Legend Biotech Corporation (LEGN) Earnings Call Transcript & Summary

Good evening. Welcome to Legend Biotech's webinar today to discuss our CARTITUDE-1 Phase Ib and II results in relapse or refractory multiple myeloma patients, which was presented at the American Society of Hematology on Saturday, December 5. I am Jessie Yeung, Head of Corporate Finance and Investor Relations at Legend Biotech. Before we dive into the program, some housekeeping reminders. Today's call is being recorded and webcast on our website and will be available for replay. [Operator Instructions] Please submit any questions through the chat at any time during the event. Before we get started, I would like to note that we posted a press release that provides the details of this data, which was presented at ASH 2020. In terms of the format, we will begin with a brief overview of Legend Biotech, followed by data discussion and moderated Q&A session with our KOLs, and then we will open the floor for questions from the audience. On the call today, we have Dr. Ying Huang, CEO of Legend Biotech. We are also pleased to have Dr. Jagannath from Mount Sinai Hospital and Dr. Martin from UCSF joining us today. During today's call, we will be making certain forward-looking statements. These forward-looking statements are based on current information, assumptions and expectations that are subject to change and involve a number of risk and uncertainties that may cause actual results to differ materially from those contained in the forward-looking statements. This and other risks are described in our periodic filings made with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, and the company disclaims any obligation to update such statements. With that, we are going to play our company video now, and then I will turn the call over to Dr. Ying Huang. [Presentation]

Good evening, everyone, and this is Ying Huang of Legend Biotech. On behalf of all our team members across the world, including in the U.S. and also in China, we'd like to welcome you to our first virtual ASH event. I know it's a virtual event given the COVID-19 outbreak, but really hope that you will enjoy this informing session. So let me just give you a quick overview of Legend Biotech before we dive into the CARTITUDE-1 data that's presented at ASH on Saturday. At Legend, we're aspiring to build a fully integrated global cell therapy company, building on our lead product candidate, cilta-cel, which may have the potential to deliver deep and durable antitumor response in relapsed or refractory multiple myeloma patients. Besides cilta-cel, we also have a broad portfolio of earlier-stage autologous product candidates targeting both hematologic and also solid cancers as well as allogeneic CAR-T approaches. In December 2017, Legend signed up with Janssen, a pharmaceutical companies of J&J, for the development of cilta-cel. With that, we received an upfront payment of $350 million. And since then, Legend has achieved a total of $110 million milestone payments to date. In the near future, we are also eligible to receive other milestone payments. And there's a total of up to $1.24 billion in potential future milestones payments on cilta-cel development program. So we also are very proud of our in-house antibody generation and CAR-T specific functional screening technologies we have invented since the company was founded in 2014. In the last 6 years, the team has established early clinical proof-of-concept capabilities, leveraging our KOL relationships in China and now also in the U.S. and globally. We are starting to build large-scale manufacturing facilities in the U.S., in Europe and in China. And we have -- already have a team of over 700 employees worldwide, including in the locations in U.S., China and in Europe. So we built our strong foundation of research and development from the core technologies, including CAR and also TCR. Within our platforms, we're working on both autologous and also allogeneic T-cell therapies. And in terms of our disease areas, we're targeting hematologic malignancies, including myeloma, lymphoma as well as leukemia. We also have early-stage programs targeting solid tumors and also infectious disease. Our mission is to improve the lives of patients worldwide using T-cell therapies. Our 350 strong R&D team has been able to establish the end-to-end R&D capabilities, including the high-throughput antibody screening and also engineering capability, built on the single-domain antibodies generated from llama and also other conventional antibody technologies. We also have invented proprietary methodologies to optimize the selection of binding domains and also design of the CAR-T constructs with 2 or more antigen-binding demands, as evidenced in the cilta-cel structure. In the meanwhile, we have also started robust in vitro and also in vivo screening platforms to prioritize our pipeline assets. And in the last couple of years, we have also started to build a clinical team, and we're doing our work in proof of concept in efficient clinical translation work. This highlights our robust pipeline of cell therapies. We'll go into more detail about the cilta-cel development program in multiple myeloma. But besides that, we also have 8 Phase I clinical programs looking at various conditions, including dual-targeting CD19/CD22 autologous CAR-T for diffuse large B-cell lymphoma, a dual-targeting CD33/CLL-1 autologous CAR-T for the indication of AML and also a CD4-targeting autologous CAR-T for T-cell lymphoma. Within the allogeneic programs, we have 2 programs in the clinic today. The first one is a allogeneic CD20-targeting autologous CAR-T for diffuse large B-cell lymphoma, follicular lymphoma and also mantle cell lymphoma. Recently, we also initiated a Phase I trial for our gamma , our allogeneic CAR-T targeting BCMA for myeloma. In the domains of solid tumors, we have 2 Phase I programs, and it's an autologous CAR-T targeting Claudin 18.2 for treatment of gastric cancer and also pancreatic cancer. And lastly, we also have a Phase I program, which is the auto CAR-T targeting mesothelin for treatment of ovarian cancer. So let me give you some idea of the clinical development programs for cilta-cel. As you know, multiple myeloma is a blood cancer with a high unmet medical need, accounting for more than 10% of all hematological cancers in the world. Every year, more than 160,000 patients are diagnosed with multiple myeloma. In the United States alone, the incidence is about 25,962 per year. And unfortunately, more than 13,000 patients will succumb to this disease and die from it. In the right of the slide, you can see the prognosis for the refractory patients are very poor. In fact, the median survival is less than 12 months for patients who have refractory multiple myeloma treatment. For example, in patients who are penta-refractory, which means they refract to a class of up to 2 immunomodulators, such as Revlimid or POMALYST, and refracted to PIs or protease inhibitors, including VELCADE and KYPROLIS. And lastly, it also refracted to a class of CD38 antibody. For these patients, the median survival has been estimated at about 5.6 months. Next slide, please. And at ASH of 2019, we presented the detailed data of the 2 cohorts. In the first cohort of 57 patients enrolled at a Xi'an hospital, the overall response rate was 74% -- sorry, 88% with a CR rate of 74%. In the other cohort of 17 patients enrolled in 3 hospitals in the area of Shanghai, the overall response rate was 88% as well with a CR rate of 82%. Impressively, the duration -- median duration of response was 27 months in the Xi'an cohort, and the median time to initial response was 1 month. Median PFS was determined to be about 20 months in this cohort, and median overall survival was 36 months. In the other cohort consisting of the 3 hospitals in Shanghai, which enrolled 17 patients, the median time to initial response was also 1 month, and median PFS was reported to be 18 months. Building on strong data from the LEGEND-2 Phase I study, we embarked on a clinical program called CARTITUDE programs in the U.S. and also CARTIFAN program in China. Right now, our partner, Johnson & Johnson, and also Legend are conducting 2 confirmatory studies, namely CARTITUDE-1 in U.S. and also CARTIFAN-1 in China. The CARTITUDE-1 program is a Phase Ib/II multicenter registration study for cilta-cel in relapsed or refractory multiple myeloma. And then the CARTIFAN-1 trial is a Phase II multicenter confirmatory study -- registration study in China. In the meantime, we're also conducting a multicohort Phase II trial called CARTITUDE-2. This is a global, 5-cohort study, and it's an open-label study of cilta-cel in various earlier line settings of multiple myeloma. Right now, we're enrolling patients in the U.S. and in Europe. We also started enrolling a Phase III randomized study called CARTITUDE-4. This is also a global study, and we're planning to enroll up to 400 patients in multiple myeloma patients who have had prior 1 to 3 lines of therapy and also refractory to Revlimid. Right now, we're also initiating the enrollment in U.S., Europe and also other countries. So with that, let me turn over to Dr. Jagannath of Mount Sinai Hospital to give you a presentation of the CARTITUDE-1 data that was presented on Saturday, December 5 at the ASH 2020 Conference.

Thank you, Huang, for giving me the opportunity to present the data that was already presented in the ASH by my colleague, Dr. Deepu Madduri. She did a great job. First slide, please. So CARTITUDE-1 is a Phase Ib/II study of ciltacabtagene or cilta-cel in -- which is a BCMA-directed chimeric antigen receptor CAR-T cell therapy in relapsed and refractory multiple myeloma. Next slide. Okay. So you can see that this CAR-T cell is a single chain and heavy chain from the llama. It is a single chain with 2 BCMA-binding domains. This allows these CAR-T cells to bind to the tumor cells or BCMA-expressing myeloma cells much more effectively. That is the uniqueness of this particular CAR-T cell program. In the Phase Ib portion of the CARTITUDE-1 study, the cilta-cel yielded deep, durable responses with a manageable safety profile in patients with relapsed and refractory multiple myeloma that was already presented by Dr. Berdeja in the ASCO -- in the last ASCO. And this was called a Phase Ib portion because this was not really a dose-finding. It was more of a dose confirmatory study of what was already conducted as a clinical trial in China. And now we report here the initial results of the combined Phase Ib and II CARTITUDE-1 study of cilta-cel. Next slide. So this is a registration trial, as Ying Huang already mentioned. So the primary objective is -- in the Phase Ib is to characterize the safety of the cilta-cel and confirm the recommended Phase II dose. And in the Phase II, it's to evaluate the efficacy of cilta-cel by overall response rate because that's critical for an accelerated approval. The key eligibility criteria are patients should have progressive multiple myeloma or IMWG criteria; and the ECOG performance status of less than or equal to 1; with a measurable disease; patients should be exposed to 3 or more prior therapies or at least they should be double refractory; and exposure to prior PI, IMiD and anti-CD38 monoclonal antibody. Now on the right-hand side is the schema or study design as shown then. The patient is screened. Then the patient undergoes apheresis to collect the T cells, and then some of the patients get bridging therapy as needed. And then they get the cyclophosphamide/fludarabine as a lymphodepletion. This is followed by cilta-cel infusion on day 1. And then the post-infusion assessments are done for safety, efficacy, PK, PD, biomarker and the follow-up. The median administered dose in this clinical trial was 0.71 million cells, and the range was 0.5 million to 0.95 million. That was the goal, that was dose confirmatory dose. And these were all CAR-positive viable T cells per kilogram body weight. Next slide. So 113 patients were enrolled. And as you can see, these were quite advanced patients -- advanced relapsed/refractor myeloma patient. And therefore, you could see that there were 12 patients who discontinued due to progressive disease or withdrawal of subject due to the performance it is getting, deteriorating quickly. And actually, 8 patients died. Then 101 patient went on to receive the lymphodepletion. Again, 4 patients discontinued because of progressive deterioration of the patients: Withdrawal by subjects, 3 patients; and 1 patient progressive disease and died. So there were -- the total number of patients who were infused with cilta-cel were 97. And of that, Phase Ib was 29 and Phase II was 68 patients. And what is impressive is a total of 73 patients received bridging therapy. Median turnaround time for cilta-cel was only 29 days, and no patient discontinued due to manufacturing failure. And naturally, over 85% of the patients are still on the study. Next slide. The baseline characteristic for the 97 patients are shown here. Median age, 61, but it ranges from 43 to 78. And patients with extramedullary plasmacytomas, 13%, and this excludes patients who are perimedullary or intramedullary plasmacytomas. The high-risk cytogenetic profile, you see 23% of the patients, and those are listed there. And prior lines of therapy, median is 6. This is important. So this is really an unmet medical need condition for the patient coming on to this clinical trial: Triple class refractory, 87.6% of the patient; penta-refractory, 42% of the patient. And you could see the patients who are progressing on their last line of therapy, 96% -- the 99%, 96 out of 97 patients, 99%. So everybody was progressing on the last line of therapy. This was really an advanced refractory myeloma population. Next slide. So the hematologic adverse events are shown on this slide. Patients all get their lymphodepletion, fludarabine and cyclophosphamide. So hematologic toxicity is not uncommon. You could see neutropenia, anemia, thrombocytopenia. Any grade is almost -- neutropenia is 96%, leukopenia in 62% and lymphopenia in half of the patients. And Grade 3/4 toxicities also encountered, mainly hematologic. But if you look at the hematologic recovery, you could see that it is a rapid recovery of WBC and neutrophils and thrombocyte. So you could here see late recovery greater than 1 month Grade 3/4 cytopenia from onset, neutropenia is only 10% and thrombocytopenia is 26%. Then any grade infections is only 58%, and you can see Grade 3/4 infection is 20%. Pneumonia was encountered in 8.2% of the patients. On the right-hand side, you could see the rapid neutrophil recovery and then somewhat delayed platelet recovery. Next slide. The nonhematologic adverse events are shown on this slide. And they are broken down here on the left-hand panel, metabolism and nutrition disorders. Any grade ranges between 20% to 30%, anywhere between hypocalcemia, hypophosphatemia, hyponatremia, hypokalemia, et cetera. But if you look at the Grade 3/4, it's all in single digits. The GI toxicity, again, ranges from 20% to 30%. But Grade 3/4, it's 1%. So these other adverse events are really very low. Then you go to other, fatigue and cough, you can see 37% and 35% in any grade. But Grade 3/4 fatigue is only 5%. Transaminitis is at about 5% of the patients. And chills, pyrexia is common. We will talk about it as part of CRS. Now the most important toxicity we want to know or adverse events with any CAR-T cell administration in any diseases is CRS and neurotoxicity. So you could see that the CRS is seen in almost 95% of the patient, 92 of the 97 patients. And neurotoxicity was encountered in only 21% of the patient. Grade 3/4 CRS is very low, 4%, and neurotoxicity is about 9.3%. Next slide. Now we shall go in -- dwell and deep dive on CRS. So 97 patient, CRS event was encountered in 92 patients, which is 95%. The median time to onset is 7 days. So this is quite different from other CAR-T cell therapy you would have heard about. This is delayed. And what is the advantage of that? That means not only you can give the lymphodepletion chemotherapy outpatient, you can also give the CAR-T cell as an outpatient. And later on, you can admit the patient as needed. And this pilot is actually going on, on CARTITUDE-2 or CARTITUDE-4 trial. So this is an important distinction. And then you could see what were the duration of this CRS. Typically, it's 4 days, but it has ranged 1 to 97 days. And the supportive measures that were used, you can see tocilizumab in 69% of the patients, steroids in 22%, Anakinra in 19%. Vasopressors to support blood pressure is very low, 4%. Intubation or mechanical ventilation, very rare, in 1% of the cases. And other drugs that have been used rarely in 1 patient, cyclophosphamide or Etanercept. So the cilta-cel CAR-T cells shows a maximum peripheral expansion at a median of 13 days. And you can see the CRS grade. Yes, the CRS happens in 95% of the patient. But look at them. It is predominantly Grade 1 or Grade 2. 5 persons had no CRS at all, and only 5% had greater than Grade 3 or greater. And there was 1 Grade 4 and 1 patient died of the CRS in this study. Next slide. Now the neurotoxicity. Here, what is the incidence of any neurotoxicity is it was seen in 20 patients or 21% only. And Grade 3 or greater, it was only in 10 patients or 10.3% of the patients. That's important to keep in mind. Then in this particular study, they were broken into ICANS and other neurotoxicities. But if you look at the other studies, they had grouped them together as a single one. Here, we kind of separated it out slightly to distinguish what kind of toxicity that happens. So the typical ICANS that happens at the time of CRS, any grade is 16.5%; and Grade 3 or greater, only in 2 patients or 2%. But there were some other neurotoxicities that were encountered: Again, any grade in 12%; and Grade 3 or greater, in 9 patients or 9.3%. And here, if you look at it, in the same patient view that ICANS could later on have neurotoxicity, that's a difference here. On this right-hand side, you have 16.5% and 12.4%. But overall, the total number any grade was 20 patients. It's 21%. Now in the other neurotoxicities that occurred after resolution of CRS or ICANS was in 12 patients. Five had adverse events, including movement or neurocognitive changes. And 7 patients had adverse events, including nerve palsy, peripheral motor neuropathy that was encountered. And you can see the time to onset median is 8 days. And for the other neurotoxicities, somewhat delayed, it is about 27 days, ranging from 11 to 108 days. Time to recovery for the ICANS is 4 days, within 1 to 12 days. It's acutely associated with the CRS. The other neurotoxicities is somewhat -- it occurs a little later, and recovery is somewhat more delayed. So the outcomes for the CAR-T cell neurotoxicity, ICANS resolved in all patients. The other neurotoxicities resolved in 6 patients and did not resolve in 6 patients. One patient has an ongoing neurotoxicity. This patient had a motor neuropathy palsy but is slowly improving. Now as soon as the palsy clears, that patient would have resolution of the neurotoxicity. One patient died from complication of neurotoxicity. Four patients died due to other causes before the neurotoxicity had resolved completely. No additional movement or neurocognitive adverse events were seen in the CARTITUDE development program, including the clinical trial, which is going on in Japan as well as in CARTITUDE-2 and CARTITUDE-4 programs. Next slide. So deaths are shown on this slide. Total deaths were 14, but treatment-related death due to AE was only 6. So that roughly amounts to 6%, due to: Septic shock, 2 patients; CRS/HLH and 1 patient, lung abscess, respiratory failure and neurotoxicity. There were adverse events unrelated to treatment in 3 patients, this including a para-influenza pneumonia much later in a patient who had fully recovered and then 2 patients developed acute myelogenous leukemia. In each of these patients, there was a preceding MDS with cytogenetic abnormality, including deletion 20q or loss of 5q. And another patient had prostate cancer and squamous cell carcinoma of the scalp. So the rest of the 5 patients actually died due to progressive disease. So again, to reiterate, mortality due to adverse event related to the treatment was only 6% in this study. Next slide. The overall response rate and MRD assessment is shown on this slide. This is phenomenally effective in this really advanced unmet medical need population. You saw an overall response rate of 97%. 94 of the 97 patients, actually partial remission or better. And most of the responses were VGPR or better. The partial response is only 4% in this case, so majority of VGPR or better, and 67% are actually stringent complete remission. Now if you look at the MRD negativity, it was done in 53 patients, and it was tested all 53 patients. You can see in the 57 evaluable patient, 93%. So what is meant by 57 evaluable patients? Because this was next-gen sequencing, we had to have a previous DNA fingerprint before we can do the next-gen sequencing. That was only available in 57 patients. So when we tested for MRD negativity in those evaluable patient, 93% were in MRD-negative status. MRD-negative and stringent CR, you can see, 33 patients or 58% of the patient; and MRD-negative and -- but greater than VGPR, 86% of the patient. But if we put it in all patient, 97, whether we were able to get their DNA fingerprint before starting, et cetera, that is shown there for all 97 patients for completeness' sake. The median time to first response is 1 month. Responses are ongoing in 70 patients. After evaluable patients, 93% achieved MRD-negative at 10^minus 5, and the time to achieve MRD negativity was very fast, within a month. And among the patients with 6 months individual follow-up, most had cilta-cel CAR-T cell below the level of quantification. So circulating cilta-cel, 2 cells per microliter, in peripheral blood was gone by 6 months. Next slide. And this gives you the progression-free survival. And you could see the overall 12-month progression-free survival is 76.6%. So the median progression-free survival is not reached at a median follow-up of 12 months. So in this study, the median follow-up was 12 months, and yet the median progression-free survival is not reached. And 76.6% of the patients are still in progression-free survival, something which is very remarkable. And the progression-fee survival by patient achieving stringent CR and VGPR is obviously better. Next slide. So in conclusion, cilta-cel has a manageable safety profile at the recommended Phase II dose. CRS was mostly Grade 1/2. Median time to onset is 7 days. CAR-T cell-related neurotoxicities occurred in 20 patients or 21%. 10.3% had Grade 3 or greater. Low dose of cilta-cel yielded early, deep and durable responses in heavily pretreated relapsed/refractory multiple myeloma. This is almost an unmet medical need population, 97% of overall response rate and stringent CR in 67%. Median progression-free survival is not reached with a median follow-up of 12 months, and the 12-month progression-free survival rate was 77%. Overall survival rate was 88.5%. Cilta-cel is under further investigation in other population of patients with myeloma in earlier-line settings, CARTITUDE-1, CARTITUDE-4. And last slide. So I definitely want to acknowledge the patients who participated in the study and their families and caregivers, especially in this difficult time, in an unmet medical situation where they had no other option with a lot of anxiety and hope; the physician and nurses who cared for the patient and supported the clinical trial; staff members at the 16 study sites in the U.S. that enrolled the patient; staff members involved in data collection and analysis. This study was funded by Janssen Research and Development, LLC and Legend Biotech. Medical writing support was provided by Jaya Kolipaka of Eloquent Scientific Solutions and funded by Janssen Global Services. Thank you.

Thank you, Dr. Jagannath. Before we transition to the moderated KOL event, reminder to please share your questions on the chat. [Operator Instructions] We will now invite Dr. Martin to join the discussion with Dr. Jagannath and Ying on to our moderated KOL session.

Thank you, Jessie, and thank you, Dr. Jagannath, for that presentation, very informative. I'm sure all the audience wants to know that your experience by treating multiple myeloma at Mount Sinai. Then -- so maybe you would ask Dr. Jagannath to first talk about your practice and also how you treat multiple myeloma. And then we will also ask Dr. Martin from UCSF to weigh in. So there's an interesting episode here for Dr. Martin, who is also another prominent doctor treating myeloma, because our first-ever U.S. patient on cilta-cel, or back then used to be called LCAR-B38M, actually was a patient referred by Dr. Martin. This patient unfortunately relapsed from the other treatments available here in the U.S., and then he flew over to China to get treatment. And we're pleased that he also achieved CR, complete remission, after treatment. So that's an interesting story I must share about Dr. Martin. With that, I'm going to turn over to Dr. Jagannath to maybe give us a quick introduction on how you treat multiple myeloma today. And also, in terms of CAR-T as a novel treatment modality, so which factors are considered by treating physicians in the field that are important versus other treatment options for myeloma?

Well, first, let me introduce myself. I'm Sundar Jagannath, Professor of Medicine at the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai. I'm the Director for the Center of Excellence for Multiple Myeloma at the Tisch Cancer Institute. I have been in this field for the last 31 years, moving to University of Arkansas with Bart Barlogie, and I was the Director of the transplant program from '89 to '98. Then I moved to New York and established the myeloma program, which has predominantly concentrated on relapse and refractory multiple myeloma, and have participated in all the registration trials, starting from thalidomide and lenalidomide and pomalidomide as well as the proteasome inhibitor VELCADE and carfilzomib and the monoclonal antibodies, et cetera. So as a physician who has been in this field for the last 31 years just in myeloma, this is a really interesting time in the field of multiple myeloma with CAR-T cell therapy and bispecific antibodies and the monoclonal antibodies, antibody drug conjugate, et cetera. So especially as I was thanking in my last slide, for patients who are participating right now in the CAR-T cell study, which was given in patients who were penta-refractory, these are patients who have already failed all currently approved regimen. And to be able to receive cilta-cel and achieve complete remission is a big dramatic bedside event for the patient, what a difference from almost dying to have the cancer disappear completely. And to find out that at the end of 1 year, the median remission is not reached, over 75% of the patients are still progression-free, that is indeed remarkable. And their quality of life, which was shown on the slide, is dramatic. After the onetime treatment with a CAR-T cell, these patients are back to work. They are back to their life. And of course, they are all stunned at what was happening to them. And some of them actually go through a stress period for going from almost dying to being feeling disease-free and feeling good. There is some adjustment there. So this is a dramatic period. Now coming back to the general question, actually, I would listen to Tom Martin on this, too. We are all very optimistic. You always try to approve this drug in an unmet medical situation in relapse refractory, but the best opportunity to use this drug is an earlier phase of the disease so that the patients are cured when the disease burden is low. And this is especially suitable for CAR-T cell therapy because the side effect of the CAR-T cell is these CAR-T cells recognize the tumor cells and then they expand. How much they expand partly depends upon the tumor burden, and the tumor burden decides how much side effect, how much CRS-related toxicity or ICANS you are going to have. And so if you're able to treat when the disease burden is lower and earlier, you would be able to eradicate the disease with less toxicity. So I think today's presentation, for me, about the take-home message of cilta-cel is almost every patient who got cilta-cel responded to treatment. Only 4% had partial response. So people who responded had VGPR or better, and this CAR-T cell therapy would be phenomenal as we move this forward in the earlier phase of the disease. I will now ask Tom Martin to introduce himself and give his feeling.

Yes. So thank you for having me. I'm from UCSF in San Francisco. And we also, on this coast, have a very large myeloma program focused predominantly in the relapsed/refractory setting, although we participate in the newly diagnosed trials also. But I don't think either Sundar or myself anticipated this being upon us so quickly. And we went from, 5 years ago, celebrating a 20% to 30% response rate from some drug to now having this therapeutic that produces a 95% response rate. That's unbelievable. And I would tell you, and I'll focus on the quality of life part, and I presented a quality-of-life abstract from cilta-cel at ASH this year. I encourage you to go look at my abstract. And patients had dramatic improvements in many parts of their essentially quality of life, improvements in fatigue, pain, physical function, just general life stuff. But that pales compared to sitting in the room with a patient who's 9 months or 10 months or 12 months or 15 months after a CAR, and they haven't been on therapy for that period of time. And they say, "I haven't felt this good since 20 years ago or 10 years ago or since before I had myeloma." This is game-changing, for sure. There were plenty of products at ASH. But universally, everybody is actually talking about this one, cilta-cel, because of the high response rates. And because at 12 months later, there's still 70-plus percent of patients that remain in remission. So this is a -- for me, it's a dramatic ASH. It's one to remember, and this has a big part of it.

Thank you so much for introducing yourself. And indeed, multiple myeloma is a rapidly evolving space. So my next question is, what is your overall impression of CARTITUDE-1 data presented at ASH? And where do you think cilta-cel might fit in the future multiple myeloma treatment landscape?

Yes. So I'll take that one first and maybe Sundar can answer after. So we do know that the bb2121, ide-cel, has submitted their packet to the FDA and also shows good responses. So I suspect that will successfully be FDA-approved in March or April. And we probably will start doing therapy soon thereafter, maybe by June. But this product will hopefully be approved soon thereafter, maybe within 6 or 9 months. And then we're going to have a choice. And that's a big -- it's a big difference when you invest all this time, money and effort into it in terms of the PFS. And we all know that the PFS for bb2121 is 12 months. And the data is extremely encouraging, encouraging from this CAR that the PFS is likely going to be more. I think we all know it's going to be more than 12 months, and we'll have to just see how much more. If it's 15 months or more, certainly, that's going to put a lot of enthusiasm into choosing this CAR. Probably, the other very important component is the CRS that Dr. Jagannath mentioned. And that the CRS occurs at 7 days after in almost everybody -- over 80% of the patients who had CRS had it after day 4. Now why day 4 is important? Because for us, for CMS and for reimbursement, we would love to give the lymphodepletion chemotherapy and the cells in the outpatient setting and keeping them outpatient for 72 hours and then can bill all that component under our outpatient billing procedures. And we get better reimbursement in that regard. So that in itself is also, in my mind, a game changer in terms of which CAR to use. We know in lymphoma, there's a couple of approved, but most of the lymphoma teams are going to the CAR that has the later CRS and allows for outpatient administration. So I'm extremely impressed by the data, and I think it probably will be the preferred CAR in 2021.

I think, Tom, you articulated it very well about the cilta-cel and its unique advantages, the improved overall response rate being high, progression-free survival being longer and the ability to administer the lymphodepletion and CAR-T cell in an outpatient setting before the patient care has to necessarily, if necessary, to move on the inpatient side. I agree on all those points. But I think for patients, access to CAR-T cell therapy at this time, because there are a lot of patients in this particular situation, will become critical. And hopefully, there will be a role for these CAR-T cells for patients with myeloma.

Thank you very much, Dr. Jagannath and also Dr. Martin. So I've got another questions here that is asking, for the 2 commercially available CD19-targeting CAR-T therapies, there was a so-called or tail of the PFS and also overall survival curves in the lymphoma patients there. Do you think that if there's any potential to see something similar in the BCMA-targeting CAR-T for the treatment of multiple myeloma?

At least, I'll take this one first. And then Tom, you can go after me. At least for the cilta-cel, there was long-term data that was presented from China on the LEGEND trial from the 2 institution you, Huang, who had presented in your presentation. And there, they had 3-year follow-up. And there were patients still in remission going on. So I think this is remarkable, granted that the patients who participated in the cilta-cel trial here were much more heavily pre-treated in the United States. But so far, looking at the PFS, it is almost matching what had been previously shown from China. So I have a good feeling that there will be a tail. But the tail proportion will continue to increase as we use this CAR-T cell therapy earlier in the disease. Right now, we have no choice, but we are using it in unmet medical situation where patients are penta-refractory or -- and so on and so forth. But hopefully, in the future, patient will be able to participate earlier as in Karma 2 or Karma 4 trials and the other studies from here. So we will see what happens there. Tom?

Yes. I agree. We hope there will be a tail. It's really hard to compare myeloma to non-Hodgkin's lymphoma diffuse large B cell. That disorder can be cured sometimes with autologous transplant, maybe up to 50% of the time. In myeloma, we maybe cure 10% of patients with autologous transplants. So the diseases are different. But wow, that would be great if we got a tail.

That makes sense. So Dr. Martin, you touched base a little bit on the meaningful PFS 12 month to 15 month for the doctors to choose one CAR over the other. So I guess my next question is related to that. Are there any standards for determining a clinical meaningful PFS increment to existing therapies for this patient population? And in addition, what are the key drivers for durability of response with CAR-T therapies in multiple myeloma?

I would say -- I mean, it's a good question. There's many answers to that question. But what Dr. Jagannath just said a minute ago was when we have something that is so active in the later lines of therapy, we do want to bring it to the earlier lines of therapy. And there are studies that are investigating this product in 1 to 3 prior lines of therapy, where we hope to see even higher response. It's hard to go above 95%, but maybe we'll hit 100%. But -- and then have the duration of the response be higher. What will be interesting is in the high-risk subgroup of patients, to see if we can get similar long-term responses in the very high-risk or higher-risk patients based on cytogenetics. That will be really interesting.

Yes. No, I -- picking up on what he said, first of all, the patients who participated in this clinical trial, they're all functionally high risk, whether they had deletion 17p or gain of 1q25, and those who did not, they were all ready for hospice because they have exhausted currently available treatment. So cytogenetic high risk is only one part of the story in multiple myeloma. These are all functionally high-risk patients. And as you pointed out, to get 95% response rate, and only 4 of them were even PR, most of them were VGPR or better. And in those where we were able to do the next-gen sequencing properly, they were also MRD-negative in most of the patients. I think to be able to accomplish that so late in the game, I feel that this is phenomenally good. It is even better than high-dose therapy melphalan. Melphalan wouldn't give you 95% complete response rate and VGPR rate. So I think this -- as a cytoreductive potential, it is phenomenal. And I have a belief that in that process, it would eliminate even the stem cells. And so patients would not relapse, and there will be a subset of patient who will be cured. And obviously, the cured fraction will be greater if you apply it sooner rather than later, when their immune system is also more intact. Then once you wipe it out, that the patient's own immune system make sure the disease doesn't come back, whereas these patients are really advanced refractory myeloma patients whose immune system is also not that great. So I think -- I have a feeling that this is really a game changer. And for me, who has spent 31 years in the field, I finally feel I can truly look in the eye of a patient and say there are potentially curative treatment options that have become available. And any newly diagnosed patients who's seeing me, I can say, "In your lifetime, there will be a cure," because I believe this CAR-T cell therapy like cilta-cel and bispecific antibodies will be available for these patients.

Yes. We're saying the same thing in terms of how great the responses are. And I actually -- I think Sundar believes this, too. It's going to take the place of autologous transplant because I think we both feel it's better than melphalan in terms of its ability to debulk myeloma. And in terms of the high risk, I want to take them from the get-go, from the minute they walk in the door, and give them one of these products because I think they'll go a lot longer in terms of their duration of remission from -- right from the start, which will be really interesting to watch.

So Dr. Martin, Dr. Jagannath, at this ASH, we heard quite a lot of exciting data from other BCMA-targeting treatment modalities, including bispecific antibodies and also allogeneic CAR-Ts. What are your views of those 2 treatment approaches in the treatment of multiple myeloma?

Tom, do you want to take it first?

Sure. So well, the fact of the matter is with CAR-Ts, there are going to be patients that can't make it to the treatment center and, for whatever reason, won't qualify for a CAR-T. And for those patients, we're going to have other options like these BCMA-directed bispecific T-cell engagers. It's going to be at least 2022 before we have one of those approved, in my mind. And so we're going to have a whole another year of CAR-Ts under our belt before we get those drugs in our hands and available, et cetera. I actually think they're going to play together nicely. I think they can work together either as a dual component for somebody that has relapsed disease or, if we use it earlier lines of therapy, that somebody presents with early relapse, they can get into remission with a cycle or 2 of a bispecific T-cell engager and then get a CAR and be off therapy. The advantage of the CAR and the advantage that every patient talks to me when I see them is, "Oh, my god, it's great to be off therapy." And so that's one of the big advantages.

I think you said it well. The CAR-T is a onetime treatment. And as you presented in the ASH on your poster, is their quality of life is phenomenally good, especially when you see the patient a year or 1.5 years later in your office. As you pointed out, that's the best time they ever had. First few months even goes into adjustment. It's like in traumatic stress syndrome, they were almost going to die, and now they have no disease and they are feeling good, almost like a guilt conscience. So I think that is the good. But as you pointed out, bispecifics are also needed. Both will play an important role. Patients who are elderly and frail, maybe bispecific may be a choice, 85-year-old, CAR-T may be better for younger patient. Just like we use autologous transplant, up to the age of 75, 80s, we had to use autologous transplant. We know it does improve the outcome. But still, we don't go and jump and give an 85-year-old an autologous stem cell transplant with high-dose melphalan because you have to dose modify. So I think there will be a way that it will pan out. Bispecific being off-the-shelf, it has some other advantages in terms of being applied in the community-wide compared to CAR-T cells in the center of excellences who typically do cellular therapy. So that would be another thing. But I also have seen patients who have failed bispecific, especially non-BCMA bispecific, and then went on to get CAR-T cell and go into remission. And then also the flip side, patients who had failed BCMA CAR-T cell therapy and then went on to non-BCMA-containing bispecific and went into remission. So we still have to understand the biology of the disease, who it will -- which one will work best. And also, there is a possibility of combination. So I think there are a lot of questions to be had. Today's data only shows the most important thing: will cilta-cel make the cut for overall response for an accelerated approval? Of course, yes, hands down, with the 95% overall response rate, absolutely. And with the PFS at 76% at 12 months with a median follow-up of 12 months, that is phenomenally great. So I think the product is fantastic. But the future, as we are developing all these things, the science is also progressing. So we would know how to use them sequentially, together or one over the other or which patient should get what, all of those will be slowly because we can't answer all of them today.

That's great to hear. So this is my last question for the day before I open the floor up to investors. So what is the biggest challenge in using CAR-T therapies in clinical settings?

Tom?

So I'll say the biggest challenge for us honestly is going to be to make sure that the community docs know when to refer a patient for a CAR-T cell therapy. That is going to be the most important thing. We all know now the 70-plus centers in the U.S. that do CAR-T cell therapies now have been doing them for a while in lymphoma. We know how to treat CRS. We know how to take care of neurotoxicity. We know how to put patients on prophylactic medications if we're worried about infection. We know how to do this. This is okay. We're not having a lot of treatment-related deaths because we're -- we know to handle the toxicities. We know how to handle them. Our biggest issue, in my mind, is going to be to make sure that these referral docs know when to send the patients so that we can get them the therapy that they need.

I think, Tom, you hit it on the nail. As I said in my presentation, there are patients whose performance here goes down very quickly. Even after collection, they couldn't even wait for the -- what is called as a lymphodepletion. Then there were patients who are progressing to very rapidly with all these things. And we do know that the CAR-T cells are better tolerated when the disease is under -- not massive disease in the patient because the CAR-T cell expansion and the side effects is related to that. So I think we can do, as you pointed out, all of the centers which are doing CAR-T cells. Now because of multiple usage and application, lymphoma, leukemia, myeloma, everything coming in, the experience in the so-called cellular therapy centers have improved. We know how to take care of them, how to avoid -- mitigate toxicity. But one of the critical element is choosing the patient and referring them at the right time so that they can actually benefit from the treatment with minimal toxicity. I completely agree with you.

Thank you so much, Dr. Jagannath and Dr. Martin. Now the moderated Q&A session is ended. We will open the floor for questions from the participants. Please feel free to submit your questions into the chat now and include your name and company, if possible.

This is Surabhi Verma from the Investor Relations team at Legend Biotech. For this section of the event, we're going to take some questions from the audience now. The first question comes from Matthew Harrison at Morgan Stanley. "Are there any correlations between the severe adverse events and the number of prior lines of therapy?" Ying, do you want to start us off?

I'll ask Dr. Jagannath to comment on this, please.

Yes. The more the prior lines of therapy, you could have the patient's performance status, et cetera, and the disease acceleration, et cetera, could be higher. But in this particular study, right now, all the patients responded, as you saw, 95%. So it will be very, very difficult for us to show the number of prior line therapy was somehow inferior in any of the outcome. So we cannot say that. But I think what Martin and I were alluding to is also asking the community physicians to refer the patient earlier rather than keep giving ineffective therapy to buy 3 months and 4 months of responses. I think these patients should be referred for CAR-T cell earlier. Thank you.

Dr. Martin, would you like to add anything to that?

The only thing that I would add is it really isn't the lines of therapy, but it's the bulk of their disease. So the people who have really bulky disease may have more CRS and may have more potential for neurotoxicity, and we know that. So we want to be able to give therapy to these patients who have bulky disease before they get their CAR-T cell. And in the clinical trials, what has been available to us has been to give them something they've had in the past. But there's going to be -- obviously, when it's approved, there's going to be an ability for us to give something they haven't had that potentially could debulk them before they get the CAR. So I actually think when it gets approved, we're going to have less toxicity than -- rather than more toxicity.

So I presume Matthew at Morgan Stanley also wanted to ask about specific neurotoxicity association. So we actually did not see any clear etiology in the neurotoxicity patients. But there may be some bio-association with the combination of factors, including high tumor burden, prior upgrade to a higher CRS, prior ICANS or in higher expansion persistence of CAR-T cells.

Great. The second question comes from Cory Kasimov at JPMorgan. So he says, "We spoke to J&J this afternoon, and they talked about the management of neurotox in ongoing studies that have minimized adverse events. Can you please comment on these amendments and their success in eliminating or significantly decreasing the neurotox?"

Yes. That's very good. When we realized that the patients who were progressing rapidly, and especially when they have received bridging chemotherapy and they were progressing on it, because as just now you heard Dr. Martin say that we were limited in what we could use as a bridging therapy in order for the FDA to assess the efficacy, they did not want any drug that was not previously given to the patient who's coming on. And of course, these patients were quite often exposed to penta-refractory. But you couldn't give something like DCEP or something which they've never had to reduce their tumor. You had to stick within that so that the FDA can assess what the CAR-T cell did. But that limitation mean some of these patients' disease could not be controlled, and they were rapidly progressing. And the earlier phase of the disease, we noticed that rapid progression of disease, and then you come and give the CAR-T cell, they expanded explosively and created much more CRS, and that they had some ICANS and then delayed neurotoxicity also. And once we said, okay, patients, if they are rapidly progressing after their bridging chemotherapy, they should not come on. And if the patients were deteriorating rapidly with the disease progressing, even if they start a lymphodepletion, we should stop it, and we should bring the patient later on. And so there, we held the CAR-T cells back. And we said, "You can treat them, but go ahead and get the disease under control and then bring them back." So once -- exactly like Tom Martin said, once we were able to make the patient in a much better situation and not coming at an explosive relapsed, uncontrolled, under that circumstances, a lot of things go wrong in the patient anyway, even without any other treatment in the -- by disease biology. So once we did that, I think it has not happened anymore. And that speaks for itself because this study itself, the last patient entered in February or something like that, but they have 9 patients accrued, and they're Japanese because they had to have their own approval, proof of principle, some patients have to be treated in Japan. Nine patient, none of them had this delayed neurotoxicity. And then they have CARTITUDE-2, CARTITUDE-4. They have additional patients treated. None of them have experienced this. So we really learned our lessons, and we have modified how we manage a patient and pay specific attention, what is the patient's clinical condition at the time you're infusing the CAR-T cell. That's really mitigated this toxicity. Thank you.

Ying or Dr. Martin, would you like to add anything to that?

So we do very aggressive management of CRS these days, too. And we're giving a lot of tocilizumab even with Grade 1 CRS or steroids to try to just turn down the heat because we know that the use of those drugs does not temper the responses in any way, shape or form. But it may actually help the snowballing effect of the immune activation. And so that's what we've been doing. And at UCSF, we didn't see any of the late neurotox. We had none of the late neurotox, and we are very quick to turn on the tocilizumab and the steroids as needed. And I think that, that's going to be everybody -- it was a learning curve for this one. Everybody's I think better able to pick out the patients who are the right patients for the study and/or for the therapy and also how to treat them very aggressively.

Well said.

Okay. Let's go to our third question. That comes from Yaron Werber from Cowen. What are the gating factors to filing cilta-cel for approval? Are all CMC elements checked on showing equivalents, original -- between original product in China and JNJ-4528?

Okay. Thank you. Thanks, Yaron, for that question. So this is Ying. I'll help answer that question. So what we can say is that J&J, our partner and also who is the IND holder of cilta-cel in the United States, remains on track to initiate the BLA filing with the U.S. FDA by end of this year. So stay tuned. We only have a few days left for 2020. And then in terms of manufacturing, what we'll say is that J&J and Legend teams are working very, very hard to ensure we have a robust manufacturing process to meet the regulatory standards of global regulators and also to meet the expected commercial demand from multiple myeloma patients. That's what we'll say. And in terms of our application in Europe and in China, again, our partner, J&J, plan to submit the MAA, the marketing application, in the Europe to the EMA in early 2021. So these are remaining the same. And then Legend also plans to submit the BLA filing to CD in China in 2021. So these are our time lines for regulatory submissions.

Great. So we also got another question from an investor. Ying, if you can comment on it. On the neurotox and how the 9 patients in the Japanese cohort and 41 patients in the CARTITUDE-2 did not experience any neurotox following the amendment in patient management. Also, any comments on how he sees -- on how you see BCMA CAR-T fitting in relative to bispecifics? J&J seems to think CAR-T likely -- is likely first or second line.

Thank you. So Drs. Martin and Jagannath already answered the question, but I can reiterate the fact that we did dose additional 9 patients in the CARTITUDE-1 Japanese cohort and also another 41 patients in both Phase II CARTITUDE-2 and also Phase III CARTITUDE-4 studies. And so far, we see no additional motor and neurocognitive events in those patients at all. And then again, as both Dr. Martin and Dr. Jagannath mentioned previously, Legend and J&J did implement mitigation strategies. So that allows the patients to have more bridging therapies, and that helps debulk the tumor burden. We have also instituted more aggressive steroid use for ICANS and also earlier interventions with the extensive monitoring of early signs of any late onset neurotoxicities. So that's the mitigation strategy J&J and Legend have been adopting. And again, like I mentioned, we're very happy to report that among the CARTITUDE-12 -- CARTITUDE-2 patients and also Japanese patients, we did not observe any further late onset neurotox.

Thanks, Ying. So the last question we have, "When can we expect data updates from CARTITUDE-2 cohorts? Which cohorts will be prioritized?"

Okay. I'll answer this one as well. So CARTITUDE-2 remains ongoing. And we have opened 5 cohorts, including the most recent cohort, the 5th cohort. That is expected to enroll patients with frontline newly diagnosed multiple myeloma with high-risk disease. And right now, we cannot produce -- we cannot provide any detailed guidance on the time line for reporting data. However, we do expect to start to report some of data in the year of 2021, again, depending on the status of the enrollment of each cohort and also how long a follow-up we will have for these patients in each cohort. So stay tuned.

That will be the end of the question-and-answer session. Thank you again, everyone, for joining the call today to discuss ASH 2020 data and your thoughtful questions. Best wishes for continued safety and health. You may now disconnect.