Legend Biotech Corporation (LEGN) Earnings Call Transcript & Summary

Ying Huang, followed by data presentations on the CARTITUDE-4, CARTITUDE-1 and [indiscernible] Legend-2. And then we will open up for Q&A. For those joining us virtually, please feel free to type in your questions in the chat box at any time, and we'll try to get to as many as we can before the hour. Participating in the Q&A today are our 2 KOLs, Dr. Binod Dhakal from the Medical College of Wisconsin and Dr. Shambavi Richard from Mount Sinai. And then from Legend, we are joined by Ying Huang, CEO; Steve Gavel, Head of Commercial Development; and Nitin Patel, Executive Medical Director of Clinical Development. Before I turn the meeting over to Ying, I do need to mention that we will be making forward-looking statements today. These are discussed in our filings with the SEC, which can be found under the Investors section of our website. Thank you.

Good morning, everyone, and thank you for coming and joining us today. So my name is Ying Huang, and I'm excited to speak with you about our new and updated data that will be presented at this -- here at ASCO meeting. So here at Legend Biotech, we have had a very exciting year as we continue to explore the potential of CARVYKTI our BCMA-directed CAR-T cell therapy. In additional patient population as part of the CARTITUDE program. Since the U.S. FDA approval of CARVYKTI in February last year, it's been approved recently also by Brazil in April 2022. EMA in May 2022, Japan in September 2022, Canada in February 2023, and then most recently, U.K. in April 2023. We continue to collaborate with health authorities around the world to bring this innovative treatment to patients with unmet medical needs. This year at ASCO, we presented new data from the first prespecified interim analysis of the CARTITUDE-4 study, which met its primary endpoint of PFS in January 2023 and was unblinded following the recommendation of independent data monitoring committee. The CARTITUDE-4 study investigates the cilta-cel in patients who have had 1 to 3 prior lines of therapy, were also lenalidomide refractory. We're excited to share that data, which show continued efficacy and also safety in early lines of treatment, and we remain dedicated to exploring the potential of CARVYKTI in additional indications. We're also at this meeting is sharing the final readout from the CARTITUDE-1 study, which is a Phase Ib/2 study that supported our first approved indication of CARVYKTI. This latest data continue to demonstrate the deep and durable responses that can be generated by CARVYKTI for patients with heavily pretreated. Lastly, we're also very pleased to share the 5-year follow-up from the Phase I LEGEND-2 study. This data readout is also the longest follow-up from any BCMA-directed CAR-T cell therapy to be extended. We're encouraged by the possibility of cure as evidenced by the number of patients who remain cancer-free after 5 years of CAR-T [ infusion ]. The data at this year's ASCO meeting demonstrates our unwavering commitment to developing treatment options for patients with difficult to treat [Technical Difficulty] and hopes of 1 day finding a cure for [Technical Difficulty]. In partnership with Janssen Biotech, we're committed to investigating the full potential of CARVYKTI across patient populations. Thank you again for joining us. It is now my pleasure to introduce Dr. Dhakal [ lead PI ] for CARTITUDE-4 and also Associate Professor of Medicine at Medical College of University of Wisconsin. And also Dr. Richard, Associate Professor of Medicine at Mount Sinai, who will also talk about the other studies. Dr. Dhakal?

Yes. I just can talk from here. So thank you. Good morning, everybody. Here you go. So it's my pleasure to present this data on behalf of my quota, which I'll be presenting in next 1 hour at the ASCO meeting as well. All right. So on behalf of my quota, I'm pleased to present the results from CARTITUDE-4, which is a Phase III clinical trial evaluating ciltacabtagene autoleucel or cilta-cel versus standard of care treatment in patients with lenalidomide refractory multiple myeloma. The cilta-cel is a dual-binding, BCMA-directed CAR-T therapy. In CARTITUDE-1, the median PFS was an unprecedented 3 years in patients with 3 or more prior lines of therapy. So this new longer-term data are being presented at today's posted session and will be discussed at 3 p.m. as well. In Phase III CARTITUDE-4 study, we aim to test cilta-cel in earlier lines against 2 highly effective standard of care regimens in patients with lenalidomide refractory multiple myeloma. Widespread early use of lenalidomide has led to a very growing lenalidomide refractory population as early as after frontline treatment. And this patient population typically has 4 outcomes with PFS of less than 12 months. CARTITUDE-4 compared cilta-cel versus [ registers ] choice of either DPd that is daratumumab, pomalidomide, and dexamethasone or PVd, that is pomalidomide OT supplement dexamethasone in patients with lenalidomide refractory multiple myeloma after 1 to 3 prior lines of therapy. These are the first results from CARTITUDE-4 with a median follow-up of 16 months. Eligibility criteria included being refractory to lenalidomide and having 1 to 3 prior lines of therapy. This was the first Phase III CAR-T study to include patients after the first relapse. Patients in the cilta-cel arm undoing apheresis, one or more cycles of bridging therapy, lymphodepletion with fludarabine and cyclophosphamide for 3 days before receiving a single cilta-cel user. In order to avoid bias, bridging therapy was designed to be the same as a standard of care arm, either PVd or DPd based on patient's choice. Time from [ randomization ] to start of PVd or DPd either in the standard of care arm or bridging therapy was similar. The primary endpoint of the study was progression-free survival and [indiscernible] testing procedure were used to analyze the secondary endpoints. Here, we have a patient flow diagram of 419 randomized patients, 208 were randomized to cilta-cel and 211 to standard of care. This was the intent-to-treat population for efficacy analysis. Safety was assessed in patients who received any aspect of treatment, and that would be any part of apheresis, bridging, lymphodepletion and/or cilta-cel in the cilta-cel arm. [ CAR-T ] specific adverse events were assessed in 176 patients who received cilta-cel as study treatment. In the cilta-cel arm, 32 patients had disease progressing or died before receiving CAR-T cells, and they are counted as PFS events in the efficacy analysis. 20 of these 32 patients received cilta-cel as subsequent line of therapy, and the outcomes of these 20 patients will be reported elsewhere. As of November 20 -- November 1, 2022 data cut off, the median follow-up was 16 months. The first patient was randomized on 10 July 2020 and the last patient on November 17, 2021. The median time from apheresis to first infusion of cilta-cel was 79 days. When looking at the baseline characteristics, the 2 treatment arms were well balanced. 2/3 of the patients had ISS stage I, 1/3 of the patient had only 1 prior line of therapy [indiscernible], 21% of the patients in the cilta-cel arm and 17% in the standard of care arm had presence of soft tissue plasmacytomas. Approximately 60% of patients had high-risk cytogenetic abnormalities, including the gain and amplification of 1Q. If you exclude gain or amplification of 1Q, around 34% were at high risk. 22% of the patients had presence of 2 or more high-risk cytogenetic abnormalities. About 15% were triple-class refractory and 22% were refractory to daratumumab. The study met its primary endpoint and significantly reduced the risk of disease progression or death versus standard of care. The hazard ratio was 0.26. The median PFS was not reached in cilta-cel arm and was 11.8 months in the standard of care arm. The 12-month PFS rate was 76% in the cilta-cel arm and was 49% in the standard of care arm. You'll notice the orange coloring of the curves in the beginning of the study. This is to denote that patients on both arms were in the same treatment for the first 8 weeks. For this reason, a weighted log-rank test to focus on events that occurred after this time period were used to compare the PFS. However, an unweighted sensitivity analysis also showed a significant difference in PFS with a hazard ratio of 0.4. You'll also notice that during the time when both arms were in the same treatment, there was an imbalance in early PFS events with 22 in the cilta-cel arm and 8 in the standard of care arm. By 3 months, post randomization here were 31 PFS events in the cilta-cel arm and 27 in the standard of care arm. In the prespecified subgroup analysis, cilta-cel consistently prolonged progression-free survival in all subgroups, including the key subgroups as 1 to 3 prior lines of therapy, patients with high-risk cytogenetics, patients with soft tissue plasmacytomas, ISS stage III disease and triple-class refractory disease. Cilta-cel improved progression-free survival versus standard of care whether the patients had 1 or 2 to 3 prior lines of therapy. In the cilta-cel arm, you may be seeing better outcomes in patients with only 1 prior line of therapy versus later lines. However, the data are immature, and will continue to analyze this at longer follow-ups. In the intent-to-treat population, cilta-cel led to higher response rates versus standard of care. 85% of the patients had partial response or better in cilta-cel arm versus 67% in the standard of care arm. The rate of complete response are better was 73% versus 22%. The median duration of response was not reached in the cilta-cel arm and was 16.6 months in the standard of care arm. In the intent-to-treat population, 61% versus 16% achieved MRD negativity in the cilta-cel arm versus the standard of care. Considering only the patients with evaluable samples, the MRD negativity rates were 88% versus 33%. Cilta-cel led to significant improvement in depth of response with higher MRD negativity versus the standard of care. For overall survival, the data are still immature. There have been 39 deaths in the cilta-cel arm and 47 deaths in the standard of care arm. If you focus on the 176 patients who will received cilta-cel as a study treatment, 99% responded and 86% achieved complete response or better. 72% were MRD negative and 12-month PFS rate from the time of apheresis was 90%. Looking at this population allows us to compare the data from CARTITUDE-1 in which patients had 3 or more prior lines of therapy. So how does the PFS of patients treated with cilta-cel in CARTITUDE-1 compared to those from CARTITUDE-4. Here, we have re-baselined the PFS to do an informal comparison with CARTITUDE-1 and we can see that the rates of PFS in CARTITUDE-4 are better than in 18-month follow-up from CARTITUDE-1. The rates and depth of response are also superior. However, due to the sensoring of data beyond 16-month warrants caution regarding any long-term integration. Regarding safety, the data from CARTITUDE-4 are consistent with the nonprofile of cilta-cel. Grade 3, 4 treatment-emergent adverse events occurred in almost all patients in both the arms are mostly hematologic and recovered by day 30. The treatment emergent inflects occurred 62% in the cilta-cel arm and 71% in the standard of care arm. Second primary malignancies occurred in 9 patients in the cilta-cel arm, most commonly cutaneous, but there were 3 patients with hematologic malignancies. There were 10 deaths due to TEAEs in the cilta-cel arm versus 5 in the standard of care arm. The study was enrolling from July 2020 to November 2021 during multiple pandemic pics. Consequently, there were 7 COVID-19 deaths in the cilta-cel arm and 1 in the standard of care arm. 3 of the patients who died with unvaccinated prior to cilta-cel. The COVID-19 death highlights the need for strict preventing measures and aggressive treatment of COVID-19 in patients receiving CAR-T therapies. No COVID-19 deaths occur in the cilta-cel arm after safety measures consistent with international guidelines were introduced. In the 176 patients who receive cilta-cel as a study treatment, 76% experienced CRS, mostly Grade 1 or 2 and all recovered by data cutoff. 21% of the patients are CAR-T related neurotoxicities, including ICANs in 8 cases. All ICANs cases were Grade 1 or 2 and recovered. Cranial nerve palsies were reported in 16 patients, most commonly affecting cranial nerve 7, and 14 cases have recovered. There is 1 MND case, which was Grade 1. CAR-T specific adverse events were manageable with appropriate supportive care and overall lower incidence and severity of CRS, ICANs, MNT and some cytopenias were observed with CARTITUDE-4 versus CARTITUDE-1 suggesting cilta-cel may be better tolerated when used in earlier lines of treatment. In conclusions compared to standard of care, cilta-cel significantly extended progression-free survival in patients with lenalidomide refractory multiple myeloma and 1 to 3 prior lines of therapy with a hazard ratio of 0.26. This hazard ratio is the best ever reported in this patient population in any randomized clinical trial. At 1 year, 76% of the intent-to-treat and 90% of the as-treated population were progressing-free and alive versus 49% in the standard of care arm. This PFS benefit was seen in all high-risk subgroups, cilta-cel also led to increased rate and depth of response. And in the as-treated group, 99% responded, 86% achieved complete response or better and 72% were MRD negative. Use of cilta-cel in earlier lines may lead to improved tolerability. Overall, cilta-cel has the potential to become a new standard of care for patients with lenalidomide refractory myeloma after the first relapse. Thank you.

Good morning, everyone. So in the next few minutes, I'll give a brief update on CARTITUDE-1 at the 3-year follow-up and the Legend-2 at the 5-year follow-up. These were both poster presentations at ASCO this year. So this is CARTITUDE-1. Cilta-cel is a dual-binding BCMA CAR-T cell therapy for the treatment of patients with relapsed/refractory myeloma. The heavily pretreated patients with relapsed refractory myeloma who are treated with standard of care therapy have a median overall survival of about 9 to 12 months. The single arm Phase Ib/II CARTITUDE-1 study, a single cilta-cel infusion induced early, deep and durable responses in heavily treated patients with relapsed refractory myeloma. At a median follow-up of 27.7 months, the median duration of response, the progression-free survival and the overall survival were not reached. And this was in a previous publication by Tom Martin, in the JCO. 27-month rates of PFS and overall survival were almost 55% and 70%, respectively. So cilta-cel was approved for the treatment of adult patients with relapsed/refractory myeloma for formal lines of therapy in the U.S. and in Europe at 3 or more lines of therapy, including an PI and anti-CD38 monoclonal antibody. So the objective of this analysis was to report the study close out results from CARTITUDE-1 at a median follow-up of 33.4 months. The study population included 97 patients who were enrolled and treated as of October 14, 2022 with a median follow-up of 33.4 months. The patient demographics and baseline characteristics are probably quite familiar to this audience, but fresh, 88% with triple-class refractory, 42% were penta-refractory. 99% were refractory to last line of treatment and patients had a median of 6 prior lines of treatment. The previously reported primary endpoint was the overall response rate as assessed by an independent review committee, and that was about 98% and 82.5% of patients had achieved a stringent CR. At the study closeout that's being reported at this poster, the median duration of response was 33.9 months. The median progression-free survival was 34.9 months, and the median overall survival was not reached. 62 patients had samples evaluable for minimal residual disease at any point. 49 patients had samples evaluable for 12 months sustained MRD. And of these 49 patients, 26 had sustained MRD negativity at 12 or more months. And of these 26, 20 had sustained MRD negativity with the CR or stringent CR. At 24 months, both cilta-cel infusion, 18 patients remained MRD negativity with CR or better. On the table on the right, you can see this in the median progression-free survival for the overall group was 34.9 months. But when subgrouped out to CR or stringent CR, the median PFS was 38.2 months and for those who had 12 months sustained MRD negativity and those for 12 months sustained MRD negativity with [ CRO ] better, the median PFS has not reached again, again looking at this at a 30-month PFS rate, 54% overall. But for those who are [ CRO ] better, the 30-month PFS was 66.8%, and when they had sustained the MRD negativity for 12 months, that improved to 74.9%. And when combined with stringent CR, that was 78.5%. In terms of safety, no new neurotoxicity events were reported since the 27.7 month median follow-up. There were a total of 26 2nd primary malignancies that were reported in 20 patients. So that was 4 new patients who had developed these second primary malignancies since the last publication, 27.7 month median follow-up with 6 newly reported cases. There were a total of 35 deaths that had occurred, 5 new deaths again since the last report that were unrelated to cilta-cel as deemed by investigator, 3 of them were from progression of disease, 1 from pneumonia and 1 from sepsis. So the breakdown is on the table, 35 total deaths about half of whom were from progression of disease and the rest from adverse events. 2/3 of those were deemed unrelated to treatment and 6 related to treatment and half of those were from infection. So in conclusion of the 3-year follow-up, an estimated 62.9% of patients are still alive, there were no new neurotoxic events, achieving CR and/or sustained MRD negativity was associated with a prolonged progression-free survival and patients continue to be followed for safety and survival in the 15-year CARTINUE long-term study. At the study close out, a single infusion of cilta-cel provided a median PFS of 34.9 months and cilta-cel is the only FDA EMA-approved treatment to display a benefit of this magnitude for patients in this setting in clinical trials. I'll shift gears quickly to Legend-2. This is the 5-year or more follow-up, and this was presented at the poster presentation at ASCO by me at all. So this is the Legend study was the first-in-human study that preceded the CARTITUDE trials. LCAR-B38M CAR-T cells expressed a structurally differentiated CAR construct containing the 4-1BB costimulatory domain and 2 BCMA-targeting single-domain antibodies to confer avidity, and we know this now as cilta-cel. Legend-2 was a first in human Phase I study of the LCAR-B38M. This was conducted at 4 sites in China, which showed encouraging efficacy and manageable safety in 74 patients with relapsed/refractory myeloma. And at a median follow-up of 48 months, the overall response rate was 87.8%, and 73% of patients achieved CR. This was reported by Zhao et al at the Journal of Hematology Oncology. The median PFS was 18 months. The median overall survival was not reached and the median duration of response was 23.3 months. This efficacy observed in Legend-2 was confirmed by the U.S. Phase Ib/2 CARTITUDE-1 and the Chinese Phase II CARTIFAN-1 studies of cilta-cel, which express the same CAR as the LCAR-B38M. And this analysis is to report the 5-year or higher follow-up data from Legend-2. This is the longest follow-up for any BCMA CAR-T cell therapy. As of November 2022, there were 74 patients who were treated with this product with a median follow-up of 65.4 months. This is 5 years after the last patient was dosed. The overall response rate was mature at 87.8%, was unchanged since this 48-month follow-up, the median duration of response was 23.3 months, and the MRD-negative CR rate was 67.6%. 33 patients were alive at data cutoff. This was the 44.6% and of whom 12, that is 16.2% were disease-free at 5 years or more after infusion suggesting a possible functional cure in these patients. The median PFS was 18 months. The median overall survival was reached with this data cut and that was 55.8 months compared with patients who were progression-free, patients who had progressed or died had higher risk features at baseline, including a longer time from diagnosis, more prior lines of treatment baseline ECOG was a little higher at performance status 1 or 2. ISS stage a little higher 2 or 3, less IgG type, more light-chain type myeloma and presence of extramedullary disease, which are known, recognized for prognostic features. There were no new CAR-T cell-related toxicities that were reported since the 48-month follow-up and the incidence of neurotoxicity was 1%. The graph showed the 5-year PFS rate of 21.7% and the 5-year overall survival rate of 49% in these patients. So in conclusion, at the 65.4 month follow-up of Legend-2, 16% of patients remain disease-free and alive at 5 or more years. The median overall survival was 55.8 months, 45% was still alive, suggesting a long-term overall survival benefit even for patients who progressed. No new safety signals were reported at this longer follow-up demonstrating a favorable long-term safety profile of LCAR-B38M. Patients who are less heavily pretreated or have good functional status may experience a greater benefit with potential for cure after the LCAR-B38M CAR-T cell therapy. So to sum it up at 5 years, a more follow-up with Legend-2, this LCAR-B38M CAR-T therapy demonstrated a strong efficacy with a median overall survival of 56 months, 16% of patients remaining disease-free at a median of 65.4 months, suggesting the possibility of a cure for some with heavily pretreated relapsed/refractory myeloma.

If any, could introduce yourself by stating your name and your firm.

Mitchell Kapoor from H.C. Wainwright. In the CARTITUDE-4 data, you noted that -- saw a progression-free survival benefit or list of line of therapy. Is there any kind of trend in the line of therapy where you're getting better PFS as [Technical Difficulty].

[Technical Difficulty] already seeing a trend that the patients with only 1 prior line of therapy, probably going to do better, and looking there they are doing better than the later lines. So that suggests that if you use this cilta-cel in earlier lines, the patient probably will get the maximum benefit. Again, we have to -- all of these patients will be longer to see that, but we are introducing that trend.

[indiscernible] from ARI Capital. Could you speak to the higher number of early progressors [Technical Difficulty] bigger in those versus [Technical Difficulty].

That's another great question. As you saw that the 2 treatment arms are well balanced, including balanced well on all the high risk factors. So at this point of time, we really don't know what led to the early progression because if it's important to know that those 2 arms were in the same treatment, they're getting either bridging therapy, which is the same as standard of care arm. And they are all happened before the cilta-cel infusion. So we are investing in that patient population to see what really made them to progress early. But at baseline, they're all balanced for all the risk factors.

And the fact that if you look at the dose density for patients who were on cilta-cel arm, they did receive 14% lower dose for drugs, including Pomalyst and Velcade.

So that could be another factor, you are right, yes.

Gena Wang from Barclays. 2 quick questions. First, I think you showed patient median onset of CRS day 8. How many of these patients actually before day 3. And the second question is, I think you do have quite a few patients did not receive the [indiscernible] and can you provide a breakdown of those patients? And then how do you -- actually in terms of stats analysis?

Can you go to the first question is what...

Yes. So the median onset of CRS, I think it was day 8, and how many of these actually had a CRS onset before the day 3?

I don't have the data. Do you have the data? How many onset before day 3, but it's more than 50% will have around that time, right? But we have to look at the range. We have the slide we can just go back. Yes, I don't think we have that information, how many patients had that before. But at median onset on day 8 and they lasted for about 2 days, the CRS [indiscernible] consistent with what we saw in the CARTITUDE-1 patient population. The second question, what is the second question?

Second question is the patient that did not receive the drug. So cilta-cel, like how -- can you provide a breakdown of those patients who did not receive it? And how do you quantify in terms of stats?

Yes. So the 32 patients, the patients that we did not have -- we had disease progression or died before receiving cilta-cel, right? That -- we're going to report that data in the future meetings. So we don't have much detail on that. But out of that, 20 were able to receive the cilta-cel as a subsequent line of therapy. And patients do not receive the cilta-cel because of most likely because of disease progression. So they are not kind of able to receive the cilta-cel because of the condition, because of the disease rapidly progressing. And we're going to report the data of how this patients did with the cilta-cel of those 20 patients in the future meetings.

Congratulations. Maybe one question on the vein-to-vein time. I think you mentioned 79 days, if I'm not mistaken. And we saw some presentations here at ASCO, where BCMA CAR-T again tried to shorten this time. I was wondering is there an opportunity to shorten this time in the real world setting? And how important is this for you when you treat the patient? Would you look at efficacy as the most important factor or the vein-to-vein is also very important? Thank you.

Yes, that's a good question. Both are important. So if you look at the vein time to infusion was 79 days. I also want to add is that the median time from first receipt of the product to -- release of the product was 44 days. So that is not that long. I just want to remind that this is the study that was enrolling when the COVID was raising. One of the factor was the COVID was happening at the same time, a lot of new variants are coming in. One of the things that we could think of is that there are multifactoral reasons, but one is definitely the COVID [ related ] delays was one of the factor. Yes, definitely, the thing from our end is to decrease the vein-to-vein time because especially the patients in the late relapses, they kind of wait to get that to -- wait longer to get receive the therapy. And I would defer that to our liaison colleagues to answer on that. There had definitely been a strategies to improve it. And we are seeing in the real world the vein-to-vein time improving as the time went by in terms of our -- the commercial patients.

Maybe also worth [Technical Difficulty] large proportion of the patients, Europe, [indiscernible] Asia-Pacific [Technical Difficulty].

Kelly Shi from Jefferies, and congrats on the progress. First question is Legend-2 reported 16% of the patients remain disease-free after 5-year follow-up. Would you be able to use this data estimate in earlier lines trial CARTITUDE-4, what percentage of the patients could remain disease-free which I think [ define as ] it cure after 5 years. And secondly, I think if I'm not mistaken, it was mentioned on weighted hazard ratio is 0.4. So my question is what was the rationale of using weighted approach initially and for the U.S. FDA filing and the FDA label, which number will be included.

So I will answer your second question first. The reason for using this weighted log-rank test was it was a per-protocol prespecified analysis to use the primary analysis versus hazard ratio. So because if you see the patients in the first 8 weeks received the same treatment in both the arms, we want to account for that. And that's why this weighted log-rank test was used. But unweighted test was used as a sensitivity analysis, and we showed the same kind of a benefit of cilta-cel versus standard of care. And I think this 0.26 hazard ratio will be used for further filing. And for the second -- or your first question about how -- what proportion of patients will be progression-free and alive is difficult to predict this at this stage. But based on Legend-2 and CARTITUDE-1 long-term follow-up, I'm hoping that the median duration of response would be significantly higher compared to the standard of care that is available in this patient population lines.

And that if you look at some of the historical trials in cancer setting, the approval of [ PROVENGE ] and also approval for vitamin D and also [ Yervoy ]. We're using this [indiscernible] method because it does account for the so-called delayed treatment effect. And secondly, there's actually a paper published by the staff of CDER on this method. If you want, we can forward you that paper.

It's Leonid from RBC Capital Markets. So congratulations on the great data. I wanted to ask maybe on some of the practicalities here. So obviously, there's still going to be some choices that you have to make about which patients get the treatment. So as you're thinking about looking at this data, are you expecting to use this right away as it becomes available in the second or fourth line patients? Are you still thinking this is going to be primarily in that later-line refractory population. And as you think about the patients in that second or fifth-line bucket, now are there any particular subgroups that stood out to you where you want to use this first and maybe at the same time as you're using it in your later line patients?

That's a great question. So if you saw the CARTITUDE-4 data and compare it to CARTITUDE-1 population, what we saw clearly is that efficacy is perhaps better if you used earlier, but more importantly, safety is even better because if you look at the rates of high-grade CRS and ICANs although they're much lower in CARTITUDE-4 patient population that means they are early line treatment. So if I have the ability to use it, I'll definitely use it in early lines, preferably right after the first line relapse because you saw that is already a signal that the second-line patients are doing -- probably doing better than the latter lines, even with the cilta-cel. Now -- the next question is about what subgroup. That's an important question. If you look at the subgroup analysis, it benefited all subgroup of patients, including the difficult to treat patient population like high-risk subgroups, those with EMDs. And if you look at the hazard ratio breakdown on that, this is some of the best hazard ratio that you would see in this patient population. So my principle is that if it works on high risk, it's definitely going to work even better than the standard risk. So for me, I will be using all patients because why not [ standard risk ] also get the benefit as long as we have the slots, and we have the manufacturing capacities, I will use in all my patients.

And I just add that to test exactly this, I'll be -- all the cohorts of the CARTITUDE-2 trials which are looking at various subgroups because nothing is going to speak louder than the data, so to actually see in the suboptimal response after transplant for patients with high-risk disease and newly diagnosed or patients with standard risk and newly diagnosed. So all of these separate subgroups of patients are being tested separately.

[indiscernible] from JPMorgan on behalf of Jessica Fye. So we have a question probably for the investigator. So love to hear any perspective from the management on the involving treatment landscape in multiple myeloma in light of the data from CARVYKTI in both early lines and earlier setting, but also some other data from other companies or newer targets, for example, by bispecific [ GPRC5D ] plus [ their ] data and also -- the combination data with [ GPRC5D ] and the BCMA bispecific data coming out from same conference, how do you see the different agents can fit into the human landscape? And does the management also have any plan on working on [ GPRC5D ] as well?

So yes, great. The way the T cell redirected therapies are developing, there's now so many options that we didn't have maybe even 5 years ago. And the question now is, I think, very important key questions are, it's not a question of which patient gets which, but how are we going to use all of these tools. So until we can find that plateau in the survival curve, wherein we -- that would be the answer it then becomes a question of how are you going to sequence all of these different agents for the most effective use. So I think they redirect with the [ tactile ] combination and then all of these new concepts that will be coming out as to -- can you combine CAR-Ts and bispecifics and all of these things, I think these are all things that have to be studied I think we are in a good place in terms of the options that are available. These are so much better than when we had the MAMMOTH study, and we looked at the standard of care in people with triple-class refractory patients, had a median overall survival of less than a year and people with penta-refractory had less than 6 months. We are far leading those kinds of data behind. So I think we're poised in a good place to study a lot of these different concepts, varying different targets, et cetera.

And maybe [indiscernible], I can just add one comment from the company side. Obviously, we welcome all these latest developments in novel therapies in myeloma, however, we also firmly believe that CAR-T therapy as immunotherapy really should be used in earlier lines as early as possible when patients still have very healthy immune system. That's where we can get a good quantity and good quality of T cells. That is why Legend and Janssen had been studying in frontline, including CARTITUDE-5 and CARTITUDE-6. And we're planning to actually complete the enrollment of the 650 patient study in CARTITUDE-5 by end of this year. So stay tuned.

This is Ash Verma from UBS. So I had 2 questions. One is around the Moffitt cancer abstracts you might have seen comparing a bit more to CARVYKTI. I know it's kind of premature and they didn't have a lot of follow-up, but just surprised to see the CR and ORR rates to be similar. So just curious to get your thoughts on that. Second question on CD19 BCMA from [indiscernible]. So like again, early data, but just wanted to get your thoughts on this, like 38-month PFS and 26 hours of administration, how do you think this would compete CARVYKTI?

Well, I think that's all good points. The first question I would answer in a way that the real-world data of the cilta-cel patient is main limitation right now, I cannot comment further, but there's a very short follow-up. And if you look at the patient population that is included, very heterogenous patient population, with 14% of patients with prior BCMA-exposed patients and there are some patients with high risk -- very high-risk features like plasma cell leukemia, which is not included in the CARTITUDE-1. So it's difficult to compare that patient population right now. But more importantly, the follow-up is very short. So we'll have to see these patients a little bit longer and we can compare. And then number two, in terms of the other data that you just mentioned about this rapid manufacturing with this very deep responses is very encouraging definitely, with a small number of patients. And yes, again going back to the same point of how to decrease the vein-to-vein time, right? And what I would like to add on is that, yes, that is very important -- that development that we need to have. But at the same time, if you are thinking of doing a very effective therapeutic like cilta-cel earlier line, actually patient can wait versus like late lines where a patient cannot wait. So I think if you have a very effective therapy, you're getting that in early lines, you can debulk the patient with other available therapies and can wait around the time that in a reasonable time and then still give this effective -- cilta-cel like therapy. But having said that, we still will continue to improve to shorten the vein-to-vein.

Should we expect out of spec rates to go down perhaps 10% plus based on CARTITUDE-4 , number one. And if that's the case, consensus currently assumes about 1,000 patients this year worth of manufacturing [Audio Gap] next year, which is a bit linear. However, if you get a couple of hundred additional patients out of spec and another couple of hundred patients from the Novartis transition, I almost wonder if we're underestimating how much manufacturing is coming online next year.

Sure. Thanks for your question, [ Umer ]. So on your first question, without getting into any numbers, I can tell you, our current out of spec rate has been dramatically lower than what we saw in the beginning of the launch last year. It's not that far from the labor rate, and we continue to see improvement because over the last 12 months also, which Janssen and Legend have been working very hard in improving our manufacturing product. We looked at many, many different parameters and we actually already have implemented some of the measures. In fact, some of those efforts have been already bearing fruition. And part of the reason you're seeing, for example, from fourth quarter $55 million revenue to the first quarter revenue of $72 million. There's no increase really in capacity there. So it's really coming from our higher efficiency, lower OS. That is the improvement you saw, right? On the second question, again, without giving you any details, but I can tell you that from both Janssen and Legend, we're able to say that you should expect a meaningful increase of our capacity by end of this year. And you can track our capacity by looking at the quarterly results from Janssen every 3 months. We have been investing heavily in both infrastructure in New Jersey and also in Belgium. And as you know, we recently also signed up with Novartis as our CMO. So all these internal and also external efforts will contribute to, like I said, meaningful increase in the capacity, and it's continuous. And you should expect that to be reflected in the sales.

Justin Zelin, BTIG. So noted the safety improved in CARTITUDE-4 here. Could you comment on the potential for outpatient in earlier lines of therapy?

So I can tell you my experience. We're all doing outpatient CAR-T right now at our center. So the reason is we have, of course, the resources for doing any CAR-T as an outpatient, but cilta-cel is very well acute or poised to do an outpatient because the median time to CRS is around 7 to 8 days. So these patients can get lymphodepletion and then get infusion and for the first 7 days to be on. If nothing happens. We can just see them every day. The whole process of lymphodepletion infusion can be done as an outpatient. And of course, it depends on center to center, I don't know about Dr. Richard center, but there -- the lot of centers are doing as an outpatient CAR-T and cilta-cel is actually very well suited to fit that role.

At our center, we're still doing them all in patient, but certainly, I agree with the note that cilta-cel is certainly very doable as an outpatient, at least for the first 5 days or so. And then if there's any evidence of [indiscernible] to admit them at that point.

Also comment just on the outpatient question. So year-to-date, we're seeing about a 20% or so patients treated in the outpatient setting when you aggregate all patients in the U.S. So we're expecting that percentage to rapidly grow. Many of our sites are, as you mentioned, are very enthusiastic in moving that direction. Really, the rate limiter right now is experienced with this product. So as experience grows, you'll see fairly rapid adoption in the outpatient setting.

And I can tell you from our experience is that the percent of the patients who are needing inpatient after the outpatient is around 10%. That means you're able to manage if you have right resources, you can manage 90% of the patients, completely outpatients.

Sami Corwin from William Blair. I was hoping to get your perspective on the changing use of [indiscernible] in earlier line settings, both in the academic setting as well as the community setting and how that might affect how you would use CAR-T in late adverse lines?

So I mean, I think when the GRIFFIN data came out, it's become the rage now to use quad therapy upfront. And at our institution, we certainly have adopted it because those are very excellent response rates. But what this is -- what this means is that patients are becoming triple-class exposed, there are exposed much earlier in the alliance of treatment. And by the time they have gone through their first line of treatment, they've essentially seen all 3 classes of drugs. So there was a paper by [ Chari ], where they looked at what happens over 4 years from diagnosis. And patients that essentially being exposed to all 5 agents by that time. And their median PFS rates are dropping to about 3 months or so. I think therapy is very powerful tools like CAR-T being used earlier in these lines of therapy really are making a big difference because our options with other novel agents is getting to -- that are non-T cell directed are having less and less stellar response rates when you compare the 2.

[ Rohit ] from Wells Fargo. My question is regarding the vein-to-vein time. We are talking about this. The main player in the CD19 space, they talk about it is the vein-to-vein time, which takes more time than vein-to-vein, which is basically the time you conceptualize that you need to treat this patient from that time to actually getting the reimbursement, all those procedures done before you can actually get assessment from the patient, that takes more time than vein-to-vein. How is your experience as a clinician as well as the company, I would love to understand that. Is that -- is that still a bottleneck? And how much time does it take from the conceptualization versus getting the patient treated on this?

Yes. So -- that's actually definitely a very practical consideration that we have to take into account. When you think of giving the CAR-T to a patient, that is when you conceptualize the patient to give the CAR-T. So that the whole process starts of getting the insurance approval and all the stuff, so that could vary from patient to patient and also from insurance to insurance. It also depends on institutions. So some institutions probably are very aggressive on getting the insurance approval. At our institution, I can tell them my experience, yes, it was not really kind of good initially when the CAR-T just got approved, but that has -- that team have got to streamline in a much better position right now because we knew that could be a limitation for patients to get even like to get the apheresis, get the slot. So we have really used our resources to sort in that time. And I think in the future, it will continue to improve once we get the label and once people start using more and there is a beta in the real-world setting. So Dr. Richard, I don't know what is your experience in terms of vein-to-vein time, I mean, in terms of like getting insurance approval, but we're definitely getting better at our institution.

It's definitely insurance dependent. But I think based on the approval criteria, we're actually getting approvals across the board. We're not having too many denials at all. And again, depending on the insurance as long as we have all of the work up in the paperwork, and they don't have additional questions or anything we get the complete approval process takes about 3 weeks or less. So it's not bad because most patients are not ready to go right away. They come for the consultation. And while all of the work up and pretesting and everything is being done and we get the approvals back very quickly. Once the paperwork is actually submitted the approvals are coming back in about 3 to 5 business days. So it's not bad at all. There is the occasional Medicaid insurance will might push back a little bit more and ones like the additional detail. But I've rarely been actually turned down except in one situation where the patient had a prior CAR-T and then I did get some pushback from a particular...

That was my comment. The only time we've seen denials in market today in the U.S. has been commercial CAR-T to commercial CAR-T. Outside of that, we have not experienced any in terms of reimbursement.

I also had this 1 denial so far. So there is a patient on dialysis and I wanted to give because there's no other option young patients. I would say there is no data on those patients under dialysis. Otherwise, there has no [Audio Gap].

One virtual question. Is C4, CART-4 filed in the U.S. When do you expect approval? Are there any payer dynamics consider heading into next year? Or is -- or a rate limiter just regulatory and manufacturing.

I'll answer that question. As you guys know, we have already filed in Europe. The only thing I can say is that the U.S. filing is coming very, very soon. So you will know that very soon. With regard to the prep for commercial launch in second line, Janssen and Legend have been preparing for that for a while, and we'll be ready once the label comes in. The expectation is that we expect to launch the second line indication by end of this year in the U.S.

I could comment on dynamics around that and the indication. Actually, the commercial insurers are very enthusiastic around an indication like this for a lot of different reasons, given the data, obviously. But no, there's no necessarily any issues or concerns that we have around.

Kostas Biliouris again from BMO Capital Markets. Maybe one question for the physicians. Early on, we anecdotally hear from your colleagues that the supply of the CAR-T BCMA could only meet about 10% to 15% of the demand from patients. I'm wondering to what extent this has improved? And maybe one question for Steve. I think the activated centers at this point at around 47 online, maybe what should we expect by the end of the year?

The -- can you repeat the first question?

So the first question is that the supply of commercial CAR-T BCMA could only meet about 10% to 15% of the patient demand for this drug, has this been improved and to what extent?

So definitely. So when the first CAR-T was approved, the first product was approved in 2021, right? There is about -- at our center, I can tell you about 30 patients were in the waiting list per month. And out of that, probably 25% to 30% would make it to the CAR-T. And of course, we put a lot of heavily treated rapidly progressing disease as well. In the median time to wait, we looked at our own data about 5 to 6 months. And that got better after we have CARVYKTI got approved. And what I can tell you now we're in a much better position. We're getting more slots. It could be center-specific. Maybe they're not applicable to all the centers, but our centers are getting more slots, we have less patient. Now we have more CAR-T [ sellers ] than patients waiting, okay, to be honest. And we have other trials, too. So that might. The other thing that also helped is approval of the bispecific antibody. So what happened is that the patients were rapidly progressing and which by virtue of that disease is cannot wait to get the CAR-T and it's not fair for them to wait for the CAR-T and get those other highly important therapies. So I think that number, so this balance is going to get better with the increasing manufacturing capacities and then perhaps using other therapies in the patients who cannot wait, I think we're going to probably meet the demands...

[Technical Difficulty] at our institution as well. We're clearing the backlog of patients. And we did have a very long list initially, but now the patients are being -- and again, when they are distributed among the clinical trials and the teclistamab, I think all of that helps us well. So I can say that we don't really have much of a wait period. It's really more of medically -- what the patient is medically ready for, otherwise, we're able to get them in within a month.

I think there was a second part of the question around numbers of sites. So there's 47 sites in the U.S. today that's been activated and certified the projected certification number right now by end of the year is between 70 to 80.

Back according to our plan.

I'm Gena Wang from Barclays. Just quick follow-up questions for 2 doctors. What are your experience in a patient that taking BCMA target therapy and after failure and the second time taking the BCMA target therapy. What is the experience for the second [Technical Difficulty].

So my experience is what has been reported in the clinical trials, depending on what agent you use. So I haven't used most of the patients who are failing after CAR-T, you haven't used another CAR-T in those patients. Maybe in 1 or 2 cases I've used, but mostly had been using bispecific antibody. And I've been seeing almost 50% response rate in most of the cases. Again, that number pool is not that big because the CAR-T if we're using -- they don't relapse very early. But whoever patients who have relapsed after CAR-T I've used a bispecific antibody. In few cases, another CAR-T but the data is what we have seen, at least in my personal experience, consistent with what has been reported in clinical trials, yes like 50% response.

Think the CARTITUDE-2 Cohort C is actually addressing this question and Adam Cohen has presentations on it. But the response rate is lower when there is a prior BCMA exposure. But some of the things that we are learning from the data from all of this is if there is a shorter duration of time that they have been on the BCMA previously, then the response rates are better. And then if there is a longer interval and we've used 6 months of like an arbitrary cutoff. So if that prior BCMA was more than 6 months prior, then their response rate is better. Patients who had -- if the other things might be -- so I think -- I mean, I think those are like some of the main things that we are really looking at. One of the other things interestingly that they mentioned too, on that was if they used another target intervening between the 2 BCMA therapies that seemed to help as well. Intuitively, that kind of makes sense, doesn't it? Because you're now -- you've used 1 target and then we know that many of the CAR-T failures for instance, are not necessarily from antigen loss. But even if there's antigen diminishing, and if you're using a different -- a different product, a different target and kind of allowing it to recover, then you use another BCMA, that seems to be. When we've done back-to-back re-infusions for people who have not, that has not been very good. The response rate has been really low on those.

One more question. Now we can conclude. Thank you very much for coming.