Legend Biotech Corp

NASDAQ:LEGN

Earnings Call Transcript 2024-Q3

[Operator]

Ladies and gentlemen, thank you for standing by. Welcome to Legend Biotech Reports Third Quarter 2024 Financial Results.

[Operator Instructions]

Please be advised that today's conference is being recorded.

I would like now to turn the conference to Jessie Yeung, Vice President of Investor Relations and Finance. Please go ahead.

[Jessie Yeung, executive]

Good morning. This is Jessie Yeung, VP of Investor Relations and Finance. Thank you for joining our call today to review our third quarter performance. Joining me on today's call are Ying Huang, the company's Chief Executive Officer; and Lori Macomber, the company's Chief Financial Officer. Following the prepared remarks, we will open up the call for Q&A. We have our Chief Medical Officer, Mythili Koneru; and our SVP of Commercial Development, Steven Gavel, joining the Q&A session.

During today's call, we will be making forward-looking statements, which are subject to risks and uncertainties that may cause our actual results to differ materially from those expressed or implied here within. These forward-looking statements are discussed in greater detail in our SEC filings, which we encourage you to read and can be found under the Investors section of our company website.

Turning to our highlights. In the third quarter, we are pleased that CARVYKTI continued their strong momentum, delivering quarter-over-quarter growth of 53% and year-over-year growth of 87%. We are also very excited about the results from the second interim analysis from the CARTITUDE-4 trial, particularly the overall survival benefit that CARVYKTI achieved. These results were announced as a late breaking our presentation at the International Myeloma Society Meeting in Brazil in September, and they received an enthusiastic response from health care providers around the world.

Now I am pleased to turn the call over to our CEO for his remarks.

[Ying Huang, executive]

Hello, everyone. I'm glad that you're able to join us and hear about our recent accomplishments. As you can see on Slide 5, it's been another eventful quarter for us as we continued to make significant progress against our strategic priorities. I'd like to start by expanding on the importance of CARVYKTI, achieving overall survival benefit in the second line plus patient population.

Let's turn to Slide 6. To frame this achievement precisely, are is the first and only cell therapy to significantly extend overall survival compared to standard of care in patients with multiple myeloma as early as the second line. Specifically, CARVYKTI reduced the risk of death by 45% versus standard therapies after a 3-year follow-up period. Reaching this milestone is monumental for the company, for the marketplace, health care providers and patients. It puts CARVYKTI in the enviable position of providing patients with longer lives, what some call the holy grail of oncology clinical trials. Hand in hand with overall survival, CARVYKTI has also maintained significant improvement in progression-free survival as compared to standard of care. Also at the International Myeloma Society meeting, a real-world analysis of CARVYKTI efficacy and safety was also presented. The results demonstrated the importance of risk mitigation and the critical learnings from our development program and real-life experience with CARVYKTI. It is noteworthy that with over 4,000 patients treated we see a very low incidence of parkinsonism. And FDA public safety data also suggests that this condition is likely a class effect. As you know, the prior positive interim data from CARTITUDE-4 resulted in FDA and the European Commission approving carves use in second-line study for relapsed and refractory multiple myeloma patients. We, along with our collaboration partner, Johnson & Johnson, are planning to submit the Certitude for overall survival results to regulatory authorities in the U.S. and Europe in order to update our label with these new paradigm shifting results.

In third quarter, we also received approval for CARVYKTI from China's National Medical Products Administration for treatment in the fourth-line plus in. We are pleased that CARVYKTI continues to gain recognition from health care regulators around the world for the significant clinical benefits our onetime infusion provides. Importantly, for the OUS, Rest of the world market, we have expanded our ability to produce CARVYKTI for patients in Europe.

Moving to Slide 7. In September, we received approval to produce Cavity commercially at our facility called Obelisc in Ghent, Belgium. This is a critical component of our plans for serving patients in Europe and beyond. Congrats to the team in Ghent for securing the approval in what we believe to be record time. It's another demonstration of Legend's commitment to expediting delivery of CARVYKTI to all patients who can benefit from it worldwide.

Moving to Slide 8. In third quarter, net trade sales of Cavity were approximately USD 286 million, which, as Jessie highlighted, is an 87.6% increase year-over-year and a 53.2% increase quarter-over-quarter. The robust quarter-over-quarter performance was aligned with our expectations of accelerating growth in the second half of the year and was driven by continued demand, particularly strength in the second-line demand share against continued capacity expansion and manufacturing efficiencies. We are firing on all cylinders, and we expect sequential growth into the fourth quarter. We look forward to treating many more patients in need in the months and years to come. Our OUS sales increased over 100% year-over-year and 35% quarter-over-quarter. Thanks to our increase in capacity and ongoing launch expansion.

In the third quarter, CARVYKTI became commercially available in Switzerland and I am pleased to share that Swissmedic just updated label expansion to the third line plus treatment. Switzerland is the fifth country where CARVYKTI is now commercially available to patients along with United States, Germany, Austria and Brazil. In the United States, we continue to certify more hospitals as authorized treatment centers. The total number of U.S. hospitals that are approved to treat CARVYKTI patients is now 82. Recall that CARVYKTI has a unique delayed CRS onset profile that allows for extensive outpatient administration.

As you can see on Slide 10, outpatient treatment now compromised up to 48% of our volume and is a significant growth opportunity for us to reach even more patients. Usage in the outpatient setting is very important as we expand further into the community setting. This is a key consideration for hospitals as they seek to optimize allocation of limited bets and resources. Patients and their caregivers often prefer to check out the hospital after treatment. The option for outpatient treatment is a real differentiator for CARVYKTI as the number of patients increases. CARVYKTI now achieved nearly 90% market share in the BCMA CAR-T class of sales in the U.S. and Germany, and it continues to be the fastest launch CAR-T product on the market.

With the explosive growth of CARVYKTI and our evolution as a company, we're excited to announce that recently, we appointed a President of CARVYKTI business unit, Alan Bash. Alan will be responsible for managing the continued growth of CARVYKTI, overseeing Legend's commercial, technical operations and quality functions of the franchise. Prior to joining us, Alan served as the CEO of 2 oncology focused about the companies, most recently at Zovio and prior to that at Checkmate Pharmaceuticals. Before that, Alan had a 23-year career with Bristol-Myers Squibb, where he held various leadership positions across all major therapeutic areas, including oncology, where he drove the expansion of products such as Opdivo, Yervoy and Erbitux. Alan also contributed to several blockbuster products in collaboration with other companies, such as Abilify with Otuka and Eliquis with Pfizer. We welcome Alan to the Legend family and look forward to introducing him to many of you soon. Turning to midterm growth for CARVYKTI and Legend. We are pleased with the pace of enrollment for our first-line trial CARTITUDE-5 and CARTITUDE-6. As you may know, CARTITUDE-5 is fully enrolled, and we expect to complete enrollment for CARTITUDE-6 next year. The speed of enrollment in these trials is a testament to the benefit risk profile of CARVYKTI, demonstrated by our growing body of positive clinical trial results.

Looking at longer-term growth for Legend. We recently announced a new research facility being built in Philadelphia, which is a growing hub for biotechnology companies. The new site essentially located among some of the top research institutions in cell therapy and provides potential opportunities for collaborations, which would expedite our innovative cell therapy research. We expect to be up and running in the summer of 2025, and we look forward to updating you on the progress of this exciting project.

To summarize the third quarter, it's been another quarter where we executed with excellence, which sets us up for a strong finish to the year.

Now it's time to take a closer look at the financials. So let me turn the microphone over to Lori.

[Lori Macomber, executive]

Thank you, Ying, and good morning, everyone. As Ying mentioned, we generated approximately $286 million in total net sales for CARVYKTI during the third quarter, an increase of 87.6% year-over-year. As a reminder, we share equally in all profits and losses of CARVYKTI ex China with our partner, Janssen.

As you can see on Slide 12, total revenues for the third quarter were $160 million, consisting of $143 million in collaboration revenue from the sale of CARVYKTI and license revenue of $17 million from the recognition of deferred revenue in connection with our agreement with Novartis to develop manufacture and commercialize LV 2102 and other potential CAR-T therapy selectively targeting DL3. Net loss for the quarter ended September 30, 2024, and was $125 million or a loss of $0.34 per share compared to a net loss of $62 million or a loss of $0.17 per share for the same period. For the quarter, unrealized foreign exchange losses of $63 million was incurred primarily due to intercompany transactions and balances between the U.S. and non-U.S. legal entities. For the same period last year, million in unrealized foreign exchange gain was reported.

Moving on to expenses on Slide 13. Collaboration cost of revenue for the third quarter of 2024 was $52 million compared to $43 million for the same period last year. These are Legends portions of collaboration cost of sales in connection with the collaboration revenue under the Janssen agreement, along with expenditures to support the manufacturing capacity expansion. Additionally, cost of license and other revenue for the third quarter of 2024 was $3 million compared to no cost of license and other revenue for the third quarter of 2023. These caused a connection with our agreement with Novartis to develop, manufacture and commercialize LV2102 and other potential CAR-T therapies, selectively targeting DL3.

Research and development expenses for the third quarter 2024 were $96 million, similar to the same period last year. These expenses are primarily due to research and development activities in Sitael, including startup costs for clinical production in Belgium as well as continued investment in our solid tumor program. Administrative expenses for 3 months ended September 30, 2024, were $35 million compared to $28 million for the same period last year. The increase of $7 million year-over-year was primarily due to the expansion of administrative functions and infrastructure to increase manufacturing capacity.

Selling and distribution expense for 3 months ended September 30, 2024, was $44 million compared to $21 million for the same period last year. The increase of $23 million year-over-year was due to costs associated with the commercial activities for CARVYKTI, including the expansion of the sales force and support a second-line indication launch. Other expenses were $62 million for the 3 months ended September 30, 2024, compared to $0.1 million for the same period last year. This increase was almost entirely driven by unrealized foreign exchange losses for the 3 months ended September 30, 2024. In the same period last year, there were no unrealized foreign exchange losses. The unrealized foreign exchange losses were primarily driven by intercompany transactions and balances between the U.S. and non-U.S. legal entities related to research and development activities.

To summarize, our spending remains on track, and we continue to maintain a strong balance sheet. As of September 30, we had $1.2 billion in cash and equivalents and time deposits. Thus, we believe we have sufficient capital to fund our operating and capital expenditures into 2026 when we expect to begin to achieve an operating profit.

Thank you. I will now pass it back to Ying for closing remarks.

[Ying Huang, executive]

Thank you, Lori. Moving to Slide 14. We are excited that we had so much good news to share from this past quarter, and we could not have done it without dedication of our 2,400 team members globally. Their commitment inspires me every single day, but we continue to have lots of work ahead of us, and we strive to execute our strategic priorities.

Before we take your questions, I'd like to share context on the recent development. After our Annual General Shareholder Meeting in October, GenScript announced that they will deconsolidate Legend from their financial statements as they're no longer a majority shareholder of the company. This has no material impact on our operations as Legend has operated as a separate company since our spin-off and IPO in 2020.

Now it's time to take your questions. Operator, we're ready for the first question, please.

[Operator]

[Operator Instructions] Our first question will come from Gena Wang with Barclays.

[Huidong Wang, analyst]

Maybe I will ask 2 questions from -- the first question is regarding, I think, the upcoming data update investors have been very focused on CARTITUDE-1 comparison to [indiscernible] imaging 1 heading to ASH update. And now we see the ASH abstract, and we are going to see the full data at ASH in 3 weeks. So what are the key data points that investors should focus along regarding efficacy and safety?

And quickly a follow-up question regarding the OS benefit. We showed the data for a when should we see the OS benefit to be included in the NCCN guidelines and in the label, where are you in terms of the steps?

[Ying Huang, executive]

Gena, thank you for the questions. I'll take the first one. So we already saw the baseline from the IMAGINE-1 trial. And you can tell that from every metric we look at, including the number of prior lines of therapy, the percentage of only 3 pipelines of therapy, the triple refractory patient population, the penta-refractory population, I think we can conclude that clearly, the patient population in IMAGINE-1, is less sick than the patients we enrolled in CARTITUDE-1. That's first.

Now we don't know, for example, some other metrics, including the percentage of EMD patients, but that might be another metric that could tell us more, right? But even compared to their own Phase I trial, this is an easier-to-treat patient population, suffice to say.

Now secondly, if you look at efficacy, we did present CARTITUDE-1 with about a 12-month follow-up at ASH 2020. And again, if you look at the ORR rate, which is 97% and then the CR rate, it's 67%. But I want to mention that all every CR we observed is a stringent CR. Again, we would like to see whether the other party breaks down the percentage of CR versus stringent. However, as you may know, in myeloma treatment, it's always about durability. For that, unfortunately, we will not get much data from the other party. And we stand behind the consistent results we have seen from CARTITUDE-1, CARTITUDE-2, CARTITUDE-4 and all trials across all the settings. So I think it's all about durability, it's about PFS. And we have 3 years -- nearly 3 years PFS in the last time patient population as demonstrated in CARTITUDE-1.

So regarding your second question, I'm going to ask Steve to comment on maybe NCCN.

[Steven Gavel, executive]

Yes. Its...

[Huidong Wang, analyst]

Sorry. Sorry, Ying. also regarding safety. Can you comment?

[Ying Huang, executive]

Sure. I mean, we do understand that if you use a proactive management strategy in terms of selecting patients and also managing patients with both IL-6 and steroids, it can be very effective. In fact, if you look at the history of CD19 CAR-Ts, right? If you recall almost 10 years ago, there was a perception that maybe the June of CD19 was not as safe as the credit CAR-T. Yet in real life, I don't think it's been that case, right? If you look at the real-world CRS and also neurotox. So clearly, a lot of that has to do with the patient selection and also management. And we are already starting to institute those and we're talking to KOLs about this. You will see more data at ASH as well.

[Steven Gavel, executive]

Yes. It's Steven. What I was saying is that it's hard to predict the guidelines in terms of when they will be updating them in terms of new data that we would be expecting an update sometime by the end of the fourth quarter.

[Ying Huang, executive]

And Gena, just to supplement, we and our partner, Johnson & Johnson, are planning to submit the overall survival data in a supplement to both FDA and EMA in the near future. So we do expect that will be reflected in the label in both U.S. and Europe by end of next year.

[Operator]

And our next question comes from Yaron Werber with TD Cohen.

[Unknown Analyst]

This is Dana on for Yaron. Congrats on your quarter. I have 2. Obviously, for the first one, you had a strong Q3, but I'm curious how we should think about quarter-over-quarter growth going into Q4? Should we expect the same kind of cadence or is most of kind of the growth driven from the additional manufacturing already realized in Q3?

And then secondly, I think you've noted in the past that key limiting factor for BCMA CAR-T supply is the FDA cap on CAR-T production? Is this just for BCMA CAR-T because we're hearing that Gilead was never limited in their volumes for Yescarta and Tecartus. So what do you think that might be?

[Ying Huang, executive]

Sure. So let me address the first question about sequential growth in the fourth quarter. I think you have heard from both the Legend and Johnson & Johnson teams, reiterating that we confirm we will expect sequential growth in the fourth quarter. Now it is our policy not to comment or provide guidance. So I'm not able to give you any quantitative guidance. But yes, we are reaffirming sequential growth. Even though we have a fantastic growth rate in the third quarter already, but we still expect to see higher revenue number in the fourth quarter.

So regarding your second question, I guess what we can tell is that from the BCMA class in both experience for Avecma from Bristol and also for CARVYKTI from J&J and Legend. Yes, in both cases, FDA did regulate the capacity. Now I would refer you to ask Kite about their capacity for CD19. But our understanding is that a regulator does regulate or CAR-T manufactured facility capacity. It's not just even for franchise but also for each individual facility that produces CAR-T. You can also download the FDA review documents on the FDA website of the process and also how FDA determines the capacity.

Sorry. I also want to add that if you look at the performance of all commercial CAR-T brands in the market, 10 quarters in since FDA approval of CARVYKTI in February of 2022, we have been able to supply the market with the highest number in terms of revenue and also slots.

[Operator]

And our next question comes from Kelly Shi with Jefferies.

[Dingding Shi, analyst]

Congrats on the progress. So for the second line launch, can you elaborate more on the ramp-up of [indiscernible]. How should we think about it comparing to baseline launch given that now we are 2 quarters after the approval in early line? And also, do you expect a majority of the -- majority use of CARVYKTI shifting to early line from main in near future?

[Steven Gavel, executive]

Yes, why don't I take that question. It's Steve. Thanks for asking. Why don't I start with the second question first and the question, I think had to do with a percentage of patients in our CARTITUDE-1 versus CARTITUDE-4 indications. We expect to be exiting next year, for example, with the overwhelming majority of our patients treated to be in the CARTITUDE-4 population, something in terms of a ratio of 2/3 to 1/3. In terms of where we are right now for this particular year, we are well ahead of where we thought we would be in terms of early line adoption. I think that's built off a number of different things, most notably, the most recent overall survival data that we're coming out with now. So we expect that trend to continue and accelerate to where we would expect to be next year. But terms of where we're pacing right now for the year, we're outpacing where we thought we would be in terms of our CARTITUDE-4 launch. I don't think there was any other follow-up questions to that. Let me look here. I think that's it.

[Operator]

And our next question comes from Jessica Fye with JPMorgan.

[Jessica Fye, analyst]

My question is on just how we should think about the evolution of the mix of inpatient versus outpatient use. Specifically, is the shift that we're seeing driven by the conversion of existing treatment sites to more outpatient use? Or is that more a function of the new sites coming online as outpatient sites. And can you also just remind me where you think that proportion of inpatient versus outpatient could be looking out, say, 12 months from now?

[Steven Gavel, executive]

Yes, I'm happy to take that question. It's an important one. We've been monitoring this since our launch of CARTITUDE-1. So just to kind of back up to your point, the reason why -- and the reason why I think in was highlighting this in his opening on why it's so important is as we were launching our initial indication, we had basically our eye on the second indication, knowing that with the volume increase going into second line plus, it would be substantial. And it would be something that would be unprecedented in terms of the marketplace in terms of volume of CAR-T eligible patients hitting our hospitals. So it's the reason why you've seen rapid adoption almost up to 50%, and in some cases, at 50% in certain sites. So what's driving to your question about what's driving the adoption is primarily due to the fact of sites recognizing the volume impact that they will need to absorb and as a strategy to account for that many sites have now moved to as much as possible outpatient use where appropriate. Where you see inpatient use in sites that have adopted the outpatient model are in the higher-risk population, which makes sense. You see those patients often be admitted upon administration. So I think 1 of your question was -- so that hopefully speaks to what's driving the outpatient adoption.

You had a question about who's adopting? Well, we're seeing pretty much wide adoption across the board. The primary adopters are those large major academic sites in the United States, really kind of our top 18 sites that are driving the majority of our volume anyway. As sites come on board, new sites come on board, we see typically, and this is true with even our early adopting sites it takes some time for these sites to get going in terms of the outpatient setting. And the reason for that is the providers really just need to get enough patients on product to see how these patients are reacting and compare that to our label to get some real-world experience. So you see kind of a slower adoption, and we've seen that pretty much consistently with any new site that we have onboarded as far as our commercial footprint in the U.S.

[Operator]

And our next question comes from Umer Raffat with Evercore.

[Jonathan Miller, analyst]

This is Jon on for Umer. Congrats on the quarter and I'd love to start with 1 on the drivers of neurotox evolution across your trials. Obviously, you mentioned management patient selection being very important there. But where do you think the tolerability profile could go in the future for CARVYKTI, is it possible to control this even further going forward and to eventually get a better safety profile in the label?

And then secondly, maybe since nobody has asked about it, I'd love to get the latest update on your autoimmune progress. I know you're in Phase 1 there, but what are you seeing from a patient enrollment perspective? And when could we see potential data.

[Ying Huang, executive]

So Jon, I am going to ask our Chief Medical Officer, Mythili Koneru, to ask -- to answer the first question. My?

[Mythili Koneru, executive]

Yes. Thank you for your question. So regarding the neurotoxicity profile, you can see that compared to the CARTITUDE-1 and the CARTITUDE-4 data, we've seen a significant decrease in the delayed neurotoxicity including the Parkinsonism. And I think that's a testament to the improvement in the management of these patients. So improved in terms of decreased tumor burden, appropriate like identification of these patients, et cetera. So clearly, there's currently with the CARTITUDE-4 less than 1%, which I think is important to mention.

In addition, moving forward, we've identified additional factors that we think can further drive this down. And we talked to many KOLs that are already using this in the sort of the commercial setting. And as Ying mentioned before, competitors are using actively in their studies, which is the steroid use. And what we found is that absolute lymphocyte count or ALC is a good early indicator potential rapid expansion and application of steroids in that setting does potentially mitigate this delayed neurotoxicity. And this is something that the KOLs have described to us and that they're actively doing in the commercial setting.

So really good bridging therapy and sort of monitoring -- active monitoring of the ALC. We both -- we feel that both of these are important mitigations to potential neurotoxicity.

[Ying Huang, executive]

And also, Jon, I'd like to also mention that for our potential competitor, it's not fair for them to compare our data from 4 years ago when they compare efficacy. But then when they talk about safety, again, why don't they compare to our current data, right, where we do see a dramatically lower incidence [indiscernible] in the CARTITUDE-4 trial and also in real world, the physicians have been gaining experience in terms of how to manage that, and it is lower again than what we observed in CARTITUDE-1.

Now on to your second question about our autoimmune program. Yes, we have officially kicked off our first in-human study for the trispecific CD19, CD20, CD22 targeting CAR-T for autoimmune indications. And we have already opened our first site. Enrollment is ongoing now. But besides that, we also are working on a couple of other programs that are allogeneic again, targeting autoimmune indications. So that should go into first-in-human study sometime in 2025.

With regard to data. Again, we're not guiding, but we do expect some sort of clinical data to emerge in the year of 2025 for the first program.

[Operator]

And our next question comes from Kostas Biliouris with BMO Capital.

[Konstantinos Biliouris, analyst]

Congrats on the progress. One question from us on the competitive dynamics, although you already alluded to that, but given the competitor CARTITUDE product will be entering the market, potentially in the late lines in about a year or so. How should we be thinking about the competitive dynamics there? Are you focusing on protecting your market share in late lines or just focusing on getting as much market share as possible in any lines?

[Ying Huang, executive]

Sure, Kostas. Let me start by mentioning a fact, which is in the case of registration program for late-line the first assessment of efficacy at day 28 or a month after the last patient was enrolled. And then after that, FDA requires a 12-month minimum follow-up. So if you do the math, that is 13 months after last patient in. And of course, following that, the sponsor needs to clean up the data, lock up the database, get all the filing into the FDA-acceptable format and the FDA will review. So we're not expecting anything to come into the market next year or maybe even the year after that, honestly, it depends on how fast the regulatory review go, right? And that's just a fact. If you look at the regulatory history for CARVYKTI for Avecma. I don't understand why the agency FDA would take any special treatment to any others.

And then I'll ask Steve to comment on the question.

[Steven Gavel, executive]

Yes. Yes. Thanks, Ying. In terms of promotional focus, the fact that we are now clearly differentiating yourself in terms of the only CAR-T therapy in earlier lines today, which is second line plus. We will continue to promote in those earlier lines and that will remain our focus for the foreseeable future. One thing to keep in mind, and I think it's an important comment here as it relates to any downstream competitors in the United States, when a CAR-T therapy is used right now, at least in the private sector, and this is consistent with Medicare, the payers are not paying to go from a CAR-T drug to another CAR-T therapy. It's denied. So it's the primary reason -- 1 of the reasons why we'll be driving our promotional efforts in the earlier alliance, not to mention that's where the majority of the benefit is for our patients. But that will be consistent in terms of our promotional focus, again, for the foreseeable future.

[Ying Huang, executive]

And Kostas, maybe I would also add another 2 comments here. First of all, I think outpatient administration is very, very important today. And that is why compared to all the other brands, we have the highest revenue mix coming from the outpatient use close to 50% of our revenue is coming from our business. And that is a distinct important commercial advantage. Secondly, as you probably know, every hospital, every insurance land has a preferred provider has a formulary. And as a third or fourth entry into the market, that increases the degree of difficulty in terms of launching into the commercial space as well.

[Steven Gavel, executive]

Yes. Maybe before we jump off that question, I think it's important -- because we never get the question why, right? I mean, we get it once in a while. We got it early in terms of why, this is 1 of the only CAR-T therapies that have been used so frequently in the outpatient setting. And it will be -- continue to be the case in the foreseeable future, including this competitor, I think people are referring to. The reason behind the why is around the onset of CRS that you're seeing with CARVYKTI. It's the only CAR-T therapy today. where you see a prolonged time frame passed before the actual onset hit, which does allow or enable our sites to dose, monitor remotely and then have these patients being brought in at a later date.

My understanding with the competitor that we're referring to, as Ron said, is relatively acute. So that's going to be very, very difficult to, in essence, utilize outpatient by guidelines for a competitive product that has that type of acute onset. It makes it very difficult for physicians to discharge if patients are experiencing short-term toxicity. So I did want to highlight that for you because I keep hearing about outpatient use in other particular CAR-T products. It's 1 of the distinct clinical differences with this program, which enables us to, in essence, take our patients outside the hospital.

[Operator]

And our next question comes from James Shin with DB.

[James Shin, analyst]

Maybe just another question for Alan and Ying on the outpatient setting. I think we kind of have a real world preview of what short onset CRS is with ideal, right? Like that doesn't do very well in outpatients. So how would a needle cell do well in outpatients? That's my question.

[Unknown Executive]

From a medical perspective, the update will -- the onset of action or the early onset.

[Mythili Koneru, executive]

So I think that CARVYKTI being given outpatient is something that we actually recently did an advisory board on. And there are several institutions that are actually doing this quite successfully and able to completely monitor remotely and they're actually working on a publication to kind of continue to kind of promote this outpatient model, which is very easy to do because of what Steve mentioned earlier about the delayed CRS onset. Other competitors how it tend to be very early days. And so what that does is it creates a setting where right after administration, you have to kind of monitor these patients closely. It's not to say that you can't give it to outpatient, but it tends to be a higher hurdle to do so. And that, I think, is a significant advantage given that these hospitals are extremely burdened by doing all of these things in patients, keeping the patients in the hospital for prolonged periods of time. So it's a significant advantage, as Steve mentioned.

[Steven Gavel, executive]

Yes. Maybe 1 thing to add to my comments, you're all spot on. The best proxy to look at and to ask yourself, the question is, why has the market if outpatient administration is so relevant, why hasn't the market successfully moved to outpatient treatment with Avecma. And the reason for that is they also have a very acute onset CRS. It's that simple or you would have seen that migration outside of the hospital there. So again, it's a benefit that, like I said earlier, it's a very unique toxicity attributed this program that is not only the BCMA therapies but also CD19. And it's the first time that you're seeing this type of outpatient adoption across the class of CAR-T and it was something that we were hoping to have happened, quite frankly, and it was something that our investigators predicted back when we were launching back in CARTITUDE-1. So anyway, I'll stop with that.

[Operator]

And our next question comes from Leonid Timashev with RBC Capital Markets.

[Unknown Analyst]

This is Joe on for Leo. What are your expectations for Europe now that you have commercial capacity up and running? And what are some differences between European and U.S. physicians selecting CAR-T over other options?

[Steven Gavel, executive]

Yes. So it's Steve. I do want to take a crack at that one. So Europe has a very different model. So we just had a long discussion here, I think, around outpatient administration. So that model is not available for most sites in Europe. So this whole outpatient conversation. I don't think you're going to hear a whole lot about with CAR-T therapies in general. So in terms of the CAR-T adoption within Pan Europe, whether it be BCMA or CD19, it's been relatively slow and unfortunately, it's been mostly a product of coming to an agreement around pricing. It's unfortunate, but that is a situation in Europe. As I believe you know, our partner is driving CARVYKTI in the European markets today. And I won't reiterate the countries that we are launched into today because in already did that in the opening. But right now, the key driver for this brand in Europe is Germany, and we'll continue to ramp up into next year and beyond. So that will continue to be our major market in Europe.

[Ying Huang, executive]

This is Ying. I also want to add that you probably know that in Europe, where pretty much every country has a single payer system. The survival data is utmost important because those government agencies, they do care a lot about the outcome, right? So it's not about response rates or even just stringent CR. It is about durability. It is about PFS. And most importantly, they do ask questions about survival. So we're very pleased to be armed with this survival benefit we have observed in CARTITUDE-4. In fact, we're already talking to different countries and agencies in Europe, including Germany, about the latest survival benefit we observed. And I want to emphasize again, to date, CARVYKTI is the only and also the first CAR-T targeting BCA or any BCMA-targeting modalities in the treatment myeloma, that has demonstrated both clinical and meaningful and also a statically significant survival benefit with a hazard ratio of 0.55. That is probably the lowest ratio you have seen in any major myeloma trial to date.

[Mythili Koneru, executive]

I'll also add that the clinical trial enrollment, as Ying mentioned in his opening, the CARTITUDE-5 and CARTITUDE-6 had significant -- or is having significant enrollment in Europe. So clearly, the treating physicians are very interested and being able to provide this therapy for their patients.

[Operator]

And the next question will come from Vikram Purohit with Morgan Stanley.

[Vikram Purohit, analyst]

We had to on CARVYKTI pipeline efforts. First, for the CARTITUDE-2 study, we just wanted to see what you think the time line could be for an update from cohorts E and F and your guidance on the best way to interpret that data when it's available?

And then second, apologies if you mentioned this and we missed it, but I wanted to see what the status was on year and J&J's plan to discuss the MRD negativity as a potential endpoint for CARTITUDE-6 and when we could receive an update here.

[Mythili Koneru, executive]

Sure. Thank you for your questions. Regarding CARTITUDE-2 cohorts E and F, which are the frontline newly diagnosed multiple myeloma, we ultimately need longer follow-up. So we will continue to monitor those cohorts very closely. And when we're able to have more follow-ups, we'll be able to report that externally.

Regarding your second question regarding the CARTITUDE-5 and 6 [indiscernible] negative, this is obviously with the recent ODAC discussion, the FDA is more open to using MRD negative DCR as potentially as an endpoint, particularly in these frontline studies where these endpoints tend to be extremely long in terms of PFS and OS. Therefore, we hope to get in front of the FDA and have some interactions with them on using this as an endpoint. So more to come.

[Operator]

And the next question comes from Mitchell Kapoor with H.C. Wainright.

[Mitchell Kapoor, analyst]

I want to build on a question from earlier. When KOLs are successfully using steroids to manage some of the safety events such as CRS and neurotox, could you just talk about, is there a way to follow that formally and potentially include that in the label at some point? And then separately, could you talk about if there's any significant work that remains on the payer side for getting them up to speed with the second line label.

[Mythili Koneru, executive]

Yes. So regarding the steroid question, we hope to incorporate something like that in the CARTITUDE-6 protocol so that we can look at using ALC as an early surrogate marker for extension and treat with steroids accordingly. Therefore, if we're able to incorporate that, we hope that, that can also potentially go into the label. And we do have precedence for this. If we look at Yescarta's label, they do have recommendations on steroid use. So we think that this is a good management tool moving forward.

[Steven Gavel, executive]

Why don't I take the second piece of that. I think there was a question on payer coverage. Yes. So for the CARTITUDE-4 indication, I'm happy to say that no, there are no barriers at all around payment with our commercial plans at all. As a matter of fact, given the overall survival benefit that we're now seeing in that extensive treatment-free interval, private insurers love a drug like CARVYKTI because of all the downstream cost savings that it presents, not to mention, we've talked -- I think we've beat up outpatient enough. They love the CAR-T drug that can then be moved to the outpatient setting and reduce all that inpatient costs associated with that, obviously, when done effectively and safely.

[Operator]

And our next question comes from Justin Zelin with BTIG.

[Unknown Analyst]

This is Jed on for Justin. So you've talked about lymphocyte monitoring and steroid use to manage the delayed neurotox. But in your experience, are there still a fraction of clinicians that are hesitant to use CARVYKTI due to the neurotoxicity and parkinsonism in the second-line setting. And due to concerns the gain will wait as they look to the frontline setting?

And my second question was just with the China approval now in place, how should we think about that launch trajectory moving forward?

[Ying Huang, executive]

You want to take back at the...

[Steven Gavel, executive]

Clinical piece, and I'll do the commercial state.

[Mythili Koneru, executive]

Sure. I can get started. Regarding the ALC and the steroid use, this is something that some clinicians have actively adopted and we are potentially working on more publications on the [indiscernible] to create more awareness on this. That being said, clearly, I think this is going to be an important factor as we move into earlier lines of therapy. And that's why I think it's so critical to make sure that we inform treating physicians that there are ways to mitigate it appropriately.

[Steven Gavel, executive]

Yes, maybe I could provide some of the research that's been consistent for over the years. You're absolutely right. So in the earlier line setting, toxicity is becoming even more important for treating physicians. We've seen that with all the research we've done with our CARTITUDE-4 launch, it's 1 of the primary reasons why we've deployed additional promotional effort in the pure outpatient setting. So you heard earlier in the opening from Lori that there was some expenses taken in the quarter for increasing the sales organization. Well, that increase was due primarily to address some of the -- this particular question in terms of educating physicians who are not as familiar with CAR-T therapies. Most of those folks are found in the community setting, and we are now actively deployed to educate those physicians with our partner on the features and benefits of a product like CARVYKTI as well as the toxicity profile and benefits that a product like this provides them. Again, I think the -- 1 of the key differentiators now, and fortunately for us, we now have this overall survival benefit, which is extremely important. And I don't make that conversation even easier in areas where there might be concerns of neurotoxicity in the earlier lines.

[Ying Huang, executive]

So Jim, on your second question about China launch. So we're actually in discussion with our partner, Johnson & Johnson about this. But given the supply trend and also the availability of lentiviruvector, we are obviously prioritizing markets such as U.S. and Europe, where we already launched Car -- so that is an ongoing discussion with Johnson & Johnson.

And then regarding China, I do hear some questions from investors and analysts about the topic. So I may just want to add another layer of the comment here. That is with President-elect Trump coming into White House in January and also all the discussions about tariffs. Is there any impact on Legend at all. So I can confirm that we use no raw material or starting material from China in the production of CARVYKTI in U.S. and Europe. If you look at our supply chain operation to supply CARVYKTI in U.S. and Europe, 100% of all raw materials starting mature are coming from U.S. or Europe. So that is a very clear answer to the tariff question. We don't see any impact at all whatsoever. Thank you.

[Operator]

And our next question comes from Rick Bienkowski with Cantor Fitzgerald.

[Rick Bienkowski, analyst]

I have 2. So about a week ago, there were reports that Peter Marks and the FDA were reconsidering the black box warnings on CAR-T products based on having better information about the background rate of secondary malignancies. So on to get a little color on what this means from the perspective of CARVYKTI? And also if there's been any recent communications with the FDA about this issue?

And the second question, just looking at the clinical pipeline, there are quite a few Phase I trials being conducted in parallel. Could you just remind us which of these trials are in later stages and which of these programs are likely to see clinical updates from in 2025?

[Mythili Koneru, executive]

Yes. Thank you for your questions. Regarding the secondary primary malignancy, despite the comments by Dr. Marks, it still remains something that's seen across many different CAR-T therapies. We have not had any specific discussions with the FDA on this as of yet.

Regarding your second question regarding our pipeline, we do have 2 U.S. studies in Phase I 1 involving DLL3 in small cell lung cancer, which we are in collaboration with Novartis on and a second cloud and 18.2 in gastric in pancreatic cancer. Both of these studies have been enrolling, I think, well this year, and we look forward to some publications next year on the Phase Ia dose escalation, both in terms of some safety and efficacy as well.

[Ying Huang, executive]

And Rick, I would like to add that if you see some recent literature, which actually suggest that if you look at the background rate. So for patients who have been treated with molecule myeloma that are on standard of care versus the SPM rate in patients treated with CAR-T, there's really no difference in terms of the incidence rate of SPM or second primary malignancy. So really, we're not seeing additional or higher rate of in the CAR-T-treated patients versus patients treated with other method of therapies for myeloma.

And then also on the pipeline, we do have ongoing Phase 1 IT programs in China. I would say maybe we can focus more on allogeneic modalities, including our common LT programs and also our autoimmune programs. So those are probably 2 focus for the research effort.

[Operator]

And the next question comes from Sean McCutcheon with Raymond James.

[Sean McCutcheon, analyst]

Just 1 quick follow-up and then another question. The follow-up is, is there a specific reason you need additional follow-up for CARTITUDE-2 for E and F? Are you waiting for any specific metrics that would have a read-through to the frontline pivotal, say, 12-month MRD-negative CR, for example?

And then the second question is any additional color on the out-of-spec rate and where you see that moving in the near term with more distance between the widening of the release specs in April and presumably more fit patients entering the top of the funnel with earlier line approval?

[Mythili Koneru, executive]

Thank you for your question. So regarding the CARTITUDE-2 cohort E and F, just to remind you, these are both frontline newly diagnosed multiple myeloma patients. And as such, these patients typically have very prolonged course, including extensive PFS. So even for MRD-negative CR, we still need quite a bit of follow-up in these patients, and that's why we won't be able to give you an exact time frame when we anticipate this at this moment, unfortunately.

[Ying Huang, executive]

Yes. Sean, also, just as a reminder, if you look at the data from the PERSEUS trial, conducted by our partner for DRV regimen. You're looking at a 4-year PFS rate of 85%. So that is why it's really not meaningful to release data with, let's say, even 1-year follow-up. That's the reason behind it.

And then regarding our out of spec rate, in general, we are seeing quarter-over-quarter improvement and without giving any specific numbers, I can tell you, our OS in general is the range of low teens. And 1 interesting observation so far since the secular approval by the FDA is that, if we look at the preliminary out-of-spec data from the old indication based on CARTITUDE-1 and then versus the patients who are under indication of CARTITUDE-4, second to fourth line, we did notice that between the 2 groups of patients in our commercial mix here that the CARTITUDE-4 patients coming in with lower out of spec rate. I thought this is early. This is preliminary, but that is an interesting observation we are seeing already in the manufacturing operation.

[Operator]

And our next question comes from George Farmer with Scotiabank.

[Unknown Analyst]

This is Chloe on for George. We have 2. I was wondering if you could speak a little bit more to the drivers of this accelerated approval for commercial production at the Obelisc site in Belgium. And we admitted some of the regulatory requirements around that? And can we expect more stepwise issues going forward kind of similar to the U.S. or now that you have obtained kind of like a bolus approval for a bunch of commercial slots you need to go back to the [indiscernible] for further approval?

And the second question is if you could walk us through your current assumptions for penetration of the frontline market?

[Ying Huang, executive]

Chloe, thank you for the questions. I'll address the first one. So yes, we're very pleased with the approval from EMA on commercial production at our Obelisc facility in Ghent, Belgium, that happened on September 19. And on the second day, September 20, we already started our first commercial batch production in that facility. So this is, again, a testament to the quality of our manufacturing operation in Obelisc facility. And because Obelisc right now is only using for commercial patients in European Union. We don't need any cash or regulation because you probably know, EMA actually does not regulate CAR-T manufacturing capacity. This is different from the FDA policy in the U.S. And next year, when we do expect our much larger facility in Belgium called Tech Lane to be online, and that will be the same case again. So right now, we do expect clinical production to be approved in Tech Lane in probably first half of next year, followed by the official EMA approval of commercial production in that facility by end of next year.

And then I may also want to add that Novartis already won FDA approval to start clinical production in the summer. And I'm very pleased to announce that Novartis has already submitted the application to the FDA. So right now, we do expect FDA approval in the first half of next year for the Novartis facility in New Jersey to start commercial production. So everything is on track, and we reiterate that we do expect to have combined in-network capacity of more than 10,000 doses per year by end of 2025. That is on track.

And then I'll ask Steve to talk about maybe frontline.

[Steven Gavel, executive]

Is it front line or earlier lines? Are we looking at CARTITUDE-4 or CARTITUDE-5 and 6?

[Unknown Analyst]

5 and 6.

[Steven Gavel, executive]

Yes. So let me just comment on 4 because it does relate strategically to 5 and 6. So with the CARTITUDE-4 launch, we've pivoted and changed our go-to-market model quite a bit. As you could recall, when we were launching with CARTITUDE-1, the fifth line plus setting, the overwhelming majority piece of our efforts as well as our partner was within our hospitals in the United States, in particular, and that's true globally. With patients becoming healthier, as we've talked about during this call today, our focus has not only focused continue to remain in hospitals in the U.S., but also we're pivoting outside the hospital. So we're having a much broader reach in terms of the providers that will be diagnosing and eventually treating these patients. So that's a key component, which will then layer into CARTITUDE-5 and 6. By penetrating and making our presence known in the outpatient setting, that will be the same provider group, that will be diagnosing these folks that will be eventually hopefully referred on as soon as possible for our frontline indication. So it's important to note there. I guess I'll finally leave you with up to now, we have not really activated the patient or efficacy at this point in time, mostly because of supply. We are actively now engaging with the patient and the advocacy groups now within the community setting. So that's an important development.

And then finally, and I'll leave you with this because I think we're on time, is we'll also be now over time, over the next few years, also be very active with the large retail or outpatient community DPOs out there. The U.S. oncologies of the world, the Florida cancers, et cetera. to think through ways to partner to bring this type of product closer to patients that are more mobile. So that's sort of TBD, but we're actively engaged with this now with our partner. That's very exciting, and it's really a new big step for CAR-T therapies as we get closer to our CARTITUDE-5 launch. So I'll end it with that.

[Operator]

This does conclude today's conference call. Thank you for participating, and you may now disconnect.