Legend Biotech Corporation (LEGN) Earnings Call Transcript & Summary

Hello, and welcome to this Legend Biotech Investor Meeting, which we're holding on the sidelines of the 63rd Annual Meeting of the American Society of Hematology. I'm Tina Carter, Senior Manager of Corporate Communications and Investor Relations at Legend Biotech. Before we begin, on these slides, you'll find our forward-looking statements. We encourage you to review this cautionary statement regarding information and remarks included in today's presentation as well as the company's Form 6-K which identifies certain factors that may cause our actual results to differ materially from those expressed in these forward-looking statements. The information in this presentation speaks only as of the date hereof. Legend assumes no duty to update the information to reflect the subsequent developments. To see the progress and updates announced today in further detail, you can access our SEC filing and the presentation slides in the Investors section of legendbiotech.com. On Slide 3, you'll find our disclosures. We have the pleasure of being joined by 2 key opinion leaders to go over the latest developments on CARTITUDE-1 and the CARTITUDE-2 studies for cilta-cel. Today's meeting will begin with opening remarks from our CEO and CFO, Dr. Ying Huang; and Dr. Sundar Jagannath, one of our key opinion leaders, will provide important data on the CARTITUDE-1 and CARTITUDE-2 studies for cilta-cel. Then we'll open up our panel discussion with the doctors and several members of our leadership team. Now with that, I'd like to introduce you to the CEO and CFO of Legend Biotech, Dr. Ying Huang.

Thank you, Tina, and good evening, and welcome to Atlanta. Thank you for joining us today. We're very happy to be live and in person here in Atlanta at ASH for the first time since 2019. Tonight, we'll be sharing the progress made on the CARTITUDE development program, including the latest on a pivotal CARTITUDE-1 study and also the multicore CARTITUDE-2 study. Joining us to bring that data to you are 2 prominent key opinion leaders in the field of multiple myeloma treatment, Dr. Sundar Jagannath and Dr. Saad Usmani. Dr. Jagannath is the Director of the Center for Excellence for Multiple Myeloma and Professor of Medicine at The Tisch Cancer Institute at Mount Sinai. Prior to joining Mount Sinai Medical School, Dr. Jagannath served as chief of the multiple myeloma and transplant program at St. Vincent's Hospital. Dr. Jagannath has published more than 180 peer-reviewed articles in New England Journal of Medicine, Blood, the Journal of Clinical Oncology and Cancer and other leading journals. Dr. Jagannath will provide the latest data on efficacy and safety results from the CARTITUDE-1 study and also from cohorts A and B in CARTITUDE-2 study tonight. Dr. Usmani is the Chief of Multiple Myeloma Service at Memorial Sloan Kettering Cancer Center and is a Professor of Medicine at Weill Medical College of Cornell University. Prior to his current roles, Dr. Usmani served as the Director of the Plasma Cell Disorder Program and the Director of Clinical Disorder Program and Director of Clinical Research in Hematologic Malignancies at Levine Cancer Institute of the Carolinas Healthcare System. Dr. Usmani is a specialist in hematology, medical oncology and bone marrow transplantation. His clinical and translational research has been focused on plasma cell disorders in general and high-risk multiple myeloma specifically. So now with that, please welcome Dr. Sundar Jagannath to discuss CARTITUDE-1 clinical development program. Dr. Jagannath?

Thank you for that kind introduction, Dr. Ying Huang, and it is a pleasure to co-chair this session with my colleague, Dr. Saad Usmani. And today, it's my pleasure to talk about CARTITUDE-1 study, which was reported in the ASH meeting. Tom Martin presented the 2-year update on CARTITUDE-1 primary efficacy and safety. And Maria-V Mateos from Spain, she presented the comparison of CARTITUDE-1 with the real-world data, which is called LocoMMotion study. And then my colleague from Chicago, Andrzej Jakubowiak, he had a poster presentation during the subgroup analysis. So it's -- these were all presented, and it's my privilege to actually review them for you. Just as a backdrop, cilta-cel is a CAR-T cell therapy for relapsed and refractory multiple myeloma patients. The CAR concept is very unique for this product. It is shown on the right-hand side of the panel. It has 2 BCMA targeting single domain antibody to confer avidity and has a CD3 zeta signaling domain and a 4-1BB costimulatory domain to optimize T cell activation and proliferation. In the Phase Ib/II CARTITUDE-1 study, early, deep and durable responses were observed with a single cilta-cel cell infusion in heavily pretreated patients with relapsed and refractory multiple myeloma. Last year, in the ASH, we gave you the results at a median follow-up of 1 year, and we are very happy to present you this year an updated results after a median follow-up of 22 months or almost 2 years. Now CARTITUDE study design is shown on this slide. The primary objective is to characterize -- in the Phase Ib portion was to characterize the safety of the cilta-cel and confirm the recommended Phase II dose that came out of China. And in the Phase II, we had to evaluate the efficacy of cilta-cel. The key eligibility criteria are shown there. The patient should have progressive myeloma with more -- 3 or more lines of prior therapy, or they should be double refractory to PI and IMiD, or they should be triple-class exposed. Everyone should be triple-class exposed to prior PI, IMiD and an anti-CD38 antibody, and they should have measurable disease and in good performance status. On the right-hand side, it showed the flow of the patient in the study. Following screening, the patient underwent apheresis; bridging chemotherapy, if it was indicated, it happened in 73 patients. And approximately 4 weeks later, the patients received lymphodepletion chemotherapy which is cyclophosphamide and fludarabine given over 3 days followed by cilta-cel infusion. It was not a fixed dose. The cilta-cel dosing was based on patient's body weight. The patients received a median of 0.7 million viable CAR-T cells per kilogram body weight. So now this slide shows the CARTITUDE efficacy response. I've been doing myeloma for 30-plus years. This is really incredible responses in relapsed and refractory myeloma patients. Overall response rate of 98%. We don't even get that in the upfront situation. So that is indeed very remarkable. And the responses deepen over time from 1 year -- during the last 1 year follow-up. So if you look at what we reported last year, the best response after median 1-year follow-up, stringent complete response rate was 67%. But this year, Tom Martin updated it and said, after median of 2-year follow-up, it is 83%. And not only that, this is response is very durable. The median duration of response was not estimable, and 60.5% of the patients are still progression-free at 2 years. And of the 61 patients who are evaluable, 92% were MRD negative by next-gen sequencing. So the next slide shows the CARTITUDE-1 progression-free survival and overall survival. What do you see here? The median progression-free survival and median overall survival are not reached after a median follow-up of 22 months. The progression-free survival was 60.5 months at 2-year mark, and the overall survival was 74% at 2-year mark. And you can see that progression-free survival and overall survival improved in patients with MRD negativity sustained for 6 months or greater than 12 months. This was shown as a slide by Tom Martin in his presentation. So let's go to the subgroup analysis. This was presented as a poster by Andrzej Jakubowiak. And what you see the responses to cilta-cel was durable up to 2 years in most subgroups of patients with heavily pretreated relapsed/refractory myeloma with consistent safety across the subgroups. The patients which are in a box in the red, you could see the patients with high-risk disease, ISS Stage III at baseline and presence of baseline plasmacytomas had similar high overall response rate but the duration of response was shorter. So now we look at the CARTITUDE safety. In the past 1 year of extra follow-up, no new safety signals were observed now with a median follow-up of 22 months or approximately 2 years. No new events of neurotoxicity of movement and neurocognitive treatment emergent adverse event, what we call as MNT was reported in CARTITUDE-1 during the last 1 year of follow-up. And after implementation of an MNT patient management strategy, approximately 200 patients have been dosed with cilta-cel across CARTITUDE clinical development program, and MNT incidence has decreased to 0.5%. And I will share the data when I show you CARTITUDE-2 data. No new treatment-related death occurred during the past 1 year. This is indeed remarkable. That means the patients went into complete remission, deep remission, et cetera, and they made it past 1 year, they are all being still followed. And I personally have patients who have made it to 3 years in complete remission MRD negative status, because it is now coming to that place because we started in the Phase I safety first-in-human study at our center. So this is indeed a remarkable safety signal here. Now we'll go to LocoMMotion study. So what is this one? We wanted to put CARTITUDE-1, what it really means in relapsed and refractory myeloma patients. As I said, they should have had more than 3 lines of prior therapy, or should have been double refractory and should have been progressing after the last line of therapy. We set all that, and everybody should be exposed to the 3 classes of drugs. So what happens to this patient in real world as compared to what CARTITUDE can offer them? So this is where you had a real-world comparison, LocoMMotion study. It is a first prospective efficacy and safety study of real-world clinical practice. It's an observational study in heavily pretreated triple-class exposed patients with relapsed and refractory myeloma. Patients were included from 9 European countries, 91% of the patients came from there, and from United States, 9% of the patients were coming from here. So 92 unique regimens were used. This is not uncommon. They include carfilzomib, dexamethasone, pomalidomide, [ cytotoxic ] dexamethasone, pomalidomide dexamethasone, just to give you a flavor of all these different combinations that have been used. So you could see how they are bridged. There were 113 patients enrolled in CARTITUDE-1, 248 enrolled then died, progressed or withdrew consent, and then 97 patients went on to CARTITUDE-1 and were infused with the drug. So there were 97 patients on CARTITUDE-1. And similarly, there are 170 LocoMMotion patients progression-free alive 52 days post therapy, and they were the ones who were compared. Now what do we see in the comparison? So you could say the observed rates of overall response rate, very good partial remission or better or complete remission or better, were all significantly higher in cilta-cel cohort. 82.5% of cilta-cel patients achieved complete remission or better versus only 1 patient on the real-world clinical practice with the currently available agent can even dream of achieving a complete remission. Patients treated with cilta-cel were 3x more likely to achieve a response and compared to real-world clinical practice and at least 5.5x more likely to achieve very good partial remission or better. And this one shows the progression-free survival and overall survival in cilta-cel. I don't even have to speak to it, you can look at it. Cilta-cel significantly reduced the risk of progression or death by 85%, and risk of death by 80% compared to the real-world clinical practice cohort of patients. So now let us look at the safety. So cilta-cel patients experienced more adverse events of any grade but they were all manageable. Following cilta-cel, most frequent adverse events were hematologic. Then, of course, unique to cilta-cel are the CRS and neurotoxicity that we’re seeing there and treatment-emergent adverse event. If you look at it, treatment-related death was 6% or 6.2% on cilta-cel and 19% or 7.7% with real-world clinical practice. So that is why we feel that I could use the term that the toxicities were manageable on the cilta-cel because treatment-related death was no worse on cilta-cel versus real-world clinical practice in these patients. Now let's talk about CARTITUDE-2. So CARTITUDE-2, we had several cohorts in this one. And you have cohort A, results were presented by Yael Cohen from Israel. This is progressive myeloma after 1 to 3 prior lines of therapy, and they were lenalidomide refractory. And cohort B results were early relapse of myeloma within a year after initial therapy. And these results were actually presented by a Dutch person, Dr. Van de Donk. He made these presentations. So let's review what did they have to show in the ASH meeting. So the study design is shown on this slide. The primary end point is, instead of overall response rate, they actually went for minimal residual disease by next-gen sequencing, but the secondary endpoint included overall response rate and duration of response and minimal residual disease negativity, time and duration and adverse events for safety. On the right-hand side, you see the sequence of events, which is exactly the same, they will screen the patient, do the apheresis, do bridging chemotherapy if necessary, lymphodepletion. And everybody got 0.7 million viable CAR-T cells per kilogram body weight, and then they were followed. And in the cohort A, these are patients with progressive myeloma up to 1 to 3 prior lines of therapy, and they had to be lenalidomide refractory. That is considered the adverse event. And in the cohort B, we have early relapse within a year in a frontline therapy that included PI and IMiD because we all know VRd, [ KRd ] are the frontline treatment strategy right now. So now we go on to look at the CARTITUDE-2 cohort A, there were 20 patients, and look at their response rate, again, overall response rate is 95% and most of the responses are complete remission or better, 85% is complete remission or better; 6 months PFS was 95%; 12-month PFS, 84%. And of the 13 patients with evaluable samples, 92% were MRD-negative by next-gen sequencing. So all of that was very good. And safety was manageable and such that even 1 of the patient was actually treated in the outpatient setting. They got the CAR-T cell given in the outpatient setting. And the CRS all grade you could see was there. 95% of the patient had CRS and grade 3 was only 10%. The neurotoxicity was there, 20% ICANS but grade 3 was none. And no cases of MNT was encountered here. And there was one treatment-related death, but that was due to COVID-19 at day 100. That's unfortunate at this time. Now CARTITUDE-2 cohort B, 19 patients were enrolled on the study. Again, look at the overall response rate, 95%. Complete remission or better, 79%. So it is still a remarkable response rate. 6 months PFS, 90%; 12-month PFS, 84%. All of them are very good. Of the 13 evaluable -- 13 patients with evaluable sample, 92% MRD-negative by next-gen sequencing. Again, manageable toxicity. CRS, 84%; grade 3, 5%; neurotoxicity, 26%; ICANS grade 3, 5%. One patient did have MNT on this one, but there was no treatment-related death at the time of data cutoff when they were presenting for the ASH. So if I have to summarize and put them all side by side for you so you can, at a glance, look at what cilta-cel can really do. Consistent response rate, whether you do it in relapsed refractory myeloma patient, CARTITUDE-1, triple refractory group or penta-refractory or penta exposed patient, 98% overall response rate; CARTITUDE-2, cohort A, 1 to 3 lines, 95% overall response rate. And again, in CARTITUDE-2, those who have really poor prognosis progressing within a year after getting IMiD and PI, they went on this and they got 95% overall response rate. And across the board, you can see stringent complete response rate is 80% or better. So it is indeed a -- this is going to take the field by storm. It is unprecedented results that I had the pleasure of actually sharing with you. These were all presented by my colleagues already in ASH. And I'm happy to be here with Saad Usmani, my friend. We were going to be together, but I decided to stay out of Atlanta for the time being. So I'm all virtual here.

Thank you, Dr. Jagannath. We'll now prepare for a panel discussion on the CARTITUDE-1 and CARTITUDE-2 studies. Joining us to answer these questions are the doctors Dr. Lida Pacaud as well, our Head of Clinical Development; Yuhong Qiu, Head of Regulatory Affairs; Tonia Nesheiwat, Head of Medical Affairs; and Steve Gavel, Head of Commercial Development; as well as Dr. Ying Huang, our CEO.

Okay. If you're in the room today, please raise your hand and you'll be provided with a microphone. If you're joining us virtually, just put your questions into the chat and we will try to answer everything in the remaining time.

This is David Dai from SMBC. A quick question on the CARTITUDE-2 cohort B, the 1 patient with the MNT. Can you just tell me more about that patient? And what's the patient characteristics look like? And did he also have any kind of CRS or any kind of -- any other AEs associated with MNT?

Excellent question. The guy from cohort B was actually patient with poor prognosis because they were progressing on front-line therapy within a year. And this was a patient who was actually treated in one of the centers in Europe, I believe. And he was a young man, 40 years old. And MNT, we have said, one way to avoid this particular complication when they said we wanted to put in is that if the disease is out of control, you try to give bridging chemotherapy, get the disease under control and then you move on. But in the young man whose disease was already progressing on front-line therapy, they did collect the -- they did the apheresis, but then they give him a bridging chemotherapy, but the disease still progressed. This is exactly where we said we could run into trouble. And so -- but this was a young man. And as physician, at the end of the day, you hear it all, but when you are a bedside physician, you really are compassionate. And I don't blame the physician, I would have done it too, but we kind of take a little bit of risk. And this patient later on developed MNT symptomatology. He did have a CRS, so it was all expected, and he did have good proliferation of the T cell, and it was sustained as we had expected that these few patients we ran into trouble are whom there is a rapid expansion of the T cell, very high level, and it is sustained, and it was also sustained in the patient. But because of that and expected -- but he was managed and he is doing all right. As I told you, there has been no mortality in the study. I can't be -- I can't tell you more than that day to day, but all I do know that the patient is doing well and ongoing whatever physical therapy or whatever, but they were able to manage him successfully and get him out of trouble.

And we have a few questions here on expected updates. What are other cohorts presented from CARTITUDE-2? When can we expect that?

So this is Lida Pacaud from clinical team. So yes, I mean, we will report data as they mature. Some cohorts, yes, probably next year, and then some other cohorts started enrollment recently, they're not mature. So we will report some probably mid next year and end of next year.

And similarly, when can we expect first updates from CARTITUDE-4 now that enrollment is complete.

So yes, I think -- so we are very excited, obviously, with cohort A data with prior 1 to 3 lines from this, presented here, and this is exactly same population in CARTITUDE-4 trial. And with response rate we see here as well as durability of response we see in CARTITUDE-1, we are very excited about CARTITUDE-4. We have completed recruitment. And yes, as soon as data are mature for Phase III trial, we will report. So we cannot comment and speculate on exact date right now.

For the doctors participating today, when cilta-cel is available, how do you expect physicians to choose between commercially available BCMA-targeted CAR-T products? We can start with you, Dr. Jagannath.

I mean once cilta-cel available, you saw the data. And maybe I'm also a little bit biased in the sense, the responses, as I told you, are unprecedented. I've not seen in relapsed/refractory situation these kind of response rates. So I think cilta-cel will be really taking up the field by a storm. So -- and there will be a lot of patients who will be clamoring for access to this particular product. That's my feeling. Even as a physician, if I had a choice, I think this is good, but the future is also very, very good in the field. We will see how it goes.

Dr. Usmani who's joining us currently from Zoom, would you like to add anything?

No, I would echo Dr. Jagannath's impressions. We are very impressed with the cilta-cel data. And I think CAR-T cell therapies would be the preferred choice for us for a BCMA directed therapy. I think that the only piece would be the logistics of making sure that we can keep up with the number of patients that may require them. And otherwise, I think all of us are quite impressed with this one and done kind of an approach. I agree with everything that Dr. Jagannath has said.

And what do you think it will take to enable outpatient use of cilta-cel in the real world?

Well, we have to be cognizant of the fact, it will become a center-dependent experience and what -- how you are structured. In the center which is able to provide 24/7, there is an expedient way of bringing the patient in or managing the patient. That in those center, you can start giving the lymphodepletion outpatient and you can give the cilta-cel. The beauty of cilta-cel is you don't get CRS within 24 to 48 hours, which is what we see in other products. Typically, they are seen very early. So different products has different time frame, I found. There is one product which gives you within 24 to 48 hours ide-cel, then there is another product from BMS NextGen CAR-T, which is about 3 days -- 3 to 5 days, and this one is more like closer to 7 days. So you would be able to take a patient including infusion of the CAR-T cells and manage the patient up to day 5 or 6. And you have the option of electively keeping the patient for just another 5 days or so. And if they don't have any significant, then you can discharge. So this gives you a lot of flexibility and the predictability, so that's also important, of the product. So I think cilta-cel is unique in the sense that you can predict that it is somewhat delayed, and then you can manage it well. So I think -- but I'm not saying that every center is going to immediately do it as an outpatient. The center experience -- center, not only the physician experience, also the facility provider, which depends upon the hospital and the institution. So there is more to it rather than just coming here and saying that, oh, this could be done as an outpatient. I don't want to give that kind of an impression.

Yes. So I think Dr. Jagannath is hitting the point. For centers who already have the capability of doing outpatient transplants and have that kind of outpatient support algorithms and SOPs in place. And some have already started to do CD19 CARs in the outpatient setting. For those kind of centers, they may opt to do cilta-cel because of the predictability of when to anticipate the CRS in the outpatient setting. For others, it may be a learning curve.

Did we observe a negative correlation between EMT and response rate?

Extramedullary disease, is that what you refer, EMD? You know what, as I showed you, the response rate is phenomenal. So at -- we couldn't show the responses for in patients with EMD or any particular subcategory because the response rate, once you're hitting 96%, 97%, et cetera, you don't have a response rate. But I did show that, yes, durability of response will be an issue. But this is where we are learning in this particular ASH, there were sessions where people showed that there could be RAS mutation in patients with extramedullary disease. And you know there are drugs for RAS. Then you already have combinations coming with bispecific. So there are other ways to tackle it. We have not fully explored the maintenance strategy or keeping the CAR-T cell much more active, if necessary, in the patient with extramedullary disease. So there are other strategies have not been explored because you've got to remember, this is a rapid development towards FDA approval type of method. So I'm pretty sure we will be able to tackle those EMD also effectively. But tumor site reduction is phenomenal across the board. At 96%, you cannot say the EMD patient won't respond. But our challenge is, okay, how are we going to keep them and how to cure minor?

We have a question -- another question for you, Dr. Jagannath. How would you describe the change of toxicity profile, including both CRS and NT from late line to early lines of patients treated with cilta-cel?

That's an excellent question. And actually, we actually saw the data. Here we have 1 to 3 lines of therapy. Patients went through it, [ 20 ] patients, no MNT, incident response rate were fantastic. And you were able to give easily tumor site reduction. But when you moved into 1 year rapidly progressing patient who was refractory to IMiD and proteasome inhibitor, within a year and his disease is progressing. When those doctors try to give -- after CAR-T collection, when they tried to give the bridging chemo, the bridging chemo didn't work in that particular patient. And then he ran into trouble. So my feeling is cilta-cel in earlier phase of disease will do phenomenally well, but you have to respect and have the strategy. If one bridging chemo didn't work, maybe you should look at a second bridging chemo. Bring the disease down and then give cilta-cel so that you can completely avoid MNT. So you know what to do, how to avoid it. But at the end of the day, we have physicians taking care of patients and you sometimes make the decision on the spur of the moment because what you're going to do with a 40-year old young man who's in this day and age, to lose a patient within 2 years is so heartbreaking in myeloma because you have myeloma patients who are being cured, myeloma patients doing so well in relapsed/refractory bispecific this, that. And now a patient comes to see me and looks me in the eye, it will be heartbreaking for me to lose that patient within a year or 2, I tell you.

And Tina, do you want to repeat the question so that Dr. Usmani can also weigh on the same question?

Sure. How would you describe the change of toxicity profile, including both CRS and NT from later lines to earlier lines of patients treated with cilta-cel?

No, I think we would anticipate that we have gone through this learning curve in the late-line setting and how to cyto-reduce patients effectively, like Dr. Jagannath has stated. And that would be the optimal goal. But there are going to be situations where you may not have that kind of optimal control, yet you do want to get your patient to do an optimal response. So I think it's not a one-size-fit-all kind of an answer. We do anticipate better management and recognition of CRS and NT. But there are going to be instances where there will be high-grade events that we'll just have to manage as good clinicians.

Hopefully, by then, we'll have bispecific and others. So we would know how to bring the disease down.

Yes.

Yes, we are getting smarter. We are still going to medical school.

Another question for the doctors. How do you envision playing cilta-cel in multiple myeloma upon approval? In which patients would you envision using cilta-cel? I think you've spoken to this a little bit, but we'd love some elaboration.

I think Saad can speak to it more. But right now, when they approve, the FDA is going to approve it with the patients who had failed 3 lines of therapy and should have had PI, IMiD and anti-CD38 monoclonal antibody, et cetera. So just because it becomes commercially available, I don't think it is going to move -- I mean, all the clinical trials have to be done appropriately. I think it will be mainly for me at our center, there are patients still dying who have failed all treatment, et cetera. So the patients who have failed and meet this criteria as I exactly said the inclusion criteria for cilta in CARTITUDE-1 trial, those patients would be the ideal candidate right now for me for this study. But I'll defer to Saad who has a little more clinical perspective. What do you want to say, Saad?

I think we'll have to comply by the indication that cilta-cel gets approved to. But I'm also interested in seeing how the data will look like in patients who may not have met the criteria for CARTITUDE-1 such as renal. Again, on basis of renal insufficiency status, Dr. Jagannath, you and I know that many of those patients in the relapsed/refractory category do not meet those criteria. So I would really hope we can generate data to benefit all of those patients and include them. And then the other group where I hope that the field moves into is for frontline high-risk patients. I think in CARTITUDE-2, there is a cohort that's looking into this question. And that is something that I'm really looking forward to getting some of that data in the coming year or so.

Yes, you are right. Some patients who would not have qualified for clinical trial could still go on this one because non-secretory myeloma because there had to be measurable disease to be on this particular study and some leeway on some renal impairment. But renal impairment may be a little bit of a challenge because the third-party payers may also insist on the eligibility criteria meeting exactly what was there in the CARTITUDE-1. So that one, we will have to go to pharma to Legend and to Janssen and say, "Hey, you need to give us a study whereby some renal-impaired patients could be tried in a small run of 20 patients or 40 patients or something like that. So -- but I agree, there will be a lot more patients who would not have gone on the clinical trial for some other reason would be eligible to go on this study, on the treatment once it is commercially available.

Okay. Further questions online, we've seen some significant impact of MRD-negative status on patient survival generally. Could you share the information of the patient baseline characteristics of the MRD group?

Sorry, I was a little distracted. Go ahead.

There was a question regarding the patient baseline characteristics of the MRD group.

Baseline characters of MRD group. The MRD, as I told you, in those it was evaluable, it was already over 90% of the patients were MRD-negative. This is almost like asking me about who will respond the response rate. I can't find out a subset to good response. So likewise, in MRD negativity, the depth of response is phenomenal. Those in whom they can do the next-gen sequencing, et cetera, over 90% of them did achieve MRD negativity. So I don't see there is a unique characteristics to say who would achieve MRD-negative status. Saad, do you have a little different take on that or insight?

No. I agree. When we have such a high overall response rate, it's -- you're really comparing to only 1 or 2 patients who, in fact, just 1 patient, if I recall correctly, who was not evaluable for that response. It's -- so you don't have that denominator in that other category. So it's very difficult to say that certain subset benefits more than the other.

This is David Dai from SMBC again. Two questions or actually, one question for doctors. So for CARTITUDE-2, especially in the early-line setting, we're looking at 1 to 3 prior lines cohort A and then early refractory patients in cohort B. So just help us understand this for the PFS rates and CR rates in those patients, what's like the clinical benchmark that we should be comparing to? Of course, cilta-cel has shown about 84% PFS rate, which is really impressive. But what would be sort of like the clinical benchmark in those patients on standard of care?

That's an excellent question. The one short answer is this is preliminary data, early data. You need at least 2 years because then, by that time, we have done so many doublets versus triplets was the standard clinical trial in the 1 to 3 prior lines. I mean Saad has talked on umpteen number of those cocktails. I'm pretty sure Rd data, [ POMd data, KPd and KRd ] and Rd versus [ KRd ] and elotuzumab plus Pom-Dex and elotuzumab with Rd. So there, you have a lot of benchmark. But this one is preliminary safety, exciting. And the way the CARTITUDE-2 was structured, if I'm not mistaken, they are like smattering of patients 2020, 20 patients or whatever, this was not the idea behind it. The idea behind it, okay. Now are we ready to do randomized clinical trial? This is a safety run. And this gives them assurance before they invested millions of dollars to run the Phase III international trial. They wanted to know whether it is a go or no go signal. So far, the signals are all go, go. All right. Saad, it's your turn.

No, this was a mic drop moment. I think Dr. Jagannath has covered this very nicely. I think we have the safety and efficacy signal from the late relapse setting, the CARTITUDE-2, all these cohorts have set the stage up for these larger studies. And in terms of benchmark, you all have these triplets depending on the patient population that we are examining questions, whether cilta-cel can be better than some of the standard of care treatments, those benchmarks will be different for each of those categories.

Another question for the doctors. What are your thoughts on BCMA antigen loss as CAR-T moves up the treatment paradigm? And what impact might this have on BCMA-targeting bispecifics?

That's easy, slam dunk. Only 2% to 3% have this BCMA disappearing 16p deletion along with 17p. Even the Dana-Farber which published on it acknowledged it. And now there is a lot more data coming out. So I don't think that is the -- so as a matter of fact, there was a presentation from my group, from Mount Sinai group, of sequential T-cell redirection therapy, those who had failed their first one line of the bispecific antibody subsequently going on to a bispecific antibody or a CAR-T cell therapy and these patients all respond beautifully. And one of the questions in that was somebody who had failed BCMA, have they been rescued on another BCMA. Yes, somebody who had failed a BCMA, ADC or BCMA bispecific went on to CAR-T and had an excellent response. So we do know that also as a fact. And vice versa will be happening, too. So my feeling is this loss of antigen is not a common phenomenon, but it was a good basic science investigational publication from Nikhil Munshi and group from Dana-Farber.

There was a recent case report of a patient in CARTITUDE-1 who developed a progressive movement disorder with features of Parkinsonism. Could you provide additional details on this patient? And whether this case is unusual?

Okay. There was a patient who had a movement and neurocognitive treatment emergent -- in fact, adverse event encountered in our place, that was, I think, the third patient, one in Chicago, one in [ U Penn ] and one at our place in the early stage of the drug development. And in our patient, he had an adverse outcome, he passed away. And then we did autopsy and we studied the brain in great detail. And this was published in high-impact journal, probably that's why there's some inquiry and the neuropathology group at Mount Sinai you're alluding to. So what did we learn from that? Yes, under stress condition, this BCMA was expressed in the frontal brain area and also in the putamen area or caudate nucleus area there. And we all know from infant CD19 study as well as BCMA, CAR-T cells do go to the spinal fluid. So in this patient, we did show there was CAR-T cells in the spinal fluid. And -- but this patient met all the criteria for mitigation strategy, which we had . He had high tumor burden, he had a very high CAR-T cell proliferation and it was sustained beyond day 100, even up to day 180, he had it very high. And so, he encountered that particular toxicity. And this is not just to cilta-cel. It is more like class-specific for BCMA because it's a matter of BCMA. And it turned out even on cilta-cel package insert, they did say that they had encountered one patient with the same Parkinsonism type of neurotoxicity. But what is more important is once we implement the -- identified what causes this 2 of the 3 things which we noted, not controlling the disease before bringing them in, so good antitumor bridging chemotherapy was recommended, then sustained and high CAR-T cell proliferation, patients have high CRS grade and also had ICANS, these are the patients who are likely to get it and follow those patients with the handwriting regularly, so you can pick that up early. So once we implemented it, as I told you, then in the next 200 patients, the incidence of MNT had come down to 0.5%. So my feeling is, yes, there is BCMA expression. We showed it in our manuscript after detailed examination of the brain with all the special. That's how it came out in a high impact, the peer-reviewed journal. But at the same time, it is not something that's going to happen in all these patients. We got to worry about it because we found out the mitigation. And you know in ide-cel, that's already commercially available, so it does not become a problem. So I don't think it is going to be a major hurdle.

And you're referring to the ide-cel package insert.

Yes.

We've seen some usage of the gamma secretase inhibitor in combination with both autologous and allogeneic BCMA CAR-Ts. Would Legend consider exploring the use of these in combination with a GSI agent?

So yes, I guess we all have seen this data, and it potentially can be discussion with our experts like Dr. Jagannath or Dr. Usmani, so we can, yes, probably discuss them.

You can get 2 different opinion right away.

Yes, go ahead.

My feeling is CAR-T cells, it is able to get rid of even few number of antigen expression. They are all quite susceptible. So they tried many different ways to find out if the level of expression has any correlation. Again, once you have 96% response rate, you couldn't say. And this was true even for ide-cel. They tried very hard, and they actually studied it with a special immunohistochemistry and other methods. So there is a methodology problem, then there is also soluble BCMA coming out and things like that. So we -- I do not know for CAR-T cells, whether this gamma secretase inhibitor is as important as in a bispecific antibody trial. In bispecific, I think this is good. So that's my pick. Now you want to hear the counterpoint.

No, I think it really depends on the product. And for cilta-cel, the first time you're infusing it, you may not need it. The only other situation where I can think of where -- again -- and I agree with Dr. Jagannath. I think it's probably more relevant for ADC and bispecific-based strategies where GSI may actually improve the efficacy for patients. And this is -- if you are reinfusing cilta-cel in a patient who has benefited from it and is relapsing and you're concerned that you may not get the same bang for the buck, we have to ask that question in that setting that with the second infusion, do we use GSI so that we get more bang for the buck? That's my thought. What do you think about that idea, Dr. Jagannath?

You're agreeing more. You're coming to Sloan-Kettering and you're agreeing with...

I'm a city slicker now. I'm a city slicker.

The New York City is going to have an apoplexy. The thought leaders agree so much. So I got to send you a Christmas gift.

I'm looking forward to it. I will text you my address.

We only have time for a couple more questions. Next one, are there any material differences between cohort A and CARTITUDE-4 studies that are ongoing? How do you think doctors -- how do the doctors think this therapy will be implemented in patients in 1 to 3 prior lines if CARTITUDE-4 data is as strong?

I think the data will be strong, but obviously, you said that it is -- study is fully accrued. I think this is something I'll leave Legend Medical Director to speak on it. But I have a feeling it should be a strong data. I don't know.

I mean it's difficult to say, right? I mean we don't have the data, and we won't be able to say anything until we've seen the data. So maybe next year, you’ll ask the same question.

That is not a guidance from the company.

That is -- or the year after that. How about that? Who knows?

Final question for you, doctors. How do the physicians think about novel endpoints for trials in earlier line studies in order to try to get answers quicker and potentially enable accelerated approval for ex-MRD? Do you believe regulators have any interest in seeing these?

I think MRD is -- will be revisited again. I know they had all tried and earlier, the surrogate marker MRD was not quite accepted by FDA. Then the sustained MRD, now the studies are getting more mature. We are reporting 6 months and 12 months sustained MRD. I think we need even more sustained 1 year apart and 2-year apart sustained MRD data. And that would be critical for this thing. And then another thing is there is also new development in the field. So there are other methods to measure serum-free light chain or heavy chain by multi [ dope ] and other methods, very, very small quantity. And then once you have these kind of technologies, so not just the bone marrow trephine biopsy and MRD negative in iliac crest. Sometime it is false, you could have a focal lesion in the left clavicle and your bone marrow could be MRD negative. So there is some inherent fallacy also in the field. And that needs to be overcome. And I think it could also be overcome because of the newer technologies coming in. So putting it all together, that is a reachable goal. But is it something that will happen in 2022? I doubt it. But I think the groundworks are being -- I mean, are put in place. Saad, what is your feeling about some of the newer technology? And what do you think?

No, I think the sustained MRD endpoint at least 12 months apart is something that will be relevant to the regulators in the future. I think all the trials have in the frontline as well as early relapse setting are kind of looking at that end point. And there are even studies in the cooperative group setting that are trying to define, question the definition of duration of treatment and maintenance based on that goal. So that data is being generated. And I think it may be ready for prime time in 3 to 5 years, but not just yet. What we've learned from some of the trials is that response or PFS, again, those are different kind of therapies, but there are some trials in myeloma that showed early promise, but then did not deliver. So with that in mind, I think we just need to build robust data sets that we can -- when we go to the regulators that they don't question the intent of what we are trying to do with all the data at hand.

Before we close for the evening, there are quite a few questions on combination and sequencing studies, specifically looking at FcRH5 or GPRC5D. Do we just want to answer that quickly before we close?

Those are also open questions. So there is a lot of activity with BCMA-targeted therapies but GPRC and FRcH5 (sic) [ FcRH5 ] are also coming. The good news is, just like Dr. Jagannath had mentioned, we have patients dying in our clinics because of how aggressive their disease may be and because of lack of options. So seeing these new options is -- brings hope for those patients. But we need to learn a lot about those targets, too. They have their unique side effect and safety profiles that we're just learning about. With GPRC5D, some skin and nail things; with FcRH5, they were concerned about neurotoxicity as well, kind of a little bit unique. So we will just have to learn what's happening.

Yes. I think you all should listen to Tarek Mouhieddine's presentation from our group this evening on a sequential treatment with T cell redirection after failing one bispecific antibody. That will kind of give you a flavor. And patients have failed one BCMA, had responded very well to another BCMA. And then somebody asked the question, is duration of the first BCMA -- first bispecific predict for the next T cell redirection? No, there are patients who had failed quickly on one bispecific antibody, had a very sustained response to the next T-cell redirection therapy. So it did not preclude it. But whatever it was, that sequencing really did help patients in terms of longer duration of disease control. So I think I'm -- exactly like Saad said, we are very happy that there is more than one target coming into the bedside. And I'm sure we would still have to tackle patients. And I can actually say patients who have failed CAR-T cell, ide-cel therapy, we have successfully retreated them with bispecific antibody. And I think Ajai Chari talked about bispecific plus daratumumab combination of TRiMM study, in which patients have had prior CAR-T cell failure and they have responded well. So I think this is a new burgeoning area of research and data coming in. Very exciting time. At least I want to stay tuned to [ our side ] because I want to see myeloma cured in the next few years.

Okay. That brings our Q&A to a close.

So before we end tonight, I just want to thank both Dr. Jagannath and Dr. Usmani for your insights. And you 2 have been very valued development partners for the CAR-T program. So as everyone can see, these results show that in CARTITUDE studies to date, cilta-cel consistently demonstrate deep and durable responses in patients with multiple myeloma across different settings. And these are exceptional results for a patient population that has been heavily pretreated and also in need of options. So I hope you agree with us that we are changing the paradigm of care for the relapsed and refractory patients. And if you look at the CARTITUDE-2 data, which demonstrates the potential for cilta-cel in earlier lines, both cohort A and cohort B patients show early and deep responses again. And we're very excited to see the 95% response rate and also, more importantly, the 79% CR rate in the cohort B here. Regarding safety, we're also encouraged by the 0.5% of movement disorder and neurocognitive treatment-emergent AEs with more than 200 patients dosed across the CARTITUDE program. And these patient management strategies implemented by Legend and Janssen clearly have worked well in the clinic. So we're continuing to explore the use of cilta-cel in early lines of treatment and are actively preparing for commercialization as we near the U.S. PDUFA target date of February 28. And none of that, what we have achieved would have been possible without our motivated team members, some of those who are actually sitting in this room, they're very committed to translating the best of science into innovative treatments. Or without our collaboration partner, Janssen Biotech, who shares our commitment to patients. We also want to extend our thanks to the investigators who have dedicated their time to bringing this paradigm shift therapy to our patients. And finally, we owe our deepest gratitude to the patients who participated in the clinical studies. Thank you very much for attending tonight's event. I hope you guys all share our passion about fearlessly exploring the possibility of CAR-T cell therapies. And hopefully, we will see you in the audience live next year.

This brings us to the end of our meeting. For those of you who have joined online, you may now disconnect. Those of you who are here in person, we do have some refreshments to the left. Thank you all, and have a good night.