kind of -- the foundation that you've built is really for a different kind of cell therapy company. I truly believe we have the opportunity to be a leader in myeloma to deliver a transformative therapy for patients and to really build a scale business. One of the reasons I joined Arcellx, beyond the desire to work on a life-saving therapy and my belief that this was a best-in-class therapy, was to really help cement and contribute to cementing cell therapy as a category that continue to benefit patients for a long time, and we believe we have the opportunity to do that. And that all starts with our technology. I've said this many times, but I think the most striking thing about the D-Domain is when you see it visually relative to the other binders that are utilized in cell therapy. I think the thing that struck me when I first saw it was the simplicity and the elegance of that D-Domain. And the D-Domain really has 3 attributes that we believe contribute to the overall profile here, which is the safety, efficacy and scale manufacturability that we believe will allow us to be the leader, again, in myeloma. And the first is a low-overall-total-cell dose. And that is really a function of having a high transduction efficiency with the D-Domain. So we talked -- we released before that the median transduction efficiency in our Phase I study was 70%. In the Phase II study, our median transduction efficiency was actually 62%, which is quite impressive because we were able to use a wider number and a larger number of vector lots in that study and to have that higher transduction efficiency, which is still far above anything else and within the range of outcomes that you would expect is really reflective, again, of that consistency of that binder. That total -- low total cell dose, what it effectively allows us to do is to actually dose relative to some other CAR-Ts, twice as many CAR-positive cells, which we believe certainly contributes to our efficacy profile, but in a cell envelope that's 2 to 4x less than some comparative CAR-Ts. Now when you couple that with the next point, which is that we don't see tonic signaling with the D-Domain, it means that we can dose the right amount of cells to clear tumor without seeing some of the exponential growth in cells or cell expansion that's independent of antigen that we've seen with other CAR-Ts and we haven't seen with the D-Domain. So those 2 attributes together really help define the D-Domain, right? So a low total cell dose with no tonic signaling allows you to really target the cells that you want without creating any deleterious side effects. And that's particularly reinforced by the last point, which is that we tend to see a fast off rate with the D-Domain, meaning it has lower avidity and it's not as sticky of a binder, which, again, allows for more targeted clearance of tumor without creating cytotoxicities, we believe, that have been challenging with other CAR-Ts. And that really allows us, in totality, to deliver what we believe is a BCMA CAR-T without compromise. First and foremost, that is built on the potential best-in-class efficacy that we've demonstrated in our Phase I study, we demonstrated a 30.2% median PFS in a very highly pretreated and high-risk population or 68% of the patients had a high-risk feature. Those results have been confirmed in our iMMagine-1 pivotal study, which, again, Dr. Freeman is going to share with you shortly. What's really notable about anito-cel, certainly beyond this efficacy profile, which is, again, we believe, best-in-class, is the safety profile. We have seen no delayed or non-ICANS neurotoxicities in over 150 patients treated so far. But even the overall administration profile of anito-cel is differentiated. We had 86% of the patients in iMMagine-1 have grade 1 or less CRS. We had 91% of our patients with no ICANS, and we'll talk about this more in the opening here. But when you think about the need to go outpatient with this therapy, when you think about the need to move into earlier lines, these are going to be really important factors in driving adoption in this market. And if those 2 factors, certainly, they are the 2 most important factors when you think about any therapeutic, safety and efficacy, but what's really special about CAR-T and important is that you have to be able to reliably and consistently deliver these therapies. And that's where our partnership with the best-in-class organization in cell therapy, Kite really helps set anito-cel apart. Kite has an expected turnaround time of less than 17 days. They've been able to demonstrate that early on in iMMagine-3, our current Phase III pivotal study that's ongoing and we'll talk about that. They also have remarkable reliability, 96% plus commercial reliability over an incredible sample, and they have the largest footprint of any cell therapy player. Over 500 ATCs around the world. So when you combine these 3 attributes, it really helps us truly believe that, not only is this the best therapy for patients, but it can be the best-in-class CAR-T in myeloma. Now we've talked a lot about this market. And obviously, as we approach commercialization here over the next 12 months, we're going to talk to you more and more and help hopefully bring more light into the commercial opportunity here. So we've talked about that we believe that the second line plus market is about $12 billion. So 2 additional pieces of information that are hopefully helpful as you contextualize the opportunity. One, the frontline plus market, we believe can be in excess of $20 billion, and that's an opportunity we'll talk about more in 2025. And that doesn't include the retreatment of patients, which we believe is a significant opportunity that can increase access to more patients over time. The fourth line plus opportunity, we believe, is in the $3.5 billion range, which is important because our initial launch is likely, we believe, to be in that patient population that'll hopefully quickly expand into second line plus. Now in order to really help the most patients, address the most patients and maximize the value from a business perspective, we really need to overcome some of the challenges that have been seen with CAR-T therapies. And this is where we believe we're uniquely positioned to address those. So the first is having a limited footprint. One of the things that we've heard, including at this conference, now these CAR-Ts have been on the market for many, many years, there are centers that are still challenged with getting access to CAR-T therapies. And again, through our partnership with Kite, who are in over 150 ATCs in the United States alone and again, over 500 worldwide, we feel we're uniquely positioned to be able to deliver this CAR-T to as many patients as can benefit. The second element is in order to really be able to deliver this CAR-T at this scale, you have to be able to consistently and reliably deliver, if for no other reason, from a capacity perspective for many of these centers. And so one of the things that is really notable here is Kite's greater than 96% manufacturing success rate. Now we've talked about, historically, that the D-Domain in and of itself is very reliably manufacturable. We had 100% manufacturing success rate in the Phase I. We had a 99% manufacturing success rate in the Phase II, and that's with a contract manufacturing in a large-scale pivotal study. And so we believe the technology, in and of itself, is scale manufacturable and putting that in the hands of Kite certainly gives us confidence that we can be consistent with Kite's historical experience. Reliability is also incredibly important. It's not just the consistency of manufacturing, but can you do it reliably over long periods of time. And that 17-day turnaround that Kite can deliver, again, we've already seen in iMMagine-3, in the early days. They're able to meet that right out of the gate, which is really impressive and speaks to their best-in-class organization. And then lastly, and I'll talk about this more on the next slide, but we hear a lot about outpatient dosing with CAR-Ts. Something you may not know is the vast majority of those patients that are dosed outpatient are still admitted over -- close to upwards of 95% of them are readmitted. So you're not really helping the patients certainly if you're readmitting them down the road. You're not creating any excess capacity in the system, and you're not saving the system economically either. So one of the things that we're going to talk about is hopefully the potential for more anito-cel patients to be dosed outpatient and hopefully not as many of them being readmitted because of the overall underlying safety profile of this therapy. And particularly these 2 points that we have here, that there's 0 delayed neurotoxicity. So not only are you not readmitting hopefully at a high rate, but you're not getting these admissions that are going to take a very long time to resolve down the road and are very complex. And you -- we hope to have a higher percentage of patients that are -- have the ability to be dosed outpatient. So let's dig into that a little bit. and particularly focus on the iMMagine-1 results. So Dr. Freeman presented earlier, and she'll show us again here that we had 17% of patients with no CRS at all. That is 3x the rate for some other comparative CAR-Ts. And overall, 86% of patients had grade 1 or less CRS. That's over 50% more than, again, some comparative CAR-Ts. And that's going to be really important, again, from an ability to dose more patients outpatient. Now we also get this question often, which is challenging. I think Dr. Freeman said it really well earlier. It's hard to answer a question for a problem that you don't have, but paraphrasing a little bit. But one thing that we've looked at here is that nearly 95% of all cases in the FAERS database that are related to delayed neurotoxicities are related to one specific product. And what's actually more notable is that product, based on our estimates, only represents about 40% or 50% of the total cases represented here. So if you're only representing 40% or 50% of the total volume of cases and 90-something percent of that specific side effect, it seems like it's more product specific than category specific. Further, there's another CAR-T on the market, Abecma, that has noted that they only have a 0.2% rate of this particular delayed neurotoxicity side effect, and they've treated thousands and thousands of patients. And that 0.2% is actually in line with what you would expect, prevalence of Parkinson's in the general population. So hopefully, that helps. I think that's the best we can do in talking about this particular issue because it's one that we don't have. It's certainly one that, again, given the Abecma experience, I think there's a natural incidence of this particular disease that might come up. But to have this high of a result, I think, certainly speaks to something specific within a particular product. I also want to highlight, one of the important things when you talk about the market is certainly accessibility. And I think one of the great things about CAR-Ts is over 80% of CAR-T cases have favorable reimbursement through either case rate agreements or ASP plus, and that's going to really help. And certainly, a big part of it is outpatient dosing, but I think it's important to understand that in 80% plus of cases, whether you're inpatient or outpatient, it's going to be a favorable reimbursement dynamic for centers. Shifting to where do we go next. So iMMagine-3 is currently our -- running as our Phase III -- sorry, Phase III randomized study. That study is actually being run by our partners, Kite, and it is enrolling patients that are anti-CD38 and IMiD exposed. We believe this is the right study given the standard of care in myeloma today, and it's going to have a really large impact and allow us to address, again, the most possible patients in second line plus. Now the D-Domain, as I talked about earlier, is really an incredible technology, and it really allows us to build a platform to both make classical single infusion CAR-Ts that we call Dd CARs as well as dose-able controllable CAR-Ts that we call ARC-SparX. And our pipeline continues to advance. I know that given the strength of the myeloma data, it's something that we talk about a lot. But as I mentioned, we have a lot of talented scientists, including some in the room here, that continue to advance our programs into new frontiers. We currently have ACLX-002, which is our AML Phase I study that's ongoing, and we expect to bring another SparX for AML to the clinic here that's advancing in late preclinical work. We also are really excited about the progress we're making on the solid tumor front. One of those programs, in particular, again, is in late preclinical development, and we're hopeful that'll move forward soon. And then lastly, we announced that we are beginning a study in autoimmune, in myasthenia gravis. That study has initiated its first site, and we're excited about moving it forward next year. And so with that, I thank you for your attention. It is my absolute honor and pleasure to invite Dr. Freeman to the stage to share the results from our iMMagine-1 pivotal study. Dr. Freeman?

Okay. Second time's a charm. Can you hear me now. Okay. Good evening. Straight in. So thankfully, I haven't -- I've had a great introduction in terms of the mechanism of action and the unique aspects of the D-Domain, so I don't have to get back into those things. As those of you who attended the presentation today and the Phase I follow-up that was also presented with extended duration of follow-up of 38 months has shown this impressive overall response rate of 100% with 79% of patients achieving a complete response. And what's really impressive is with that prolonged duration of follow-up, you see a median progression-free survival in those patients who achieved a CR is the majority of the patients of 34 months. So certainly, a colleague of mine talks about the efficacy passing the smell test. And I think that, that's an important thing to note in these data and especially as you make whatever cross-trial comparisons you may choose to make, which I will refrain from doing. But certainly, it's encouraging to have this prolonged duration of follow-up and seeing this efficacy that's maintained over time. So these are the curves that allude to what I've just talked about. So the overall PFS as the whole population has been median reached at 30 months and then for those who achieved CR better, 34 months. And then these are the different estimates across different time points as shown here. So for anyone who's unfamiliar with the iMMagine-1 study design, this is it. It's laid out. It's a Phase II single-arm study of anito-cel in patients who had -- who are triple-class exposed, having received a median of 3 or more prior lines of therapy, so relatively appropriate relapsed/refractory patient population as we would consider for trials like this and had to be refractory to their most recent treatment line. They had to have a good performance status and good organ function, evidence of measurable disease and a target dose of 115 x 106 CAR-positive cells. So in stark contrast to some of the other data that we saw today being presented, where higher CAR-T cell doses are administered, again, speaking to this idea that you can have a higher transduction efficiency, a lower total T cell dose and a lower number of CAR-negative cells administered. The primary end point for this study for anyone who's not familiar is overall response rate as assessed by an independent review committee. So that will happen. But for the purposes of this presentation and what I presented today, this is investigator-assessed overall response rates and efficacy and toxicity. 129 patients were enrolled and [ leuko-freeze ], 11 discontinued for the reasons outlined here, the majority for withdrawal of consent or for disease progression as can commonly occur in this patient population. A single patient discontinued between lymphodepletion and infusion of cells. And as of the data cutoff that is very current of October 31, 2024, we have a safety valuable cohort to report on of 98 patients who have a minimum of 1 month of follow-up and an efficacy evaluable population of 86 patients who have a minimum of 2 months of follow-up. Importantly, anito-cel was successfully manufactured, as previously alluded to, in all but patient enrolled in this study. So I'll focus on the data for iMMagine-1 for this 98 cohort of patients. I think it's important to note that the median age in this study was 65, and that is more reflective of the patients that we actually see with multiple myeloma, in particular, if you're enrolling patients with relapsed and refractory disease. Even more impressively is the number of patients who are over the age of 70 that were successfully dosed, and we even had 13%, 14% of patients who were over the age of 75. 9% were African-American, and that's important for the community at large. We actually made a big effort towards the end of the study to really push to try and accrue more African-American patients that was more representative of the global community of patients with myeloma. And that will increase with the future data cut when we get to the completion and we'll present in future analyses. 16% of patients had true extramedullary disease. So the investigators, like myself. went back and reviewed all the scans and made sure that every patient that we're classifying as having true -- extramedullary disease is true and current. We did not include anything that was contiguous with bone in this definition because of those differences in outcomes. Patients receive 4 or more -- median of 4 prior lines of therapy. The overwhelming majority were triple class refractory, and 42% were penta-refractory. Interestingly, as the trial went on, those of us who are participating became more confident with outpatient dosing. And by the end of the study, when we report the complete data set, there will be more patients dosed as an outpatient. But at the time of this data cut, 8% of patients have been dosed in outpatient. So at this early and preliminary time point, the median follow-up of 9.5 months, the overall response rate seen on this study and reported by investigators was 97%, with a complete response rate or better seen in 62%. What's important to note as well is that of the patients who had evaluable clones for minimum residual disease testing had a sensitivity of 10 to the minus 5, which for those of you who are not familiar, was a threshold established and voted on by the ODAC advising the FDA as a potential endpoint for clinical trials. 93% of the patients in the study population with an evaluable MRD were MRD negative and the median time to MRD negativity was just 1 month. What's also interesting is those patients who are currently classified as having a very good partial response had the same incidence of MRD negativity. So it is anticipated that those response rates will deepen over time. Again, at this early and preliminary data point, we've got this estimated CR rate and progression-free survival rate, but that is potentially going to change with time. And I think it's going to be interesting to see as we've got further follow-up, how these estimates will change based on getting more follow-up for these patients as time goes on. In terms of minimum residual disease, I think it's reasonable to show these data and show that they are at least comparable with other products. And I think it's really important to note that there is this very rapid MRD negativity that can be achieved. So this is a potent therapy that is capable of affecting these very deep responses. And as I said, the MRD negativity of 10 to the minus 6, which is even more impressive, is 80.9% overall, showing this deep depletion of malignant plasma cells with aggregated data. This is just comparing the 2 time points. And I think it's important to note that the PFS estimates are still premature for the iMMagine-1 study. And again, our investigator assessees will be adjudicated with further follow-up, but they're certainly comparable and very encouraging at this early data time point to suggest that we're going to see these durable responses that were reflected in the Phase I study and presented also earlier today. So in terms of cytokine release syndrome, which is something that we, as clinicians, see very commonly and advise our patients about and anticipate to occur, this was not seen in 17% of the enrolled patient population that we're currently reporting on. And the overall CRS rate was 83%. As you can see here, the majority of events were grade 1 in nature. And management was in line of per protocol and with standard medical practice, with no prophylaxis administered with tocilizumab or dexamethasone. If CRS occurred within the first 48 hours, tocilizumab with a single dose of dexamethasone was generally recommended. And of the patients who received dexamethasone, 2/3 of the patients only received a single dose. For those patients who developed CRS beyond that time point, it was at the investigator's discretion to administer tocilizumab or dexamethasone. There was 1 grade 5 events that occurred during the study attributable to CRS. And unfortunately, it highlights that if you administer a very potent therapy in patients who've got rapidly progressive disease, these are inflammatory storms that can occur. This is a 76-year-old patient whose disease, unfortunately, progressed rapidly between screening and lymphodepletion in the absence of bridging therapy. And [ it ] just really highlights that, in general practitioners looking after patients with CAR-T-cell therapy, it is always our goal to take a patient forward with the best controlled disease to try and mitigate these toxicities. For those patients who develop CRS, the median onset was 4 days. The majority of cases, as I said, are grade 1, and the overwhelming majority had resolution within 10 days. And certainly within 14 days, patients had completely resolved these CRS events. In terms of the immune effector cell associated neurotoxicity syndrome or ICANS that we commonly see reported in association with CAR-T cell therapy, the overwhelming majority of patients did not develop ICANS on the study. And I think this is actually quite notable in the setting of a trial that enrolls a higher proportion of patients who were older, who are always at increased risk of having ICANS. So I think that's also something that we'll delve into further. I think it's notable that the rate of ICANS is really quite low with only 9 patients developing ICANS during the course of the study. Importantly, and something that we talked about repeatedly, there have been no delayed or non-ICAN neuro toxicities reported to date, including the cranial nerve palsies that we see reported, the polyneuropathies, Guillain-Barré and importantly, Parkinsonism, which is really a devastating event if it occurs in patients. So I've covered all of this already, so I'll keep going. The majority of events, as I said, have completely resolved at the time of discharge and the overwhelming majority were a great one. Okay. I've already covered most of this, but this is just to highlight for your own information. The 0% incidence that we see in this product and with this trial, so far, the trial portfolio, which includes 150 patients dosed to date. This has already been alluded to, the overwhelming majority of patients that develop these complications of delayed neurotoxicity are in relationship to a particular product, which is cell to cell. And I think most of us who are treating patients will acknowledge the fact that this is not something that we aggressively counsel patients on who are going to go forward and receive Ide-Cel, but it is something that we take a lot of time when we're counting patients to receive cell to cell that this is something that we need to be mindful of and a risk that they're taking on if they're going to undertake this treatment. And so I think that this is not necessarily something that is a class effect. At least, I haven't seen any robust evidence that, that is the case. And obviously, I wish we had more understand of why these things occurred. But as of the current time, this isn't something we've observed with the anito-cel. So in summary, as I've said, across the trial portfolio today, 150 patients have been dosed with a minimum follow-up of 25 months. And out of all of the trials to date, we've seen CRS rates in the region of 83% to 86%, overwhelmingly grade 1 in their severity. In the iMMagine-1 study, the safety, efficacy -- the safety population that are reported today, 17% had no CRS at all. 91% in this study, the iMMagine-1 study had no ICANS. And as we said many times, there have been no delayed or non-ICANS neurotoxicities reported to date. There have been no primary [ malignancies ] of T-cell origin, and there have been no secondary hematological malignancies reported thus far, although follow-up is certainly premature. And there were 3 deaths that I discussed today attributable to adverse events. Unfortunately, the first one was in a patient who developed hemophagocytic syndrome, which is a complication that can occur, sometimes in [ shedding ] a massive inflammatory storm after the administration of CAR-T. This patient had circulating plasma cells in their bloodstream, otherwise known as plasma cell leukemia, at the time of infusion and unfortunately develops this massive inflammatory storm, had a bone biopsy performed to investigate for the presence of this hemophagocytosis and that within the setting of coagulopathy, which is a bleeding abnormality and succumbed to a massive retroperitoneal hemorrhage. There was an 1 event of grade 5 CRS, as I've already discussed, and an invasive fungal infection, which can sometimes occur in these patients who are heavily pretreated and have seen multiple lines of therapy previously. So the conclusions that I presented today are that anito-cel, with its novel D-Domain and the advantages that have already been discussed was able to demonstrate at this early look at the data at 9.5 months, an overall response rate of 97%, a complete response rate of 62% as assessed by investigators per IMWG criteria. The MRD negativity rates were 93%, and we're seeing in all of the patients with an evaluable clone a median time to MRD negativity was very short at just 1 month. Of course, the median progression free and overall survival have not been reached, but the estimates are 78.5%, 12 months. I think this is still premature, and it may change with further follow-up. Previously, as we said many times, the safety profile is certainly in line with something that we would consider to be predictable and manageable in the CAR-T space, and there have been no delayed or not a non-ICANS neurotoxicities reported to date. The iMMagine-3 study is enrolling. We're very excited to open up my center and start randomizing patients' standard of care versus anito-cel, and we're excited to see the faster turnaround time that our lymphoma colleagues get to brag about when they treat patients with lymphoma with products made by Kite. It's going to be a 1:1 randomization, a large study with 130 sites globally. So we're excited to start seeing patients and enrolling them on to this trial. I'm done. Was I efficient? All right. So I'm going to sit is what you're telling me. Okay.

So it's my pleasure to be able to have this conversation with the 3 of you. As somebody who works with you all pretty constantly, I know how you tend to think about things. But our goal here is to relay what you see and what you experience in your everyday practice to this group who don't get that same interaction that I am so lucky to have. So could each of you just give a brief overview of what the practice looks like, how many patients you see with multiple myeloma and what your current CAR-T dosing strategy is looking like, just -- or sorry, number of patients that you see getting CAR-T in your centers?

So I'm Michael Bishop. I'm at the University of Chicago. I've been involved in CAR-T research since Chris was a fellow at the [ NCI ].

He's my first attending.

So I oversee the cell therapy program. I see lymphoma and see myeloma. I also see solid tumors just to -- we do -- I'm sorry. Again, I can have that same situation where my voice is -- there we go. So our center does about 120 cell therapy products a year. About approximately half of those are multiple myeloma. So a little bit of everything.

Hi, guys. I'm Matt Frigault. I think I have spoken here before, so you may know me, but I'm at Mass General. And I tend to be more of a disease-agnostic person but do a lot of myeloma simply because it consist a large proportion of our patient population. We're -- we did a little over 200 cell therapy infusions this past year. Again, the bulk multiple myeloma and then total, I think, we've done around 80 or so Ide-Cel and Cilta-cel each. So about 160 myeloma there plus whatever we've done on the Anito-cel product, and that's in-spec, commercial product. I also do front-line with auto transplant and -- for my kind of transplant routes. So again, tend to be more early line/kind of late-stage but primarily focused on first-in-human products and toxicity management.

My name is -- here we go. Can you hear me now? Here we go. My name is Ciara Freeman. I work at Moffitt Cancer Center. And I am really fortunate to get to focus my efforts solely on the patients with multiple myeloma. And I only do advanced cellular therapies for multiple myeloma. So my primary practice is in utilizing transplant and CAR-T cell therapy to treat myeloma patients, both in the commercial space and obviously, with clinical trials. We are very fortunate on Moffitt that we are one of the biggest centers in the United States that we treat -- we're going to track this year to treat 350 patients with myeloma alone with CAR-T. And for the first time, we're going to outnumber the number of transplants we do for myeloma with the number of CAR-T-cell therapies we do. So it's a very exciting and dynamic field that I get to play with every day and deliver good things for patients. So that's my practice.

Okay. Can you then, each, maybe walk us through how you think about when a patient comes into your center, how you think about whether you're going to talk with them primarily about CAR-T cells versus bispecifics and other available therapies? Maybe we'll start in the opposite order.

Okay. So we have -- we and others have a reasonable amount of confidence in preclinical work looking at the effect of bispecifics on T-cell fitness to suggest that it is definitely in the patient's best interest to have CAR-T-cell therapy first and to save your bispecific therapy for later. Now obviously, there's always, some patients who feel really will struggle to get through CAR-T-cell therapy. But actually, we've done a lot of work at Moffitt to really optimize a patient rather than exclude them on the basis of age or fitness. So we have a whole program that looks at optimizing patients, especially who are over the age of 65. I have a trial of rehabilitation with exercise for older patients to make sure they can get through CAR-T [ segment ] well. And we have very good outcomes for that reason. And so we've shown previously that older patients fare extremely well who are treated with CAR-T cell therapy, often outperforming their younger colleagues. And so generally speaking, if a patient is at all capable of undergoing CAR-T cell therapy, we will try and offer that to them preferentially, be that in a commercial setting or on clinical trial, reserving bispecifics, as I said, for either sometimes for bridging therapy for early need to control the disease in between leukapheresis and cell receipt. But otherwise, for use at relapse, and that's, generally speaking, our practice.

I'll reiterate all of that. I think more of the finding ways of getting patients safely to and through CAR-T as opposed to excluding them for whatever outcomes you want to report out. But I think these therapies are truly life-changing in the sense that many of these patients have been going for many years. Every few weeks being tied to a cancer treatment center, never really being able to travel to go abroad. One of my first CAR-T patients was a great patient who was stuck here during COVID, and I had to, like, tie him down for the first 3 months after post CARs before he would try to get back to Greece and see his family just to kind of get his IgG levels up. But these really transformational therapies for those patients. So I think just to really emphasize the -- I think we underestimate how much we give back with the CAR-T that works, right, because those patients are now free to go into what they please. And when it comes to bispecifics they have their place. I don't think they're necessarily mutually exclusive. We're using talquetamab as bridging therapy, debulking patients. And so I think these things can be used in combination. It can be highly effective. It's changed a little bit, I think, with earlier line approvals where, we have multiple agents. We can use them in second line now. I don't think that every patient warrants a CAR-T in the second line, but I think the appropriate patient does and that safety profile can improve, that percentage can increase, especially as we know, which high-risk characteristics are going to be better or most appropriately treated. So I'm excited to see a highly effective therapy, that's a safe therapy that I feel confidently that I can give to a second or third-line patient or relapsed refractory, but the risk benefit does change when you have other options. And so I think that's where safety profile really matters in that conversation with the patient.

And so I have a similar practice approach to my colleagues here. When we see a patient, and I'm thinking about what is going to be the best option for them, I truly believe and with similar data, that a CAR-T-cell offers a patient the best opportunity to achieve a complete remission, which I think actually correlates with survival. And this would be across the -- particularly with myeloma, I'm -- with the bispecifics in the lymphoma, I'm not quite sure. But I really do feel that the best opportunity is with CAR-T-cell therapy. And just to reemphasize what Ciara said is we look for ways to exclude patients. We look to include them. And so we're doing patients who are on dialysis. And we've even done Jehovah's Witnesses with CAR-T-cell therapy and very successfully and we have a similar program, which we call the TOP program which is transplant optimization. You're not trying to rule somebody out. You're trying to optimize things for them. And so it can be very broadly applied. I used to not think -- I used to think there was a difference between transplant eligible and I didn't think there was a difference. Now I do believe there is a difference, that there are patients who could far better tolerate CAR-T cell therapy than an autologous stem cell transplant.

So when anito-cel was first being developed both, Dr. Frigault and Dr. Bishop, we're part of the initial discussions, this was actually proceeding my time at Arcellx and given Rami's time. So can you give us a little color on what led to the initial development of anito-cel?

Yes. So -- and it was actually kind of cool tonight to see the product development, what's in the future. Because I thought this, my greatest fear with the SparX technology was going to go -- like, we have this great product, why do we have to do anything else. So when I was initially involved with our Arcellx was for the SparX technology. I mean for those of you who are not familiar, this idea that they had, I still have, was you're going to have a universal CAR and then an adaptive technology. So it could be, if you want to slap on a CD19, you want to slap on a CD20. And they even had the idea that eventually, patients were going to be giving themselves subcutaneous injections at home.

And that idea is not gone?

And this was just so cool technology. And again, with actually more of a normal physiology, we were all very, very excited about. And then all ready to go with myeloma. And I know there was a huge debate about where was a population that there was an advantage. And all of a sudden, the FDA comes back and says, well, you have this D-dimer. We don't know what it will to. And so they forced Arcellx to do it with a regular CAR. Now I had been an investigator on KITE-585, which had 0 responses. And the idea of trying to investigate a new receptor and a new -- with a CAR was -- I was not encouraged. And then -- and a matter of fact, really, really debated about whether or not to do this trial. And if it wasn't for friends, I wouldn't have done it because there were other things to do. And so we go, okay, let's help out. And then it was -- so we started the trial, and it was so cool because the first patient responded. And then I don't know, we had, like, the second or third patient. And I do -- I have bragging rights because every patient at the University of Chicago got a CR. So -- but when you're seeing this patient after patient after patient and then, and then hearing, Matt goes -- well, they're entering a stringent CR, it's just -- you just didn't see this in a Phase I study and at the lowest dose and the toxicity was low. And this is a person who was on the ROCKET trial, for those of you are familiar in seeing high degrees of CNS toxicity with cerebral edema, but seeing really minimal levels of cytokine release syndrome and almost no neurotoxicity. It was very exciting to be part of that.

Yes. And I think around that time, I was lucky enough to join Arcellx and look at these clinical data and also was caught off-guard how impressive it was, how quickly these responses had developed. And we -- I think most of the people in the room know the rest of the story, which is that study went on to enroll 38 total patients. The overall response rate, of course, 100% and the CR rate. I think the unique part that we haven't really talked about much of this year, but Matt, maybe you can highlight is that first patient's story, can you just give a little color around...

I jokingly say that this was the CAR-T, the little CAR-T that wasn't meant to be and are today sitting on stage looking at data for the pivotal Phase II study, which is kind of incredible, and maybe the only time in my career I'll be able to see something like that happen from start to finish. And again, to have that kind of a home run. And so the first patient, like, when you think about a brand-new car construct with a binder that's never been in a human being before ever, and who is that first patient, right? Like who's willing to raise their hand and say, "Give me this gene therapy that you can't take out of my body." And then this is around the time that Blenrep was still in the market. label use it. And this patient was a photographer and was very concerned about keratopathy and, like, what that would do, had really bad disease. And we joked, and I think out of -- Chris has said, like, everything we look back at now is, like, potentially a bad thing for high-risk features, this patient actually had. We didn't know at the time. And we treated him. He had expansion. He did great. And I still see him now for follow-up, like, 5 years later. And it just -- it is so awesome to see a patient who forgets his 24-hour urine and is annoyed that he has to come from -- he comes from one of the islands off the coast in Massachusetts and has to rush out to get back on the ferry to get back home. And his biggest concern after being the first patient in the world infused with penta-refractory disease with horrific, horrific disease, being the first one ever is that he needs to make his parity. And I call it a win, right? When you're more concerned, after having multiply relapsed myeloma, to make your ferry 5 years later, is kind of amazing. So we have a lot of stories like that. And those are the things that, I think, really motivated us and seeing the repeated responses and what happened was just incredible to see where we are now. So it really fueled the need to keep pushing the study forward. And so I think I'm even more excited to move into earlier and earlier lines and to try to get that benefit to more people.

We are running up on time. And so I'm going to have one last question for each of you, which is pretty straightforward. Are you looking forward to anito-cel being broadly available to your patients? And if so, why?

So we're very excited. And as soon as it becomes commercially available, it will become our top line treatment across the board. And I mean, sometimes we actually select Abecma, when we think there's really a fragile patient, and that's probably the only time that we choose Abecma, but now with anito-cel, it will be across the board for every single patient who's not enrolled onto a clinical trial.

Yes, I think exactly the same. We probably do a little bit more Abecma just because I think we've had a little more of a negative experience with some of our side effects with cilta-cel, but I think that could just be random. But overall, I think anito-cel is going to take over the majority of our CAR-T patients. Even having the option of using other products in the second or third line, we're actively today not choosing to do that because of the current state of affairs. And I can imagine having conversations with patients where we say we can give you a highly effective therapy and then we can consider waiting in other line or two. Now we may opt to not give a CAR-T earlier simply because we're still waiting for an early line approval, and patients are kind of having that, making that decision now. So I think that was where we're going to go in the future.

I echo everything to the others have said, we're going to be excited to have the idea that you'd have cells back in 2 weeks is very exciting. You say that, guys, come on. You got a patient you're like, "I'll have your cells back in 2 weeks." I don't even know what I'm going to do with that.

[indiscernible]

No, it will just be like, okay, I'll see you back in 2 weeks.

I've been part of every single product launch of every single CAR T-cell from the very beginning, like usually activating within a week of approval. And having been through every single product launch and all the headaches with Novartis, with Abecma, with J&J, like its torture at times. And to have Kite manufacturing, again, not to be too much of a [indiscernible], but it's amazing what Kite can do. And I can't -- I cannot underemphasize how important that is clinically for patients, for us, for logistics. And so if they can truly deliver on this, and I actually believe that they can, it's really going to be a game changer because having a reliable product is just as important as having a product in the first place.

Great. So we're going to open it up for Q&A. You're obviously going to come back and join us. And I think we are going to have somebody walking around with the microphone.

Ben Burnett from Stifel. I guess first question for Arcellx, maybe also for the physicians. What's been the, say, enthusiasm for iMMagine-3? And I'm just curious, the second-line setting, it's a setting where cell-to-cell is ramping up into. So I guess the question is how much of a headwind is that to enrollment? And is there something you can say about the rate of enrollment relative to CARTITUDE-4 you're expecting?

I mean, I think that's a better question for the physicians. I'll just say from our perspective, we don't see it as a headwind at all. I think you've heard from these clinicians that this is a very differentiated profile that maybe is even more valuable in earlier line patients, given the safety profile, but I'll defer to the physicians.

Yes, I mean there's a lot of enthusiasm for the study. As far as I understand, all the sites have been selected, and we're ready to go at Moffitt. So I think that in the U.S. environment, yes, in theory, a second-line patient has got access to cell to cell and they get to choose. And for any patient, a clinical trial is always a choice. But there are some of my colleagues who work in other centers around the world who do not have the luxury of that decision. And I previously worked in Canada, they're very excited to be enrolling. I previously worked in the U.K. where access to CAR-T is very limited. They're very excited to open any study of this kind. So I think that -- I don't anticipate enrollment to be an issue even at my center, where we have access to second-line cell to cell, patients will still, I think be enthusiastic about potentially getting access to the study because of the safety profile.

I want Dr. Frigault and Dr. Bishop to answer this question, too. But before I just want to touch on something that Dr. Frigault said. Part of the deal with Kite was an acceleration of this program. And that allowed us to make this a global study. Last year, people asked why is iMMagine-3 [indiscernible] because we changed from what was the design of iMMagine-3 to make it a global trial, specifically because these therapies are actually not readily available in the same way in most of the countries in Europe, which makes enrollment really an incentive. Even some of the standard of care that we're offering is not available in some of the countries that in Europe. So there's an incentive for patients to enroll even for the standard of care. So it's really encouraging from that perspective. Dr. Frigault, go ahead.

Oh, yes, I'm ready to get going. Need to get activated. I'm constantly just pushing the logistical team to get up and running. But I -- at this point, like we have conversations, like the conversations we're having with patients now are you meet criteria for a second or third line or you wait a month for a trial and we can see what you do, like I'm having those conversations now with patients. So patients are actively deciding not to make a decision, thinking that there could be a potential for getting on iMMagine-3. So like people are waiting or they're thinking about getting it down the road. But like even I think around ASH, people are seeing the data and asking about are all the sites picked, like there's interest in it. So I have no concerns whatsoever. And I think we may even exceed what our expectations are for enrollment based on what -- assuming that the slots are available, which they seem to be, I think we're all going to be able to enroll pretty quickly.

Let the race begin.

Yes. I'll just add one other thing, which is that clearly, the availability of cilta-cel in late line was an impediment to enrolling iMMagine-1, and that was before this data was available, and so just I think rationally one would expect that with this data, it will further help with.

Okay. I just have one question for Dr. Bishop. Dr. Bishop, I think you had an earlier comment that you made around, I think the thinking that CAR-T was -- the CAR-T candidates were similar to transplant eligible patients, but it sounds like you kind of updated your thinking there. What's behind that? And it sounds like that maybe the candidate for CAR-T might be bigger?

Yes. No, it's -- I think really the biggest thing is when we're entertaining or suggesting autologous stem cell transplantation is that, that degree of dose -- the intensity of the chemotherapy that's given to the patient, whether they're going to tolerate it in terms of their performance and what it's going to do on organ function and recovery time. And it's quite remarkable for these patients, when they go to CAR-T, they come in sick and all of a sudden they feel markedly better at the end of 4 weeks. And with the transplantation basically you tell that...

The other way, right.

Yes. So please get to the 4 weeks I guarantee you that's going to get better. I won't -- I don't guarantee. It's most likely that you're going to feel better at the end of 4 weeks. And I go -- you're almost going to feel back to normal in 8 weeks and you're going to feel really good at 12 weeks. And yet with these CAR T-cell patients that they go why can't I drive? Why can't I go back to work at 4 weeks. It just looks so markedly better. And so -- and we were better at the recognition and earlier intervention for these toxicities. But here, we have a product. I just want to come back to the prior question. There's a lot of people -- and we're all excited about CARTITUDE-4, because we -- it's just so painful, have to wait for a patient to go through 4 lines of therapy before we can give them CAR T-cell therapy. Now we have it. Now, I mean, with the increasing recognition of not only the neurologic toxicities, but the GI toxicity that have been identified, it gives you pause, do you want to -- because we have really good therapies for the patient, but yet that's pretty impressive. But, that's why there's enthusiasm, gosh, if we can bring this and bring it to -- I share the saying that there -- I mean, I thought it was an interesting question, but there is such an enthusiasm to try to use this drug in that setting that I don't think it is going to be difficult.

Tyler Van Buren from TD Cowen. Congrats on the presentation and on [indiscernible]. I want to ask on a couple of topics. First one is just there continues to be some confusion. So just to be clear and hopefully with this topic, I guess, depend or this team position on this stage, can you review the strategy of treating patients with [indiscernible] the iMMagine-1 trial, how that might have evolved, whether it's prophylactic or not and ultimately it's conceivable that it could be leading to the delay in neurotoxic patients?

I'll take this one. So the evolution of CRS management has evolved over time. In fact, when we started doing CAR-T for BALL, you had to be vented on presses in the ICU to get a dose of toci. And if you got a dose of dex, like their hands were cut off because like they were so afraid of using those agents for fear. As things have moved along, I think we've seen management move up into earlier lines of CRS across the border-cross products. And I think what we learned in the Phase I pretty quickly is that as Dr. Freeman here pointed out, patients 2/3 of patients who needed to get an intervention of dex, got a single dose of dex, dose of toci and then you were done, and you didn't have to worry about it. And so that seems like a no-brainer. And I wouldn't call it prophylactic because the patient is actively having fevers up to 104.5 degrees. I mean, like we're not treating unless we have to as 100% of patients didn't get treatment. But I'll also point out, because of that practice from the Phase I, that actually has become my practice across all commercial BCMA products. And so we're giving a dose of dex with every dose of toci and usually for most axi-cel products, too. And I think [indiscernible] practices are the same. It's everyone's getting between 5 and 10 dose toci. So it's not prophylactic. It's not like this is something you need to iMMagine-1 or the Phase I. It's actually how I think general management of CRS has evolved over time. But it's no different across what I'm currently doing between the 100 and something patients commercially I have treated or the iMMagine-1 patients I treated to date.

I think it's really important as well to just emphasize and say out loud is that prophylaxis is where you give the agent before anything has happened, and that did not happen on the study. Like if somebody was fine, I was not going to start dosing them with toci and dex. They're fine. They're coming fine, see you again tomorrow, right. So that is not what happened. We waited until the CRS evolved. And then at the onset of CRS, we would look for infection and treat them and make sure that they were okay and then we would -- with early onset within 48 areas, we give them toci with a dose of dex and as we said many times, 2/3 of patients got 1 dose, and that was it. So hopefully, that addresses that question.

Yes, let add on to just finish on the last part of Tyler's question, which was, with that one dose of toci and dex for most of the patients, is that enough to have prevented delayed neurotoxicity? [indiscernible] the question is asked.

I have no idea how those one dose of 10 milligrams of dexamethasone would delay neurotoxicity. I'll just bluntly say that, just it does not make any -- maybe I'm wrong, I did wrong a lot of in my entire career, but that seems like there were more silly things that I've ever heard.

You have disagreed?

No.

If that's simple. I think we have solved the problem.

All right. And maybe just as a quick follow-up. With the approved therapies, what percentage of patients are you treating outpatients now? And where do you expect that to go to once the anito-cel becomes available based on your experience in the trial?

So at Moffitt because we have such a high volume, as I've already said, and because of the onset of CRS with CARVYKTI is late, we treat everyone as an outpatient. We really don't use ide-cel very much at all anymore. And previously, ide-cel, we were admitting patients because the dynamics of the CRS was much earlier. We tried to give prophylactic toci, but it really didn't move the needle in terms of CRS, but now we just don't really use it anymore. So in terms of anito-cel, I think that certainly, I'm excited to get more outpatient experience. As I said towards the end of the day, I dosed a reasonable number of patients as an outpatient, and I felt very comfortable doing that. And the profile of patients that you can very reasonably treat as an outpatient are those patients who've got a well-controlled disease and you feel very comfortable treating them as an outpatient. And the CRS occurs later on set. So for those institutions where I know that admission, we don't have that issue at Moffitt, but the admission within the first 72 hours is an issue. For those low burden patients, their CRS onset being later, that's going to be no problem for them. So I would envisage, especially for treating earlier lines of patients, we control their disease while we could probably treat the majority as an outpatient, but it will be important to control the disease well, and I think that has to be stated out loud.

Yes, just an anecdote there. I remember one of the first patients early in your treating the patients you called [indiscernible]. The patient has enough to do. What's the problem?

Has this happened so far?

So I just want to emphasize that point. It's a really key point and maybe Dr. Bishop and Dr. Frigault can add to it. But we see a really clear distinction in both the management's effort that is required for CRS and the time to onset of CRS based on burden of disease. And that's something that I think is not unique to anito-cel, although every product has its own kinetics, right? So if you are looking at patients who are relatively well controlled coming in, those numbers all look even better. Obviously, this is a study of patients in the relapsed/refractory setting. So you're going to have a distribution of outcomes. But I think most would expect, I'd love to get you all to comment on that. Most would expect that if, for instance, you were in, say, second line and you know you have a much higher likelihood of decreasing tumor burden with your ridging therapy, you would expect that CRS will even be later to occur and/or easier to manage in patient. If I'm seeing anything wrong?

Yes, I agree. Like in some ways with the Phase III and even in the Phase II, like our hands are kind of tied. One hand tied behind our back. We were limited by what we could do for bridging. We were limited by having to wait for true definition to refractoriness. We needed to have exactly IMWG measurable disease. In the real world, we could consent the patient. They could have light chains in the 80s. We don't have to wait for an M protein greater than 0.5 or 1. You can just see that they're solely progressing the low tumor volume. We can collect them. I can give them a slug of Cytoxan and [indiscernible]. In general, though, you have options, and then it becomes a problem, the cells are coming back faster than the patients are ready to start lymphodepletion. Because I would say a 2-week turnaround time, if you think about like giving a CAR-T cell, from vein to vein, you really don't even have enough time to like it get...

Get a full cycle, get it settled?

Get like with inpatient get the financial approvals, get all of that done, like 2 weeks is pretty the fastest run you probably get. logistically. Does it help?

I totally agree with every aspect of it. It's going to make our lives so markedly better. I think my nurses would like jump for joy.

I don't know. My nurse might freak out because she's like I have to do it all now. What? Don't know if it's lag time to sort things out.

Sami Corwin from William Blair. Congrats on the data. I was wondering if you could provide a bit more context around the HLH event. And if there was clonal expansion of transfused leukemia cells -- if that's what led to the HLH event.

So just clarify that question one more time, so clonal expansion of leukemia cells?

Yes. It said on your slide that the patient had some...

I can. Okay. So in terms of what happens, the patient presented for leukapheresis where the cells get sent off for manufacturing. And then when they came back before an Infa depletion, they had evidence of circulating plasma cells. So nothing to the CAR, just circulating plasma cells that sometimes can happen with disease that progresses rapidly, overwhelms of bone marrow, then starts filling out into the peripheral blood. Usually, it's quite a significant event and actually is an exclusion criteria for the study. So often in that scenario, that huge tumor burden provokes a real inflammatory storms. So patients with this kind of disease burden circulating tumor cells, they'll often have very high ferritins. Prior to coming forward for lymphodepletion, that patient had also had a recent episode of COVID, which we know is quite inflammatory. And unfortunately, still shedding virus at the time of lymphodepletion. So like a pre-existing storm of inflammation occurred. And then when the cells went in their body, unfortunately, that inflammatory storm was accelerated and the patient developed evidence of hemophagocytic syndrome, which can occur with any of the products in the setting of -- usually in the setting of patients who got a lot of bone marrow-based disease, and the inflammation in the bone marrow then sets up this overwhelming inflammatory storm, which is, by definition, HLH. Does that answer your question?

Yes. So -- but just to remind you, so the patient wouldn't have met eligibility criteria with plasma cell leukemia. After that event, there was instituted a policy that there had to be a repeat check list for every patient to review these things before they can go forward with dosing so that errors like this could not occur and never get again. That said, even in the context of HLH, it wasn't 100% certain that this patient had to have died. A bone marrow biopsy missed the bone and hit a vein in the retroperitoneum that bled into the retroperitoneum. It is an incredibly unfortunate case, incredibly. But it is not on its own, just a case of did this cell therapy cause this, it was a series of events that escalated into a really unfortunate outcome.

That's helpful. And a quick follow-up. I noticed some differences between prior lines of therapy and time since diagnosis between iMMagine-1 trial and some of the other CAR-T trials. For the physicians up there, would you say one is more indicative of disease severity or more challenging to treat than the other?

No, I think you just -- I think what you're noticing is you're noticing that there's an evolution of myeloma treatment strategies, right? We have newer regimens, newer combinations that we have available to us now that weren't necessarily available at the inception of some of these early Phase I/II studies. And so you can be second line therapy and equally or less refractory to someone who could be on fourth-line therapy, depending on what agent you've been exposed to and what the timing of that has been. So I don't necessarily look at lines of therapy, especially when you're like 3 or beyond. It just really depends on how you get there and what decisions are made at what point in time and when you were treated.

Like you're exactly right. There's been more and more inclusion of daratumumab as part of frontline therapy. So all of a sudden now, you're triple refractory and refractory a lot earlier. So I totally agree with Matt. It's the evolution over time in terms of how we're managing myeloma patients.

I'll just give one other sort of caveat to that. Obviously, these are the experts, but one thing that is probably fairly clear from the literature, is that patients who are in say, fourth line and were only diagnosed about 2 years ago, those patients are considered functional high risk, because they have progressed through multiple lines in a very short window of time. So sometimes, I think we can be confused by these numbers. But one way to think about it is if you're getting all the best therapies in a very short window of time and still progressing, that means you have very resistant, very dangerous disease. And I know we are running right around 10 minutes remaining maybe 5 to 8. So if we have a few last questions, let's try to get as many as we can.

Everyone's hand went up. So we're going to have to limit you guys to like one question. Maybe let's drop the follow-up, so we can get through as many people as possible.

Mike Schmidt with Guggenheim. Congrats on the data. So I was just curious about the incident or the frequency of delayed neurotoxicities in the real world. There's been different data that has been referenced. I was just curious in the experience of the physicians if that has improved or changed perhaps relative to the [indiscernible] experience?

I think part of it is hard because we don't have a clear definition of rating system to really ultimately define this. But I think you can probably speak to this better than I can, the Moffitt consortium.

Yes. I mean [indiscernible] presented the comparative study today from collective experience. It doesn't seem to be changing all that much. So I don't know what more to say other than that. It -- what I generally cite patients is 2% to 3% risk of Parkinsonism, probably 10% risk of cranial nerve palsy is what we're seeing in our hands. And the other like Guillain-Barre, polyneuropathy, those ones are harder to cite, because they're not well defined. But those two things are kind of, they seem to be consistently robustly reported at that incidence. And so that's what I tell patients when I see them.

Just to squeeze a quick one in, Rami. So -- as we think about the commercial launch in the future, perhaps in 2026, how should investors think about the pace of the commercial scale up of that you're working on [indiscernible] other manufacturers?

Sure. I mean, look, I think it's a little too early for us to give guidance, but we certainly don't -- I think I've consistently said that we expect to launch differently from the other launches. Dr. Frigault talked about how he's experienced these launches over this time in cell therapy, and we expect to give him a new experience that is better than he's experienced before. And I think that's certainly a function of the capabilities of Kite on the manufacturing front, but also we're -- we hope to execute in a way that will delight our customers and hopefully allow more patients to experience these therapies sooner.

And just to give you an example, though, like I've already kind of experienced a second Kite launch. So actually two of them. So we had Axi-cel and find new indications come on, but then they have brexu-cel, it's a different manufacturing process. You have T-cell isolation, they launched. They had no capacity issues and they had no manufacturing issues. For BALL, no capacity issues, no manufacturing issues. So with new products coming on, we have seen Kite be able to do that already.

Do you want to go to -- right behind Michael there?

And then just to -- we have a hard stop in about 2 minutes because Dr. Bishop has to go to the airport. We, of course, will be available to answer more questions as well. So -- but I do want to make sure that we're keeping on track to Dr. Bishop's schedule to go to the airport.

Biren Amin, Piper Sandler. On iMMagine-3, there was an FDA session earlier today, where FDA put up a slide that showed a potential consideration to use MRD-negative as an end point to support accelerated approval in multiple myeloma patients with 1 to 3 prior lines, so long as the company supports that with PFS and OS as a follow-up. So a question to the company. Given the -- given that slide, along with the data from CARTITUDE-4 today around sustained MRD CR improvements that correlate with PFS and OS, would you go to the FDA to potentially amend iMMagine-3 for MRD-negative surrogate endpoint?

Yes. Look, I think we've said before, that's something we're going to explore. But I think what's more important is that we expect that to really have a meaningful impact in what we'll be iMMagine-4, our frontline study because given the readout on the time lines for those studies, that's obviously a much more meaningful impact, but it's something we'll certainly explore. All right. Let's go on this side here. We got Daina and [indiscernible].

[indiscernible] Evercore ISI. One quick question for the doc. For your CARVYKTI patients, what is the current protocol to detect delayed neurotox? And how confident are you that all the cases are being captured?

I'm actually not confident at all that we're capturing all the cases, unless the patient is seeing me monthly, indefinitely...

They're pretty dramatic.

They are, but I have examples where patients have gone back and like grandma is falling, and grandma is slowly getting better and more withdrawn. And then 3 months later, you get a phone call and you're transferring them back in their bed bound. So like you have cases where like you see some patients and they go back to the referring treatment centers. You don't know what happens. Therefore, I can't say with certainty that other events are not occurring?

Yes, that's fair. That's fair.

You're talking about with commercial product?

With commercial product, new patients come in. They want to go back to their docs, they're 3 or 4 hours away.

Yes. Some patients come to see us from another stage. So you bear in mind that like after they have their CAR-T, some patients are coming to us from other countries, other states. So we'll arrange to see them after they -- once we restage them after 3 months, our protocol is generally, we see them for when they will come to have vaccine visits and check-in. So every 3 months, if they live far away in the interim, they're getting checked in on by their local docs, and we get them to have labs.

And some patients don't want to come back.

And just to avoid confusion. I think that question might have been an application to, like iMMagine-1, for instance. How is that different?

In terms of what?

Is it possible in you're missing cases in iMMagine-1?

I mean, I find that very hard to believe. As I said, these -- well, first of all, iMMagine-1 patients are seen in follow-up more regular per protocol. And second of all, it's a long follow-up. But also like the real, the majority of these events are pretty dramatic. A patient comes in cross-eyed with one eye that doesn't move anymore. And they're basically saying, I can't see property and they've got a cranial 6 cranial nerve palsy or their face is completely full and like they've had a stroke and they're dribbling down one side. These are, the cranial palsies happen early, it's usually 2 to 3 weeks. And they take a long time to resolve. And there are so many cases of Parkinsonism are usually fairly dramatic. So I think it's unlikely that we're missing anything.

My sense is that I've had a couple -- one of my enterocolitis cases, and as one of my Parkinson's cases it took a couple of months to get the filling and call and say, "Hey, I'm really not doing well with my local doctor, I need help." And then they come in to you and you kind of sort through that. So I'm not saying that it's a huge number. I just -- if you're referring doc and you're a year out from CAR-T, and so and so is in a response and also [indiscernible] toxicities, that referring doc who doesn't do CAR-T doesn't immediately think...

They just go investigating for colitis, which they think is infectious or otherwise. Yes.

Maybe I can ask, I'm going to ask a question actually while the mike gets to you. But on this topic, we've heard some conversation around splitting these Parkinson's from the cerebral nerve policies and these other sort of side effects. Do you see them as all interrelated, or do you see them as separate?

I mean, I think it's hard to say with any degree of certainty, given that we don't understand the pathophysiology. I think to start hypothesizing about them being completely different processes when they involve neurons, they seem to be inflammatory and they seem to appear like later. I mean theoretically, you would imagine they would be part of some same spectrum of disease.

But they do -- I do think that they kind of lump together, like if a patient has cranial nerve palsy with the high ALC previously, I am more concerned about them developing more additional atypical movement disorders later on.

Maybe I think it's really hard to know. We've had some patients that get cranial nerve palsy and they're fine. And we've had patients with huge lymphocytosis and expansion and they are fine.

But I'll just reiterate Dr. Freeman's point. I think for us to speculate about whether, what's causing them, why they're happening, who's most likely to get them, like we're basically just saying, hey, high ILC because it's what we're associating but we know nothing about why they're happening in the first place. Therefore, I can't prevent them, I can't prophylax and/or just speculate.

I can't really predict risk. I think this idea that you can predict who is going to happen to, I would love to be able to do that. That will be amazing for us because I want to treat them. But I think that this idea -- we've had patients with these big lymphocytosis and nothing has happened. And then we have patients who come in very well bridged who get these cranial nerve palsies and no disease burden.

Instead of having to predict it better than just...

Asthika Goonewardene from Truist. So let me build on that. What do you do when you do see a patient who you suspect might be developing some sort of delayed neurotoxicity? What are you watching for? And what do you hope to action on that?

So I'm going to let you do Parkinsonism and I can take cranial nerve palsy. Do you want to do that?

Well, let me ask you your question just because I think I know what you're getting at, and I just want to make sure that I'm not putting words into your mouth. But if a patient has a high lymphocyte count or is there anything that would cause you to preemptively treat a patient for -- to prevent Parkinsonism?

So we have had this argument. And in the majority, we have not gone in and treated patients with lymphocytosis because we're not entirely convinced, that's it -- and we have not universally seen that all those patients ended up with Parkinson's. So I think if you're trying to hedge your bets about like, okay, well, if we draw a circle around these guys and draw a circle on these guys, what's different between the two? Okay, these guys had a slightly higher median, but these guys also had some patients who didn't get cranial nerve palsies who had the high lymphocytosis and nothing happened. So I struggle to justify interfering with the expansion of patients' CARs when I don't know that it's definitely going to make any difference.

What are you targeting? Like I think any intervention you're using should either be back on some data or at least some concept of a mechanism for what you're trying to do and steroids are just a really big bazooka that you just throw out things because we feel better about doing it. And I think in many ways, we're probably treating our own anxieties by giving steroids to patients. And so we see patients, especially older patients, high-dose steroids, cardiomyopathies, bone issues [indiscernible].

And infectious risk, you can't underestimate the infectious risk that you can have by putting patients on high-dose steroids.

I've heard of some centers and people talking about like prophylactic intrathecal chemotherapy and all this other stuff, you're just going to get leads. But in general, you treat what you have in front of you and you try not to overreact.

And I'm going to ask one quick question before I pass the mic to Daina. Chris, Rami, are you seeing the kind of spikes in ALC that's been described with some of the other competing CAR-T? And have you seen that with any new cell?

No. I think specifically, we've said this before, that we don't see cell expansion, that is antigen-independent past day 28. And I think the nature of these neurotoxicities are delayed in sort of this exponential curve type cell kinetics. So actually, did go back and look at the data from iMMagine-1 and we have not seen that.

Yes. Of course, we see differential cell expansion based on disease burden, and we will have patients that have relatively high absolute lymphocyte counts occasionally if they have high disease burden coming in. But to Rami's point, what we think is different about those cases is the sort of runaway event where the lymphocytes are just expanding when it seems there are no remaining plasma cells, and we have not seen that.

Daina Graybosch from Leerink Partners. I wonder if you guys can talk about the bridging used in the study and how the protocol changed throughout the study? And how different available therapies changed what you could use bridging? And if you've noticed anything about the bridging and the outcomes you observed?

Yes, why don't I give the overview and then we'll actually ask the physicians to comment on because both of these physicians help weigh in on what bridging regimens would be more useful to them based on their clinical practice. So as you may recall, when we went through the clinical hold about 1.5 years ago, what we observed was this specific patient case where they have breakthrough disease and plasma cell leukemia. And looking at that case, and then looking back at even cases in the Phase I, what we observed was patients who have significant disease progression are at increased risk for needing more intervention for their CRS and in this case, it obviously was beyond what could be controlled. And so we felt like that was enough evidence to go back to the FDA and say, listen, this restriction that we can only use the therapies that the patients have previously used is unfair to the patients and putting them in harm's way. And we polled the audience of our investigators who all -- every single one of them agreed with that, in fact, have been complaining to us that. And then we created a list of regimens, which we can't share today because they're just really basic regimens, there's nothing special about them that people use in everyday practice, leading to commercial CAR-T. We created that list, we shared it with the FDA and said, "Hey, this is what all these sites are saying that they use all the time. I bet you can find out and confirm if that's true". If it is, do you agree that we can use these regimens even if some of them are things that the patient has not seen and somewhat surprisingly or happily, whatever you want to call it, the answer was, yes, that seems totally reasonable. And so we did that, and we said patients still, at that point, we said patients still have to have measurable disease after we bridge them so they still have to meet IMWG criteria for measuring of disease, but this was a way to prevent runaway disease from happening. So I'll let Matt and Ciara talk about just their experience with that and what the experience would be like if you didn't have those things available to patient population.

Yes. It's hard because like you look at patients' history early on in the study, and we're trying to figure out like what the best thing I can potentially use.

I put together I put [indiscernible] in the bridge Well, because they had a transplant. So if I put [indiscernible] put that in, but it's nothing we would ever use.

And but to reiterate the point to, like every patient had measurable disease going in. These patients weren't going to stretching CRs and the relapsed/refractory setting after being penta-refractory based on a random regimen that we're now newly allowed to use. So it makes things more practical. It makes things like I'd rather land the plane, I don't want to crash it. And it's easier when you have more options available to keep disease under control.

Yes. So these are obviously two of the people who we're pushing and pushing to have this conversation with FDA. Unfortunately, the triggering event that allowed us to be able to convince FDA was unfortunately a patient's death. And I think in retrospect, that's something we would never want to have and happen again. And I think, hopefully, it's a lesson for FDA for future trials.

And we're seeing it with future trial protocols that they're allowed to use something the patient hasn't been exposed to in the past, but the patient then has to come forward with measurable disease. And it's just safer. You can't expect to control disease with agents that the patient's already progressed on. This is the whole reason you're enrolling them in this clinical trial. If they were still responding to those agents, you wouldn't be enrolling them.

So let's move on, still we have enough time.

So Ash is next, we're going to take like two more after Ash.

Ashwani Verma from UBS. I just fast forwarding to 2025-'26, I wanted to see the impact of this clinical data on the adoption of CARVYKTI. For physicians who are considering that I want to use like a one BCMA CAR-T on one patient, do you think they might likely delay using CARVYKTI and not taking the risk and wait for anito-cel to come to the market?

Yes. I'm doing that now, like actively, not -- choosing not to use cilta-cel. We're seeing more use of ide-cel in higher risk elderly patients or frailer. So we are choosing something we view as potentially less efficacious in an older patient because of concern for toxicity. So we're already kind of making those decisions. But we were talking earlier, like we would probably wait to use something like anito-cel if we thought we had other regimens available to us.

Yes. I think especially if you feel like it was approaching, I could imagine, obviously, I can't speak for other physicians, but I would imagine a situation where if you saw it on the horizon, you had a patient in front of you and you told to yourself, well, I could cancel this patient about these risks or I could just have them toddle along, on whatever I can bridge them with and hold on. I think that, that is probably something that patients and some physicians might entertain.

John Newman, Canaccord Genuity. Nonclinical question, so maybe not quite as exciting. But what is the difference in reimbursement for the CAR-Ts in the commercial setting for inpatient versus outpatient? And do you anticipate any friction as maybe more patients get patient administration.

So maybe I'll just take this one just for the interest of time. So I talked about this earlier in over 80% of cases you're going to get a case rate or ASP plus. And so whether you're treating inpatient or outpatient shouldn't be an issue. From like a covered lives perspective, about 16-ish percent of patients fall under the Medicare fee-for-service category. And those -- as those patients are aware it is more challenging to treat inpatient. Now with the improved billing and improved education, you could still get those cases fairly well covered. But again, this whole kind of conversation around outpatient dosing, like number one, as we talked about with the 4-day median onset, we don't see this as an issue. We always expected that to improve as we go into healthier patients, as Chris talked about. And the overall CRS profile is very, I think, advantageous for anito-cel. But in any event, even if you were talking about that and ignoring all of this, it's a really small percentage of patients anyway that fall under this bucket where there is a differential reimbursement that could be challenging. All right. I think Peter is going to take us home with last question.

Peter Lawson from Barclays. As you think about your second line and fourth-line patients, what percentage of those have been treated with BCMA CAR-T now? And how do you think that's going to change in 2 years time? And what do you think that mix could potentially be of the different BCMA CAR-T products by then?

I can speak to my practice. So there are still patients coming forward now to see me who are like third, fourth, prior line, because they're only just progressing now having had those multiple lines in the past. There are -- so they would still, they would be eligible for a later line product. There are patients who are progressing on their maintenance or on their continuous plan having not received a transplant who are eligible for second line. Those are the ones you have the debate with where you have this option to use CAR-T versus you could give something else second line, which could buy them 1, 2 years of benefit with a good safety profile and then you wait and you give them CAR T-cell therapy later. In terms of relative proportions, there's a small number of patients that I think most of us would argue, we will preferentially choose to take them second line to CAR T-cell therapy. And usually they are the patients the worst behaving disease. So patients who are blowing through 4 drug induction progress very early after transplant. Those are the kind of patients where we say we can't really wait for you for a subsequent line of therapy. Have I answered your question? So I mean, I think with the way that therapies are evolving, there are still going to be patients trickling through who are in later lines that will be eligible for sure. I don't think that we're going to treat every single patient who's second line with cilta-cel. And then when you're in the third line plus space, now you've got a whole lot more options. So I think that the patients may well decide to hold out to get access to anito-cel versus...

But I think one thing that I would just -- I completely agree with everything you said is, my hesitancy, this CARTITUDE-4 did show a potential overall survival benefit. My hesitancy is what happens and what's real rate of these toxicities and how is that going to impact quality of life and what can I do? I think in our practice, we're not doing much second line, if not at all right now, unless for those with high-risk people progressors. If you have a product that has a better safety profile, if this continues to pan out the way it's looking and it is just as effective. I think the conversation completely changes. So if safer profile, same efficacy, the likelihood of me using in second line increases substantially.

Yes. And then you've to bear in mind as well that there are always patients who come with their own preferences. So some patients will preferentially come saying, "I want to have CAR. I want to have a one and done. I want to be off this continuous therapy. And so they will often come to you choosing to go for CAR T-cell therapy sooner and making a decision almost for you.

Great. Well, thank you again for joining us. I want to thank our speakers, Dr. Bishop, Dr. Freeman, Dr. Frigault. We really do believe anito-cel is an incredible therapy, and we're really hopeful that in collaboration with our partners at Kite, we can bring it to market as soon as possible and help a lot of patients that have a really big impact for the myeloma community. So thank you all for your support, and have a great evening.