Great. Good afternoon, everyone. My name is Jessica Fye. I'm a senior biotech analyst at J.P. Morgan, and we're continuing the healthcare conference today with Legend Biotech. I'm joined on stage by the company's CEO, Ying Huang, and he's going to give a presentation on the business, and then we're going to go into some Q&A. Anyone in the room, you can raise your hand to ask a question, someone will bring you a microphone, or if you have questions you want to submit on the portal, you can do that too. So with that, let me pass it over to Ying.
Thank you, Jess, and I want to also thank J.P. Morgan for inviting Legend for this conference. So with that, I'm going to give a very brief overview of the company's operation, and then we'll go into Q&A with Jess, and anyone feel free to pose questions as well from the room. So first, standard disclaimer. We are a public traded company, and we are going to make some forward-looking statements here. For up-to-date disclosure, please go to our website and follow our filings with SEC. So Legend Biotech was founded in 2014, and it's more than nine years since the inception. We have grown tremendously in the last nine years.
Today, we have more than 1,800 global team members with about 1,000 in the United States, 500 in China, and 300 in Europe. Out of that, we have more than 300 research staff dedicated to research and development. Today, we're jointly marketing CARVYKTI with our partner, Johnson & Johnson. That is already approved in the United States, in Europe, and also in Japan. We're actually awaiting CDA approval in China. In our research pipeline, we're working on eight different programs covering both hematology, malignancies, and also solid tumor indications. Our R&D platform is based on three core technologies. So our first and lead product, CARVYKTI, is an autologous CAR-T targeting BCMA, and we're also working on allogeneic alpha beta T.
At the same time, in the research and also clinical stage, we're evaluating CAR NK, allogeneic modality, and also a gamma delta T modality that's also allogeneic. Jointly operating with our partner, J&J, we're actually working on six global supply sites for CARVYKTI. We do have a main site in New Jersey that is supplying all the commercial production of CARVYKTI today, and we have two sites in Europe. Both are in Ghent, Belgium. I'm pleased to announce that the first one just went into production, so we're actually live and up and running for clinical production in Obelisc in Ghent. The other one that is being constructed, it should be coming online by end of this year. We have two sites in China. So the first one is already GMP-ready.
That's where we have been manufacturing for the clinical supply for CAR-T Find One trial in China. And then we have another larger scale facility that just finished construction. We're actually in the process of installing equipment and qualification. Last year, we and JNJ entered into a three-way collaboration agreement with Novartis, with Novartis serving as our CMO, and we signed a three-year clinical supply agreement with Novartis. So that's another site in Morris Plains, New Jersey. As of September thirtieth, we had $1.4 billion liquidity, including cash, cash equivalents, and short-term investments. So CARVYKTI was approved by FDA in February of 2022, and this graph shows you the commercial launch trajectory.
Last quarter, which is the Q3 of 2023, our partner, J&J, reported a total revenue of $152 million in sales, out of which $140 million came from the United States and $12 million come from the European market. So if you look at the right side of the slide, you will see that, year-over-year, from Q3 2022 to Q3 of 2023, that represents 155% growth in the U.S. market. And from last quarter, Q2 of 2023, that was still a very respectable 23% quarter-over-quarter growth in the U.S. In Europe, we just launched in Germany last year, so globally, the quarterly growth was 30%, and the year-over-year growth was 176%.
That is actually a result of very successful launch execution by us and also by our partner, J&J. Both teams have been working on deepening our market share. In fact, last quarter in Q3, we had two-thirds of market share in the BCMA CAR-T field, with our competition getting about one-third of market share. We continue to improve our capacity from our New Jersey site. Last year, we received two FDA approvals in increase in the manufacturing capacity from our Raritan site. And also, we've been continuously increasing the number of hospital sites that can be certified to use CARVYKTI. At the end of 2023, we ended the year with 64 hospitals in the United States, which can use CARVYKTI and administer CARVYKTI. We're actually very proud of what we have achieved 6 quarters after FDA approval.
In fact, this graph shows you CARVYKTI launch, six quarters in from FDA approval, represents the best CAR-T launch in the whole category. So you can see from this graph that the bright red curve with a $152 million number that is the six-quarter launch curve for CARVYKTI. And compared to the other five brands, including Yescarta, we're actually supplying the best slots into the market, also the best revenue number six quarters in, and we continue to see that steep launch curve in the next few years. So this is a result of the best-in-class efficacy demonstrated by CARVYKTI in late line, and also now you have seen last year in second line plus in the phase 3 CARTITUDE-4 trial.
Also, it's a crystallization of our manufacturing effort jointly with J&J in terms of improving our capacity, reducing our out-of-spec rates, and also improving our manufacturing efficiency. So this shows you, again, we have the best-in-class manufacturing capability and also best supply into the market six quarters in. Our goal is to build the number one cell therapy franchise here at Legend. In the last nine years since inception, our team was able to build a fully integrated global leader in cell therapy. That starts with, of course, the market-leading multiple myeloma franchise. So, we have, again, jointly with our partner, J&J, filed the supplemental BLA with the FDA in June of 2023 for the second line indication. Also, we have filed the label expansion into the second line with the EMA in May of last year.
The PDUFA date for FDA to act on the second-line indication is April fifth, 2024. The application was supported by the randomized phase 3 study called CARTITUDE-4, which compared CARVYKTI to standard of care. It's a triple combination. 90% of the standard of care arm chose DPd, which is Darzalex, Pomalyst, and Dexamethasone. We have a compelling multiple myeloma efficacy and also a very innovative pipeline. So far, if you look at our trial in China, the phase 1 LEGEND-2 study, and also the joint study with J&J, CARTITUDE-1 in the U.S., that's the basis for FDA approval. We have consistently demonstrated best-in-class, deep and durable efficacy in late line.
In CARTITUDE-4, we demonstrated that compared to standard of care, we were able to reduce the disease progression or death from disease by 74%, with a hazard ratio of 0.26. That was published in ASCO of 2023. Additionally, we're also continuing to evaluate CARVYKTI in early lines, including the two frontline phase 3 trials, CARTITUDE-5, which we already concluded the global enrollment, and the US enrollment would also be completed this quarter. That is a total of 650 patients, 1:1 randomized between CARVYKTI and RVD. So these are for patients who either are not physically fit or young enough to get a transplant, or they decided to defer transplant. And the comparison arm is RVD, so it's a triple cocktail of Revlimid, Velcade, and Dexamethasone.
The other phase 3 trial we just recently initiated last year was CARTITUDE-6. It was also 1:1 randomized. Total enrollment is planning to be about 750 patients globally. We started enrollment in October of last year, so this will be comparing CARVYKTI with transplant and also DRVD regimen. Since we collaborated with J&J in the end of 2017, we have gained significant manufacturing experience that's developed through our collaboration here, including Lenti and also scale-up of Lenti, as well as the global supply chain operation for CARVYKTI in the sites I just mentioned in the previous slide. So that actually gave us the leadership in CAR-T manufacturing and also CMC capability. Right now, we're expanding this manufacturing capability in U.S., in Europe, and also in China.
And lastly, we do have an integrated cell therapy platform within the company, starting from early discovery research to early development, preclinical research, and also our clinical development capability. We have a differentiated R&D approach, because our goal is to come up with potentially best-in-class therapy, and also we have end-to-end capability. For example, in solid tumor programs, we have been using armoring strategy for the solid tumor indications, including the most recently partnered program, DLL3, with Novartis. That comes with a tandem binder design, and also there's an armor to improve the penetration of the CAR T cells into the organ and also overcome the immunosuppressive tumor microenvironment. We also have excellent antibody screening and engineering capability. In fact, you know, people always ask us, why do we see best-in-class efficacy here?
Because the company was formed in 2014. In 2016, we started our first in-human study called LEGEND-2, evaluating ciltacabtagene autoleucel in late-line myeloma. So it took us two years and hundreds of antibodies to screen. Finally, that came up the structure of CARVYKTI, which is best-in-class therapy for myeloma. We're also working on a very diverse platform for allogeneic treatments. If you look at our pipeline, we're working on allogeneic modality of alpha beta cells and also gamma delta T cells, as well as CAR NK. In fact, we do have two active phase 1 programs in China. One is BCMA-targeting CAR NK, the other one is BCMA-targeting CAR gamma delta T cells. We're dosing patients as we speak now. This describes our comprehensive global collaboration with J&J.
In Greater China, we have a 70-30 partnership, which means Legend leads the development and commercialization with 70% of the cost responsibility. Once the franchise is commercial, then we'll also derive 70% of pre-tax profit from the Greater China commercialization. Outside of Greater China, everywhere else in the world, we have a 50/50 partnership, including U.S., Europe, and also in Japan. In the U.S., we have opted in the co-promotion agreement with J&J, which means both our commercial teams and also their colleagues from J&J side are co-promoting and marketing and promoting for CARVYKTI use today. Japan and also Europe are what we defined as a Janssen territory, which means J&J is leading any commercial activities over there.
Since we entered into this collaboration in 2017, we achieved a $350 million dollar in the upfront payment in early 2018. Since then, we have achieved actually more than $330 million in milestone payments from J&J on different milestones of clinical and also regulatory milestones. CAR T is very complicated in terms of manufacturing CMC, and that is why sometimes people say that the process itself is CAR T, the product itself. So this gives you an idea of our global supply chain map.... In the United States, our main commercial facility is located in Raritan, New Jersey. That's where we have been manufacturing since 2019 when we manufactured for clinical trials, and now we're also supplying the global commercial production from Raritan, New Jersey. That is jointly operated between Legend and J&J.
And in the bottom, you will see that in Somerset, New Jersey, we also have our own GMP-ready clinical supply site for us, our own Legend, the proprietary pipeline programs. In the middle of the slide, you will see the two facilities we're actually are working on, again, jointly with J&J in Europe. Both are in Ghent, Belgium. The top one is a architecture rendering of the design of the greenfield facility. The total square footage is about 220,000 sq ft. We broke ground in 2021, and right now the construction is scheduled to complete by end of this year, so we're looking forward for clinical production to initiate at this site by end of this year. And then at the bottom, you will see there's a single standalone building. It's Obelisc site.
We're very pleased to announce that we just finished all the required regulatory process, and as we speak now, we're starting the clinical trial production from this Ghent site. That is for CARTITUDE-6 trial. And in about 6-9 months, we hope to start commercial production also from the same site in Obelisc building in the second half of this year. In the right side of the slide, you will see these are the two facilities we have in China. On top of that, this is a GMP supply site in a science park in Nanjing, where we have been manufacturing for clinical trials since 2016. And we hope to also launch our commercial production from this site once CDA approves in first half of this year.
Then in the bottom of this, there's a 75-acre campus which we're constructing, and the Building E just finished the physical construction last year. So that is going to be our future commercial GMP site for our cell to cell in China. Right now, we're actually qualifying our equipment and installation of all the equipment, so hopefully in the near future, we can start commercial production from the 75-acre campus. A little bit more detail in terms of how we expand our capabilities, because last year at the same conference, twelve months ago, we and J&J both announced that our goal is to exit 2025 with a global supply of 10,000 doses per year of CARVYKTI production. So how do we get there?
Well, first of all, I just mentioned that, we recently received the license from FAGG, which is the local, counterpart, in Belgium for FDA, for clinical supply manufacturing. And, we also finished the, IMPD process, and we received the GMP certificate. That is why we just recently started our clinical trial production from the Obelisc site, and, we're hoping to start commercial production from this site in the second half of 2024. A few years ago, we mentioned that in terms of the supply, there are two constraints. One is the, slot, the capacity, that in the U.S. actually is regulated by the FDA. The other one is the lenti, lentiviral vector, which is a very important drug substance that is used to transduce the CAR into the T cells.
So we're very pleased to announce that, you know, recently we did receive FDA approval for a J&J facility in Switzerland. That is a larger scale reactor for lenti supply. And, right now, all commercial CARVYKTI production, we use in-house supply of lenti, and, we are already at this point are self-sufficient. So going forward, we don't believe, lenti will become a obstacle or constraint anymore. Additional lenti supply expected, to come online include another facility in the U.S. in this year, potentially, and also in Netherlands, in 2025. So we're actually executing according to our plan on our global supply of lenti, which is, by the way, using the latest state-of-the-art suspension technology.
Lastly, as I mentioned, we executed into a three-year clinical supply agreement with Novartis last year, and we're on track to actually produce clinical material in the first half of 2024, pending FDA approval of the IND filed by Novartis. In November, we also announced that we entered into a global collaboration partnership deal with Novartis on the autologous CAR-T program targeting DLL3 for small cell lung cancer. With that, Novartis just paid us recently $100 million in cash for the upfront payment. Going forward, we're also eligible to receive up to $1.01 billion in total milestone payments. That include regulatory, clinical, and also commercial milestones. And once the product is commercialized, we're eligible to receive tiered royalty on net sales. So why do we do this?
Well, it's actually a win-win situation between Legend and Novartis because we bring our best-in-class binder and also our knowledge of the DLL3 biology here in coupling with the T-Charm platform of Novartis, which is a two-day manufacturing technology. That's the only fast CAR-T manufacturing that's been cleared by U.S. FDA for IND and clinical use. So, I would say a couple words on why we think that's important. Small cell lung cancer, if you look at the treatment today, the standard of care in frontline is chemo, and the median PFS in the U.S. is about 10 months. After the patient progress on chemo, it becomes really quick progressive disease.
So this is why, if you look at clinical experience with CAR-T, typically, you wait for one to two months before you can deliver experimental treatment to the patient after collecting blood sample. Now, with this two-day manufacturing, we can significantly cut down the time of delivery for this treatment to small cell lung cancer patients. That is why it's very important to use a very fast manufacturing technology in this indication. Right now, we are conducting the phase I for LB2102 in the U.S. We have already opened three clinical trial sites. We have already enrolled a few patients, and the first patient will be dosed very soon this month. After phase I, Novartis will take over, and they will conduct any further development, including manufacturing and also commercial activities. This is a very quick snapshot of our pipeline.
If you move to the right side, you will see these are the Phase II and Phase III programs in CARVYKTI, CARTITUDE, and also CAR-TFIN program. So as I just mentioned, we're actually still conducting a pivotal Phase II program called CAR-TFIN1 in China, and we have already submitted initial data to the CDA for approval. We're expecting a CDA approval in the first half of this year in China. CARTITUDE-1 was the basis for U.S., Japanese, and European approval for later indications. Based on that result, we received fifth-line indication in the U.S., fourth-line indications in Japan and also in Europe. CARTITUDE-2 is a multi-cohort Phase II trial where we're evaluating CARVYKTI in different settings of early multiple myeloma, including front-line settings. CARTITUDE-4 is the one we just submitted to FDA last year.
We're awaiting FDA approval and also EMA approval in the first half of this year. So pending approval, we are going to launch into second-line plus indication for CARVYKTI based on the results from CARTITUDE-4. And then CARTITUDE-5 is the phase 3 trial in front-line patients who are not transplant eligible or they decide to defer transplant. So this trial, as I mentioned, already finished global enrollment, and we're just trying to wrap up the US enrollment this quarter. Then we're going to be going into the follow-up phase. Last one is CARTITUDE-6. It's our front-line trial, head-to-head against bone marrow stem cell transplant. We just started enrollment in October of last year, and manufacturing recently started in our Ghent site for the first patient.
If you move to the phase I stage, most of these programs are proprietary pipeline programs, including the two ongoing phase I programs in the US. One is the autologous DLL3 targeting trial for small cell lung cancer, and then the other one is Claudin 18.2 targeting autologous CAR-T for gastric cancer. So both trials are enrolling patients and dosing patients in the US as we speak. The other trials I want to highlight, including a BCMA CAR gamma delta T program, which we initiated in China, and we have already dosed several patients. And also we're continuing to follow up the LEGEND-2, which was the first in-human study we conducted in 2016, and we just recently submitted the results also for publication at ASCO in 2023.
You see that, in fact, now we have a five-year follow-up for those patients, and we continue to see very deep and durable response. In fact, there are still a very large number of patients who are still alive and also in remission. About 18% of patients, after five-year follow-up, continue to be in remission state and alive. We're also conducting an allogeneic CAR NK program targeting BCMA for multiple myeloma. And there are two other ongoing phase I in China. One is GPC3 targeting for liver cancer, HCC, and the other one is a tri-specific CAR-T, CD19, CD20, CD22 CAR-T for non-Hodgkin's lymphoma and also ALL indication.
We're about to bring another solid tumor program into the clinic in the next couple of months, and that is an autologous GCC targeting CAR-T for colorectal cancer. So to wrap up my presentation, what is our focus for year 2024? So we continue to increase our manufacturing capacity in New Jersey and also in Ghent, as well as with the help from our CMO organization. Our goal is to begin commercial production in the first Ghent facility in Belgium, and then we're going to complete all global, including and also US, enrollment for CARTITUDE-5 in the first half of this year. We'll continue to enroll for CARTITUDE-6 and advance our early-stage programs. And very importantly, pending FDA and also EMA approval, JNJ and Legend are ready and committed to launching CARVYKTI for second-line indication in myeloma.
Longer term, our goal is to position CARVYKTI for early line, including front-line therapy, pending positive results from CARTITUDE-5 and CARTITUDE-6. Because we believe, scientifically speaking, there's very strong rationale to use this immunotherapy in the very beginning of the disease when the patient's T cells are very healthy and also, less exhausted. We'll continue to focus on unmet medical needs in our pipeline effort in both solid tumor and also hematology malignancies. Our goal is to develop cell therapies with transforming potential here, such as CARVYKTI, and, we continue to, increase accessibility through our initiatives to lower the cost of goods in manufacturing and also trying to scale up manufacturing in order to bring down the, cost.
Eventually, you know, we continue to build a leader in cell therapy by leveraging external collaborations such as the ones we signed up with both JNJ and Novartis recently. With that, I'm going to go into the questions with Jess.
Thanks for the presentation. So maybe we can start with kind of the outlook for CARVYKTI in second line. When you think about CARVYKTI moving upstream, what do you see as the key opportunities and maybe the key challenges as it relates to adoption?
Sure. So maybe we can talk about key opportunities here. What we have said previously is that if you look at the current addressable market for CARVYKTI in the three major markets we target, namely United States, Europe, and Japan. The total addressable market is about 20,000 patients per year. That's our current market under regulatory approval. Once we receive second-line approval from global regulatory authorities, that market will quadruple to about 80,000 patients per year. So that is the opportunity we're looking at. It's really significant compared to what we have today. Now, secondly, also, which patients in second line would be willing to get CAR T, right? So, after the ASCO presentation in June of last year, we and our partner conducted a large-scale physician survey.
That includes about half of the physicians from community setting and half physician from academic setting, based on CARTITUDE-4 results. So we're surprised that actually the average survey results suggest that the physician is willing to prescribe to about one third of second-line plus patients. This is actually above our initial forecast because we thought our initial early adopters for CAR-T in second line would be what we call high-risk patients. So these are patients whose cancer harbor certain cytogenetic mutations that render them really difficult to treat. They don't even respond very well to front-line regimens such as transplant and DRVD. But in addition to that 15%-20%, we're pleasantly surprised by the fact that there's another 15%-20% of standard-risk patients who are also willing to take CAR-T.
The reason is, CARVYKTI offers the convenience of once and done, and we don't require any follow-up maintenance therapy. So there are many patients who are still young enough. They would like to go back to work, they would like to travel, they would like to go about daily activities. That is why they're willing to take a one-time CAR-T treatment. On the other hand, we also demonstrate in CARTITUDE-4 that, compared to standard of care, has a ratio of 0.24, suggests that we're reducing the risk of disease progression or death from myeloma by 76%. So that's another strong, I guess, incentive for patient to use this. Now, of course, there are obstacles, right, compared to the opportunity. I think right now, CAR-T is by and large used in academic tertiary treatment centers.
Now, in order to target that second-line market, we have to branch into the community. The reason is, if you look at the late line opportunity, it's 80/20. About 80% of the patients are being managed at those tertiary academic treatment centers. Only 20% are being cared in community. Now, if you go to second line, it's actually reverse. Only about 20% of those second-line patients are being cared by tertiary treatment centers. So what do we do there? First of all, we are promoting for outpatient use. For example, last quarter, we already saw about one-third of CARVYKTI was being used in outpatient setting. So that actually renders that a possibility for a patient to receive a CAR-T treatment in the community setting.
We believe CARVYKTI is the only CAR-T out there that's actually uniquely positioned because the median time to onset of CRS is about 7 days, which means in the first week, you likely won't see that. While for any other CAR-T in the market or being developed, you're talking about immediate onset with the median onset at 1 day. So that gives us a very great opportunity to promote the outpatient use of CARVYKTI. And we're very pleased that, you know, year two in the launch, even in late line, we're seeing about a third of patients being treated in outpatient setting. So that is actually a very important initiative for our commercial team and also our colleagues at Janssen commercial team. As you know, J&J has a very significant presence in community.
Those sales force already are selling drugs, including Imbruvica and Darzalex. So they have a very large presence in the community, and we're going to educate the community physicians about the treatment benefit of CAR T. We also believe that it will be a patient-driven phenomenon, that is, patients know about this CAR T efficacy, and they also know about this one-time convenience. If you survey the patients, they will tell you that, "Hey, even though they're in remission off the RVD, they don't want to be reminded every day you have cancer because you have to take Revlimid every day. You have to take the injectable drugs every week, because that reminds you, you have cancer, you have cancer." That's actually a big mental burden for patients.
Also, if you think about it, if you have to travel, even just briefly for holiday to see your family, how do you deal with a refrigerated sample, right? It's very difficult. That's another reason why we see opportunity, because patients actually will want this one-time treatment so that they can go about their daily living.
What about the potential for frontline use of CAR-T, and I guess CARVYKTI in particular? What’s the bar for efficacy in both the transplant-eligible and ineligible settings?
Sure. So, typically, if a patient is newly diagnosed with myeloma, the-- if the patient is physically robust enough, the doctor would typically recommend a regimen of stem cell transplant. However, if you look at United States, only about 8,000-9,000 transplants are performed, even though every year, 36,000-37,000 patients are being diagnosed with myeloma. Why? Because, a, part of the patients, like about half, are not eligible. They're either above 70 years or older, or they're younger than 70, but their physical status is not ideal for a therapy such as a transplant. And the other half, why do only half of those then choose to receive transplant, even though they're eligible? Well, in order to get transplant, first, you have to subject the patient to a very high-intensity chemo drug called Melphalan.
That is associated with also mortality. About 5% of patients die in that process. And after treating with the Melphalan to wipe out the patient's immune system, you do the transplant of the stem cells, then you have to put the patient in hospital for weeks. So you're talking about weeks of hospital stay, very high-intensity toxic drugs such as Melphalan, and that is why many patients choose not to receive transplant. In fact, what we're seeing is that in the last couple of years, since introduction of commercial CAR T available in the myeloma, you're seeing every year the number of transplants being performed is going down already. So that is why, you know, we think there's a lot of adoption here for patient to choose over transplant.
Secondly, we always believed, even from day one of the CARVYKTI development program, that this immunotherapy is the ideal therapy for frontline, because that is when patients are relatively young and healthy, therefore, their T cells also are young and healthy. After cycles of immunosuppressive drugs such as Revlimid or Melphalan, then the T cells are exhausted. So when you collect the T cells, your starting material is weak, therefore, you don't get ideal efficacy. So why do you reserve the best therapy in the later lines? It doesn't really make sense economically or scientifically. So that's another reason why you want to use this immunotherapy as early as possible in the spectrum.
Lastly, if you look at economic benefit, so if in the US, if your patient receives a bout of standard procedure for transplant, the total treatment cost is about $400,000, which is no different from CAR T. Yet, you have to be subject to the hospital stay and also chemotherapy. Now, if a patient unfortunately cannot get auto transplant, you have to go to the allo transplant. Now, the cost is very significant. It's usually at about $900,000 for allo stem cell transplant. So if you look at the benefit we provide and also the economics here, in fact, we think CAR T can come ahead of transplant. Now, in terms of the bar, so we're conducting two phase III trials. One is CARTITUDE-5.
We're looking at the patients who are not eligible for transplant. Therefore, the standard of care is RVD, which is a tri, tri-drug cocktail consisted of Revlimid, Velcade, and dexamethasone. There, in the IFM 2009 trial conducted by Celgene for the approval of basis for FDA, the median PFS was 34 months in that regimen. So as you know, just in CARTITUDE-1, in mainline trial, we already demonstrate 35 months median PFS of CARVYKTI. So we have high confidence that in CARTITUDE-5, we'll be able to demonstrate superior efficacy in PFS compared to the standard of care. Now, in CARTITUDE-6, we're actually choosing a very difficult comp, that is transplant, followed by DRVD. So just last month at ASH, you know, based on the Pursue trial data, you see that there's a landmark analysis.
That regimen resulted in 84% PFS rate at 4-year, 48 months. So that is the bar we're going against in CARTITUDE-6.
What about the competitive landscape now? How do you see the use of CARVYKTI evolving relative to that of Abecma, you know, in the current indications and then down the line?
Yeah. So in Multiple Myeloma, there's only one gold standard for a treating physician to decide which therapy they would choose to use, that is PFS. So if you look at the KarMMa trial, the median PFS was 8.8 months. Even in the high dose, 450 million dose, the median PFS was about 12 months. In our trial, CARTITUDE-1, our median PFS was 35 months. That is why we think we have best-in-class efficacy, and as I mentioned in the Q3 last year, if you look at CAR-T BCMA as a field, we have about two-thirds market share, and the competition has one-third market share. So we feel really confident about the profile of CARVYKTI. Now, in early lines, again, BMS and two seventy are awaiting FDA approval in third line based on the results of KarMMa-3.
So over there, the median PFS was about 14 months. In CARTITUDE-4, with median follow-up of 16 months, we have not reached the median. In fact, if you overlay the Kaplan-Meier curve, it looks like we have deeper PFS curve than CARTITUDE-1. So we think at least it will be, you know, 4 years or longer in CARTITUDE-4 in second-line indication. So again, we think we have best-in-class efficacy in second line versus our competition in third line. At this point, we really have demonstrated that CARVYKTI really has the best efficacy in second line, third line, and various settings in CARTITUDE-2, based on the results we have seen.
Okay.
Oh, I think there's a question from audience.
Yes. Hi, this is Rick Xu from RSL. Just curious, for this CARTITUDE-6, you compared to the transplant, is designed a superior trial or non-inferiority trial?
Yes. So both CARTITUDE-5 and CARTITUDE-6 are designed for superiority.
Is that kind of little bit risky?
Based on the data we have seen so far, if you look at the curve for CARTITUDE-1, LEGEND-2, and now CARTITUDE-4, in both PFS and OS, we're seeing that there's what we call long-term tail effect. That is, there's, you know, about... Like I said, in LEGEND-2, it's close to 20% of patients. After five-year follow-up, those patients are still in remission and alive. So we think there's a chance we can beat transplant because in previous trials, down in myeloma, transplant has been shown to have significant PFS benefit, but not significant survival benefit so far in historical trials. So if we can see that, CARVYKTI not only improves on PFS, but also survival, we think there's a chance we can beat transplant.
We've gotten some investor questions around whether neurotox will hold back the use of CARVYKTI in the second line. What have you heard from the physician community, on the trade-off between efficacy and that, and neurotox risk?
Sure. So first, I'll talk about the data. In CARTITUDE-1 trial, we enrolled a total of 97 patients, and we saw 6 cases of so-called delayed neurotox or Parkinsonism. That's about 6%. But that was actually before we and our partner, JJ, knew anything about this delayed neurotox, because we didn't see anything in the phase 1, LEGEND-2 study we conducted among those 79 patients. So after we saw those 6 cases, we studied those 6 cases, and we found a couple of risk factors. For example, if a patient had very high tumor burden, you're talking about more than 60% of plasma cell in the bone marrow, that is high tumor burden, then, typically, you see very quick CAR-T expansion. Also, you see very high peak expansion for CAR-T. That correspond to this type of a specific neurotox....
Secondly, all these delayed neurotox actually corresponded to grade 2 or above CRS. So what you do is you tell the site to manage CRS aggressively, even though it's grade 1, maybe give them 2 shots of IL-1 or IL-6 antibody, then that address the problem. Lastly, every single case started with grade 1 neurotox. So right now, every single site that uses CARVYKTI, they administer this writing assessment test. Basically, you just ask the patient to sign their name whenever you suspect there might be some neurotox. If they sign their name with very tiny characters, also, if you look carefully at the characters, everyone comes with those tiny twists and turns. That is a very good telltale sign of this type of neurotox.
Once you see that, you start a standard 4-week course of oral steroid, that resolves more than 90% of the cases. So after we and J&J instituted that risk mitigation strategy in CARTITUDE-2, CARTITUDE-4, and 5, 6 trials, we saw a dramatic decrease in incidence. For example, in CARTITUDE-4, we reported at ASCO, among 208 patients randomized to CARVYKTI arm, we saw only one grade 1 case. So we were able to lower the Parkinsonian from 6% in CARTITUDE-1 to now 0.6% of Parkinson grade 1 in CARTITUDE-4. So based on that data, we think clearly there's overwhelmingly positive risk-benefit here in second-line. Now, in terms of physician feedback, I don't think it will be held back. Like I mentioned, when we conducted a large survey, we gave the full dataset, including all the safeties findings, to the physicians.
Again, they tell us that they would like to prescribe CARVYKTI up to one-third of their patients in second-line.
Maybe sticking with safety, what impact, if any, do you expect from the updated labeling on secondary malignancies?
Sure. So maybe I want to give a little bit of context on this, because we were asked by investors in the last 2 days here that, why was CARVYKTI or why were JNJ and Legend singled out? Well, that's not the case. In February of last year, we went to the FDA asking for label update because we have this minimum 2-year follow-up that was presented at ASCO for CARTITUDE-1 that showed a material PFS of 35 months. So we asked the FDA to write this updated efficacy data in the label, and we had a PDUFA date of December 23 last year. So 2 weeks before that date, the FDA said, yeah, they will approve this efficacy update in label.
But given all the SPM news and everything, they also asked to put us, detailed information about SPM in the label as well. So we're not singled out. It's simply that it is a regulatory, process we're already in, and then FDA just asked to put our details in. And I want to say something about that, too. So, we saw 10 cases among nine patients because one patient had both AML and MDS. So we saw those, 10 cases among 97 patients. It sounds scary, right? Because you guys do the math, it's 10% SPM. Well, if you look at the, data, you will be, scared much less.
First of all, if you look at the background, there's a paper that came out at ASH last last December that showing that among the triple class exposed patients, so those patients have all been treated with an oral IMiD, an injectable proteasome inhibitor, and also dexamethasone. The annualized rate for AML and MDS is about 3%. So if you do the math, right, every year is 3%. We started CARTITUDE-1 trial back in 2018, so it's been already five, six years. The accumulated rate of 10%, it's not really higher than the background rate for those patients in this treatment category at all. Secondly, the median onset of this AML, MDS is 485 days, about one and a half years already.
You guys know that among those patients we treated, these are patients who failed everything on the market already, typically without CARVYKTI. The PFS is 4 months, and they die within 8-9 months. So the fact that these patients are seen with second malignancy, about 1.5 years later, it's actually a good thing because that means they actually lived that long to see this, right? And also, these patients, out of the 10 cases, 4 progressed on CARVYKTI, then they received further therapies, which we don't even know the details about. Then they were diagnosed with those SPM, but still, out of the abundance of caution, FDA asked us to write that in, right? So 6 cases happened within the CARVYKTI trial, right? The other 4 happened later.
If you look at the reason of the death, five actually died from other adverse events, such as respiratory failures or septic shock.
Okay, great. Well, we're out of time, so we'll leave it there. Thank you.
Thank you.