Welcome everyone, and thank you for joining Galapagos here in San Diego or virtually for our KOL event following yesterday's presentation at ASH of our ongoing Phase I-II EUPLAGIA study in CLL and Richter transformation, and our ATALANTA study in NHL. I would like to remind everyone that we will be making forward-looking statements during today's webcast. These forward-looking statements include remarks concerning future developments of the pipeline and our company, and possible changes in the industry and competitive environments. Because these forward-looking statements involve risks and uncertainties, Galapagos's actual results may differ materially from the results expressed or implied in these statements. Today's speakers for Galapagos will be Dr. Paul Stoffels, CEO and Chairman, and Dr. Jeevan Shetty, Head of Clinical Development Oncology. We are very pleased that we are joined today by four key, key opinion leaders in the field.
Professor Davids of the Dana-Farber Cancer Institute and Professor Ghia of the University of Milan will discuss the results of the CLL and Richter transformation trial. Professor Anguille of the University of Antwerp, Belgium, and Professor Bishop of the University of Chicago will discuss the NHL study. Paul will kick off today's event with introductory remarks. Then Jeevan will discuss the Euplagia results in CLL and Richter transformation, followed by a KOL discussion. Next, he will talk about Atalanta results, which will be discussed by Professor Anguille and Professor Bishop. Paul will then present concluding remarks before we open it up to Q&A to the public. To ask questions in the room, please tap on the microphone. Participants that joined virtually are welcome to ask a question via the Q&A function. With that, I would like to hand it over to Paul.
Thank you, Sophie. First of all, thank you all for being here this morning with us. Especially big thanks to our distinguished key opinion leaders being with us here in the room for the discussion of the results. It's also a very big day for us. The first time we are public with a number of the data on a big meeting, as well as with our CAR-T activities and the instrument, which draw a lot of attention yesterday at the meeting, for which of course, we are very proud and very pleased. Our CAR-T pillar is based on three pillars to bring CAR-T to more patients to save lives.
And first and foremost, we want to improve patient outcomes by infusing a product containing fit cells with vein-to-vein time of seven days. With this, we believe we can deliver and improve efficacy and safety outcomes in a patient population that is in urgent need. The second pillar is our innovative delivery model. By implementing a decentralized CAR-T manufacturing near point of care, we minimize logistic hurdles and maximize the physician's control in the process. This results in an exceptional patient experience and shows a commitment to access for patients globally. Finally, we are committed to building a portfolio of best-in-class CAR-Ts in hemato oncology, also in solid tumors and in immunology, through our decentralized manufacturing network. Here you see a picture of the Cocoon and the cassette. This, the Cocoon we have in this very extensive and strong collaboration with Lonza, developed over the last four years.
It is the cassette which is the end-to-end sterile box, where we can generate the CAR-Ts, but it's the environment around it with the Cocoon and the xCellit platform, the digital platform, which manages the whole program, production program, the vein-to-vein administration program, which makes it all happen. And this allows us to go decentralized, where we can control, the local people can control in the laboratory, in the space, what is going on, but also we, through this, the network, we can give back up from Leiden, from our team on day to day, day and night, 24/7 support. And that allows to be very confident about manufacturing and delivering cells in the seven day vein to vein process.
The collaboration with Lonza is one which was established as an exclusive collaboration on using the Cocoon for point of care in the world, and that is a strong collaborative effort to produce as well Cocoons as cartridges and the development around it. In the whole development of this system, we used first principle thinking, focusing on simplification and streamlining every aspect of a current centralized production. You see on the left, the weakness that led to critically ill people, not or delayed, getting life saving treatments, while there is involvement of transportation across the ocean for the cells, centralized manufacturing and transportation back to the patient, which takes time, efforts, logistics.
In our innovative system, what we are developing, it consists of end-to-end automation for manufacturing, functionally closed systems, allowing to do quality control during and of within the process, timing, comprehensive real-time monitoring, both centrally and remotely through our xCellit platform, as I explained before, and 24 clinical manufacturing, 24 hour clinical manufacturing support. We aim to make the CAR-T available globally. We started in Europe, expanding fast now into the U.S., and very soon also in other regions of the world during our clinical trial activities in the next two to three years. The seven day vein-to-vein and fresh-to-fresh cells are at the heart of our platform. On the top half of the slide, you one see the seamless and continuous CAR-T production with the innovative QC review through the integrated Galapagos xCellit platform .
In the lower half of the slide, you see the condition regimen being given at day -6 to -4 from administration. This is giving in parallel to the manufacturing of our CAR-T product, which is unique to our approach, a testament to our confidence in our reliability of manufacturing process and critical to deliver a seven day vein-to-vein fresh product. Through our unique platform, Galapagos delivers life-changing service to patients and a step-change experience to clinicians and providers. Today, only a small portion of patients that are eligible for CAR-T receive the treatment. High unmet need cancer patient populations that are not helped today would benefit from CAR-T therapy.
These are patients with fast-progressing cancers and can be helped by quick access and a seven day to vein, vein-to-vein time, as well as patients with poor prognosis, or which cancers for which no standardized treatment strategy is available. And as I mentioned before, within the pool of patients that have been found eligible for, for CAR-T treatment, we see that today only 30% receive a CAR-T product due to barriers being limited manufacturing capacity, complex logistics, and restricted access. With our work, we hope to be able to increase the addressable patient population, leveraging the point of care model globally. Here, we show today's pipeline in oncology. We have ATALANTA study in refractory relapsed NHL, where we currently enrolling patients in the phase II dose expansion, while still running a dose escalation cohort to test dose level 3 in patients with DLBCL.
In EUPLAGIA-1, we are testing our construct, GLPG5201, in patients with CLL, relapsed refractory CLL, and we have just initiated a PAPILIO-1 trial in the first patients screened with the PCMA. Today's session will focus on the important progress that we are making with our oncology programs. The data in the posters underline that our CAR-T programs manufactured at point of care, delivering on their promise. In today's presentation, we'll discuss the encouraging data in CLL and NHL, observed with our product candidates. Importantly, we initiated a tech transfer following the agreement with the Boston-based Landmark Bio. This is a key milestone in the geographic expansion of our CAR-T, point-of-care production technology, and the start of clinical development of our CAR-T programs in the U.S.
In parallel, we continue discussions with multiple centers in Europe and in the U.S. to further build our point of care manufacturing network. In addition, we continue to strengthen our capabilities in oncology with key hires, among others, in regulatory, clinical, BD, and strategic marketing. We are embarking on setting up a U.S. office to accelerate our activities in the U.S. With that, it's over to Jeevan to present the story of EUPLAGIA data. After the clinical results, we'll invite Professor Davids and Professor Ghia to talk about the unmet need and their opinion on our data. Jeevan?
Thank you.
The floor is yours.
Hi, everybody, and thank you for attending today. I just wish to spend a few moments just talking about high-risk CLL and Richter's transformation. As we know, chronic lymphocytic leukemia is one of the commonest hematological malignancies, among within the hematology family, and we know that that disease remains relatively maintained and controlled for a long period of time. After a period of time, these patients become move from becoming asymptomatic to symptomatic, and then progressive aggressive disease. Really, with that in mind, this is the area that we're really attempting to address with our platform. We will share with you data on high-risk CLL and also Richter's transformation. The epidemiology of the disease, as you can see from these slides, is one that appears to be increasing over time.
This underserved patient population, the epidemiology on both sides of the pond, in the U.S. and also in Europe, is quite consistent. You can see there that in Richter's transformation in particular, the unmet need is significant, and the disease is fatal, with six to eight months median survival. Here's the design of our high-risk CLL Richter's transformation study, the EUPLAGIA study. The design of the study incorporates all of the unique components that Paul talked about with our Galapagos platform. You see it here in action. There's the seamless innovative IT and QC technology, which enables fresh cells in, fresh product out, and continuous production and expansion of the QC review.
The T-cell expansion, the transduction sampling, and also the batch release. But the key to the seven-day vein-to-vein time is really the fact that we give concurrent conditioning regimen being given at day -6 to day - 4, and this is all in parallel to the manufacturing of our CAR, CAR-T product. And that's really the unique nature. Looking at the baseline characteristics of the EUPLAGIA-1 study population, you see that this is quite consistent with the population at risk, with unfavorable outcomes shown here by age and gender, and also by the prior lines of therapy, as well as the disease characteristics. In particular, TP53 mutation and the high rate of unmutated IGHV. I'll turn to some pretty interesting translational data that we undertook on 13 of the 15 patients that were in the study.
Looking at the expansion and the persistence of GLPG 5201, we saw robust CAR-T expansion, which was observed in all patients measured by quantitative PCR as the vector copies per microgram of DNA on the y-axis, over time on the x. Dose level 1 is actually depicted in green, and dose level 2 in orange. The median time to peak expansion, as you can see from this graph, is 14 days, regardless of the dose received and or whether CLL or Richter's transformation. Follow-up is ongoing, and so far we have one evaluable patient with detectable persistent CAR-T cells at month 15. This is a further important observation.
We know that the literature suggests that early phenotype T cells have been shown to correlate with better in-patient expansion and favorable outcomes, and in our study, we clearly see this. Comparing the starting material with the final product, we observed that GLPG5201 enriched for early phenotype for both CD4 and CD8 CAR T cells. Our product may result in higher quality fitter cells, so this fresh process appears to be key to that. This comes to the piece about whether it's the number of cells. I think Michael Sadelain's quote about it's not the number of cells, but it's the quality of cells. If you have better cells, you can give fewer cells.
We assessed the T cell phenotype of both the final drug product and the apheresis material. We observed this increase in percentage of the early phenotype T cells in both CD4 on the left and CD8 on the right, and the final drug product was compared to the T cells in the apheresis starting material. Turning to the safety, I think we see a very good safety profile with our drug. It appears to be well tolerated. There were no grade three CRS. Only seven patients experienced low grade CRS, grade one, grade two, and no ICANS was reported. No deaths occurred, and most treatment emergent adverse events were grade one, grade two.
Most observed grade three or four adverse events were of a hematological origin, and they're all well managed with standard supportive care. Turning now to the efficacy, we observed excellent efficacy with our drug in patients with relapsed refractory CLL, with or without Richter transformation. The objective response was assessed as per iwCLL for patients with CLL, Richter's and RT was assessed as per the Lugano classification. As you can see here, the objective response, we're able to show that 13 out of 14 patients responded with at dose level two, which is our RP2D, we had a 100% response rate, with eight out of 14 patients responding to complete response, so 57%, and five out of eight patients in the dose level two reaching a complete response, 63%.
We believe this phase II data is compelling, and it's really informed our choice of RP2D, and also our plan to accelerate our regulatory journey forward. In the RT subset, this was even more prominent, with eight out of nine patients responding, an overall response rate of 89%, and all patients on dose level 2 are also responding. Six out of nine patients achieved a complete response, suggesting an overall, a CRR of 67%. At the time of analysis, 77% of responders had an ongoing response. Duration was up to 15 months post infusion, and the last available response rate and assessment is indicated here. I'm sorry, it's moving again. With regard to what we are planning on doing with regard to the next steps, it's very exciting.
Dose level 2 has been selected. We're initiating the phase II expansion study imminently, and the tech transfer has been initiated to the U.S., as Paul discussed, to Landmark Bio, and the IND submission is ongoing. So with that, I'd like to turn to Professor Davids and Professor Ghia to just discuss with them their perception of the data that we've had and the potential impact on the disease. I'll just return back.
When it's red, it's on. Yep, there you go. Counterintuitive.
Okay. It's counterintuitive.
Yes.
Right?
You've seen the data. I think you're both familiar with the data, that's been submitted. We appreciate it's early, but we are very keen to understand what you feel the real unmet need in CLL actually is. Would you be able to give us some insights and thoughts?
Yeah, definitely. I mean, the unmet clinical need in CLL is that, CAR T cells don't work so far, so that's the major point. We have been an exception in, among all the B cell lymphoproliferative disorders because despite the initial enthusiasm, the first original study with CAR T cells in the world has been done in CLL, and there are two patients, two individuals all over the world who achieved the durable remission. One of them, actually died during the COVID pandemic, but then all the other patients, did not respond or relapsed quite early. So it, well, it is still very disappointing for us. I would say that in the CLL field, when we hear about CAR T cells, it's really, "Show me," because nobody believes so much anymore. And indeed, I was compelled by the results.
I mean, of course, the numbers are limited, so one has to see how durable the response is, if the results are reproducible in larger number of patients, but are very promising. And in particular, what I was concerned is not RT. So Richter transformation is definitely an unmet clinical need, but we have, in particular, patients who are relapsing after the best drugs that we have, so BTK inhibitors and BCL-2 inhibitors. So the story is not over in CLL. We have these patients, sooner or later, will relapse, and therefore, having another option is definitely welcome.
I fully agree with what Paolo said. You know, we have a couple of great mechanisms to target CLL, BTK inhibition, BCL-2 inhibition, but we're finding more and more patients in our clinic who have started to exhaust these options. We had pirtobrutinib FDA-approved last week, which probably benefits patients for a median of another 16 to 17 months. So it just kind of kicks the can down the road a little bit. I think initially there'd been a lot of excitement for pirtobrutinib. I think it's, it's a good drug, but it's, it's certainly not gonna provide very long-term benefit for these patients. Paolo and I have been collaborating on CAR-T studies for a while now. We worked on the ZUMA-8 study together, with axi-cel, the brexu-cel product, and then, looking at the liso-cel data together.
This really feels different from the start, and I think all the data to me are looking like they're lining up. You know, with the ZUMA-8 study, we didn't see very much CAR T cell expansion early on, so we had concerns that we would not see clinical benefit, and that's what happened. You know, here it's very different. All of the patients are having robust expansion of the CAR T cells. I think this live process where you don't have to freeze cells and ship them and then ship them back, particularly in CLL, I think is gonna be important because the sort of the more fragile nature of the cells, the immune suppression and the disease, etcetera. So, I'm also very encouraged by the early efficacy data.
Again, need to see more numbers, but from what we're seeing so far, everything's lining up for a very effective product.
Yeah. I mean, if I can add on that, it's really. We talked about efficacy and promising results, but it's really from a technical point of view, I think it's really a game changer because especially in CLL, cells are more fragile, the T cells are more energized than in other, in other lymphomas. That's the real key issue in CLL, immunosuppression. So the less you handle the T cells, the less you manage the T cells, so you don't freeze and thaw, you don't keep them for a month in expansion, I think that's beneficial. Otherwise, we are really, as you also showed with the data, I mean, we are really exhausting even further the cells.
Therefore, that's probably an explanation why we do see such a difference, because from a technical point of view, it's a completely different approach, and I think it's even more beneficial in CLL than probably in other diseases.
Yeah. The other thing I would add is that the CLL disease itself is immunosuppressive, and I think their results are particularly impressive in the sense that the patients they were treating had very high disease burdens. So you can imagine, as this product maybe gets moved into an earlier line or in a setting where the patients are more debulked and they have less CLL disease around it, it may be even more effective due to, you know, better immune function.
Thank you. And with regard to the actual platform itself, the practicalities of the decentralized model, do you see any barriers to that in terms of the real-world practice? Or do you see that as being something that is relatively easily incorporated?
Yeah, I think that's gonna depend. Obviously, center to center is gonna be different. I know at Dana-Farber, we have a long-standing experience with CAR T cells, and we've for a while been looking for a product to partner with at a point of care and manufacturing, and this is really one that looks very straightforward to work with. So we're enthusiastic to work with this group. You know, I think there's gonna be centers, obviously, that can't do this, so having partners of manufacturing nearby makes a lot of sense, sort of that decentralized model. But I think for larger academic centers, it's gonna be great to have this in our center, to be able to have some control over the process, but also to have the support from the company with the expertise.
Thank you very much.
Yep. I think that I might envision really decentralized approach, meaning in each hospital, at least large hospital, in Italy, we don't have community doctors in when we speak about hematology, hematological disorders. All patients with hematological disorder, they have access to hematologist that is working in a hospital. So I see the decentralization, and I'm very in favor of it because of a tradition. I've been for many years, and I am still a president of the ERIC, the European Research Initiative on CLL, that is really creating a network of hospital-based units where all patients can have access to the most advanced prognostic and diagnostic techniques. So immunoglobulin gene analysis, minimal residual disease assessment, P-53 assessment, that 10 years ago everybody said it was complicated, it was difficult.
It's not something that every laboratory can do, and therefore, we show that indeed, if through the correct education, you can actually have everything done everywhere. And I think, I envision the same approach with your Cocoon.
Sure. And just based on the data that, I think you alluded to this, Matt, the potential to move to earlier lines of therapy, is that something you can comment on?
Yeah. As I said, I think from a scientific point of view, it makes a lot of sense to go into earlier lines. You know, I think as you start to approach frontline and CLL, the bar does get very high because we do have such well-tolerated therapies. So I think maybe frontline use, probably not so much, even in high-risk patients, because those patients will typically start with a very effective and well-tolerated therapy. But that being said, you know, most patients, at least in the U.S., are being treated with covalent BTK inhibitors, and they'll typically be on them for a few years. But then, when they progress, those patients do have high-risk disease, and we have other options available, like venetoclax, for example.
But if they have high-risk genomics, and they've already progressed on their frontline therapy with a covalent BTK inhibitor, I personally would feel very comfortable, you know, having a CAR-T product in, in that patient, if it's, if it's relatively safe and, and effective, especially, you know, I think for our younger patients who have a long time horizon, you know, having the potential for, for cure?
Yeah.
with immunologic therapy is really appealing.
Yeah. Thanks very much.
Yeah, definitely. Also, because we didn't speak enough about the safety profile. So at the moment, the safety profile looks quite nice. I mean, no neurological toxicity and grade 1 and 2 cytokine release. So that makes it really affordable, as you mentioned, especially for young people. So it's. You try. If it works, good, you have a long remission. So it might be even in frontline, who knows? Someone who says: "Yeah, let's take our chance and have it. Maybe I have to spend a couple of weeks in the hospital," but you don't die. So the issue in our disease, in particular because we have a lot of comorbid patients, is that you don't want therapies that are bringing in too many safety issues, and this seems not to be the case.
We will see. In particular, again, you are treating patients who already received a number of lines of therapy, so they are definitely more fragile. So maybe the safety profile will look even better when you move it to earlier lines.
All right. Okay. Thank you very much. We'll move on to the Atalanta-1 study, which is our relapsed refractory NHL study. I'll maybe just stay put, actually, based on the technology. Here's the epidemiology for non-Hodgkin lymphoma. Clearly, it's a subset of many different subtypes of follicular lymphoma, marginal zone, mantle cell, and primary CNS and Burkitt's, which are all represented in our program. With regard to the incidence and then the potentially CAR-T eligible population, we can see that this is a representation as things stand at the moment.
This is the design of our study, which is quite similar to what you've seen before, and really has all of the unique components of the Galapagos platform with regard to what we do with leukapheresis and in terms of the T-cell selection, as well as the expansion and the continuous monitoring. In addition to that, you can also see the conditioning that runs between minus day eight and minus day six. So that really allows the seven-day vein-to-vein time. You can see that the key eligibility criteria are not controversial. They're consistent with what we have seen in the studies that are running at this point in time. Unusual, though, is the fact that we included transplant-ineligible patients.
With regard to the baseline characteristics, we think this represents the aggressive patient population who have significant unmet need and are in need of therapy. This is clearly just the phase I, phase II data. As we expand, we will determine the kind of inclusion criteria to a greater extent. Turning now to the expansion and persistence, it's important to note that we're actually seeing something very similar to what we actually saw in the CLL study. You have the same setup here with the Y-axis and the X-axis in terms of over time, and the green represents dose level 1, orange representing dose level 2.
What we see here is this robust CAR-T expansion that was observed across all dose levels, as measured by quantitative PCR with vector copies per microgram of DNA on the Y-axis. And with the phase I study on the left and now the phase II part of the study on the right. For phase I dose levels, you can see this rapid expansion and then this persistence. We believe, based on what we've seen, this consistency is as a consequence of the process. Clearly, we need to follow up over a longer period of time. And then the other component, which is about the product characteristics with the enrichment of the frequency of the early phenotype CAR-T cells, both for CD4 and CD8.
Compared to the starting material, we see a very consistent elevation in the benign early phenotypes. We believe this fits in with the fresh cell, seven-day vein-to-vein time approach, resulting in fitter cells. Turning now to the safety profile. What we were able to see is that there was only one case of grade three CRS and one case of grade three ICANS. There were two deaths in the study. Remember, these patients have got very aggressive disease. The first was a patient with a double-hit diffuse large B-cell lymphoma, who had significant comorbidities and developed thromboembolic disease, for which he was anticoagulated and succumbed to a bleed.
The second was a patient who developed significant infections that were ongoing and died six months after the infusion. What we see here in terms of efficacy is very encouraging. 12 out of the 14 patients responded across the whole population in phase I, with 11 out of 14 patients reaching a complete response, CRR rate of 79%, and in dose level two, a CRR of 86%. In phase II, we saw something similar. Seven out of nine patients were efficacy evaluable. Six out of those seven patients responded, relating to an overall response rate of 86%, with four out of seven patients achieving a complete response. Clearly, early, small patient numbers, but compelling nonetheless. Median duration of response was not reached.
Median time on the study was 8.6 months, with a range of 2.8 to 15. Eight out of 12 patients responded in phase I, and six patients responded in phase II with ongoing response. In phase I, four patients progressed after the initial response. Again, very exciting period for the ATALANTA-1 study. We are planning on expanding into the indications that we talked about with regard to NHL unmet need indications, and we've implemented dose level 3, and there's a completion of tech transfer to the first U.S. site with Landmark Bio that is ongoing.
So maybe at this point, I hand turn to Professor Bishop and Professor Anguille, just to comment on your thoughts on the data that you've seen so far with regard to the total population and maybe the subpopulations.
Yeah, maybe I'll, I'll speak first. Thank you. From my experience with also the, the, commercially available CAR-T, these efficacy data, they really remind me about the best-in-class CAR-T cell therapies that we are now currently, using. So I think from an efficacy point of view, these are indeed, as you were telling, compelling data, even although the numbers of patients are quite, quite small. I think from an efficacy point of view, it's, convincing. And from a safety point of view, from the real-world experience we are now having with these, point-of-care manufactured CAR-T cells, it's, it's actually easy to handle. We, we are not afraid of CRS. It's something we expect.
We want CRS because it proves that your immune system is acting against the lymphoma, and it's usually very manageable, and we can handle it. So I don't think it's these are big problems at the moment.
Thank you very much. Professor Bishop?
Yeah, I just want to echo those. When I try to think about, we're all looking for what's the next, what's going to be best in class, and I think that's a very good and so it's either better efficacy, less toxicity, but what has entered into the equation now is logistics. And I agree, these are the efficacy is extremely promising, and we're seeing a, what's particularly, you know, when the first CARs were approved, they just set a really kind of a naive bar of overall response. We want complete responses. There are not partial responders going long term. And a signal of that success is CRs at six months. So you were seeing those swimmer plots, and those are very impressive. And so there's a strong signal.
We need to see them out beyond that, but that's a good signal. The safety is, I would agree, best in class, in that regard. And then logistically, you know, the seven days means a lot. I mean, when we're sitting around waiting for commercial CAR-T cell products and just biologically, what we're seeing phenotype-wise, that is a big difference. And matter of fact, it is actually being demonstrated that the subsets of T cells that you were seeing here are the ones that lead to the greatest success. So you put that all together, and these results are extremely promising.
Yeah, great. And with regard to that seven-day vein-to-vein time, those aggressive patient subtypes, do you think the Cocoon platform is something that's gonna help?
Well, the answer is yes. And the reason is, so when we think about it, so, you know, we're seeing a variety of disease here, but let's focus on diffuse large B-cell lymphoma. So two-thirds of patients are gonna do great with our available therapies. One-third, though, unfortunately, are going to recur, and 75% of those are gonna recur early. So when you look and as a participant on Belinda and also Zuma-7, you know, you think about it, you know, how soon can you get the patient there to be treated? And do they need right away? But when you're waiting, and particularly what we saw on Belinda, but even with Zuma-7, you know, you're still having a minimum of 21 days. And think about the logistics of trying to get a slot, getting their cells shipped, and everything else.
That's a critical time for our patient population. All of a sudden, I, you know, feasibility-wise, other than insurance approval, you know, that may be potentially a two to seven-day delay, but we can still actually collect the patient's cells and have them, say, ready to go or have it, you know, as soon as we get a go, and all of a sudden now we're able to treat a patient within seven days, and actually, you could even envision them getting their conditioning regimen while you're generating the cells. I mean, that would be a game changer, right?
Yeah, just to jump in, that's actually what's happening now, because a lot of people talk about vein-to-vein time, manufacturing time, which is indeed longer with the centralized manufacturing. But here, what is more important to me is actually the time from patient identification?
Yeah
To actual infusion, and that can even happen in maybe 10 days. I identify a patient, even the same week I can do the apheresis. The next day, I start lymph for the patient, and one week after the apheresis, the cells are infused. So that's really what we are, we are speeding up the entire process, and with this centralized manufacturing, it's not only the manufacturing time, which is three weeks nowadays with Yescarta, for example, but it's about having your patient, identifying him, and getting him to the actual infusion. It can last sometimes several months.
Right.
Now.
We refer to it as brain to vein. You think about if a patient's eligible and getting it into them.
Do you feel that in terms of the commercial therapies, I think, Sébastien, you talked about three weeks now? Have you seen, like, a decrease in that from origin? I mean, and do you see that continuing to improve?
Yeah. So it has, it has decreased. In the beginning, it was longer. It was more than a month. Now it's usually quite standard, 28, 21 days, 18, 21 days, so three weeks. But I think it will stay with that because, of course, here you have a fresh product, so it's fresh out and fresh in, which is different with the, with the other models?
Yeah.
In the United States, I would relatively agree with that. I think with the axi-cel product, it's very consistent.
Mm-hmm.
The other product, not so much. And again, it's a longer time. So when you look at those median times, I think Kite Gilead's did a very good job, but they can't go any faster, because they are set in their manufacturing process. And so. And even if they could get a short incubation time.
Mm-hmm
You're still gonna have this logistical problem of getting it, shipping it, the product, cryopreservation. So here, having it, and you don't have to worry about waiting to coordinate between the company and getting a slot and then finding out when your apheresis time you go. Again, the identification and moving forward logistically is going to be.
Yeah
Quite significant.
Yeah.
But it's, I think it's not only about logistics, it's, it's also about the physician or the hematologist, the treating hematologist, who is more in charge now?
Yeah.
We have control over the process or more control because we also have direct links with our manufacturing unit. So that's also something that is really important.
Yeah, agreed.
Sébastien, I think you're unique in this group of being the only person who's actually recruiting patients and using this platform.
Mm-hmm.
Any kind of practical, pragmatic insights that you want to share?
Yeah, for me, it's what I told it. It gives us a lot of flexibility.
Yeah.
So let's say that I have several patients that are eligible for CAR T. I can select the one that I think is the one that is in the highest need, where we can wait. And I just, I can plan the apheresis even the same week, and next week, the cells are infused. So it's really easy also to use, because, you know, a lot of hospitals, and especially those that do stem cell transplantation, have experience with cell therapy, so it's not something that we are not familiar with.
Yeah.
And even this, this entire model for our cell manipulation technologies, it's quite intuitive. It's easy to handle, easy to use, and especially with the support we are now receiving, it's, yeah, it's very, a very fluid, or a very easy-to-use model, actually.
Good. Thank you. Just maybe last question before I hand over to Paul. Just with. Based on the data that you've seen, the platform, I mean, do you think this is a game changer?
It certainly looks like it has that potential. I mean, I do wanna see more numbers and longer follow-up, but yeah, I think it has potential.
Yes. In terms of CLL, it can be game changer if- From two different aspects. One, as I said, the technological one, definitely having there in your hospital very close by, you can really plan it as a another drug. I mean, like an infusion drug. I mean, you have anyhow to order to the pharmacy couple of days, and then you get it. So it's exactly in the time frame that goes well for the patients and the doctors. For us, it can be also game changer because it's effective. So this is a two times the game changer, and that's what I'm looking forward because really, I think I have a strong background in the laboratory.
I did my career working in the lab, and I know how bad is to freeze and thaw the cells, so I really think that can be really the key.
Key.
The key thing.
Professor Bishop?
Yes, I think it. I think this can be quite significant and impactful on our patients, and so that's actually what gets me most excited, is that we are now gonna have this option. And again, it's both quality and logistics.
Mm-hmm. I agree. I think it's game-changing at the individual level, the patient level. I included or recruited the first patient in ATALANTA-1. It's now almost two years ago. Patient is still in complete remission, whereas he was in on death row actually. He had no treatment options left. So on an individual level, it can be game changing. But I also think from another perspective, this model is also extrapolatable to other diseases, other types of cancer. We're now going to start a PAPILIO-1 trial in myeloma, which is fairly similar. The process is similar, only the target, the target CAR-T is different, but the entire process is the same. And even this Tuesday, we are going to do the apheresis of the first patient in this trial.
This model is extrapolatable to other diseases and hopefully in the future, also to solid tumors.
Perfect. Thank you very much. Paul, maybe hand over to you?
Well, just for me to thank Professor Davids, Professor Ghia, Professor Anguille, Professor Bishop, for their contribution here in the discussion. I think the teams of Galapagos and previous CellPoint have worked very, very hard for many years on getting this to this point. Also including here the teams at Lonza, which were very collaborative in making this happen. It has been a collaboration, extensive collaboration to get this CAR-T instrument, which can make it at point-of-care, really function, and now us being able to decentralize and implement, resulting in the seven-day vein-to-vein. It's very important for fit cells, fresh cells to be able to administer, as we demonstrate now in small numbers.
The high manufacturing success rate is key, because, yes, if you deplete a patient during the manufacturing process, you need to be able to deliver, and so far, so good. We have been very constant in delivering. The ability to use fresh cells goes together with the results. Initially, it was like a concept and idea. But as you have seen, the expansion curves in both the CLL and the NHL, it is like, yes, the transfection and the first growth is done in the incubator. The patient is a real incubator where the cells grow, and most likely that has its effect on its safety and its efficacy, all to be further scientifically evaluated and confirmed.
And then the rapid, robust expansion observed in vivo, as I said, is key to this success. And the preserved early phenotype was a theoretical idea, but it looks like it works out in practice. So with this, I think we are at a good start. The team said, the advisors also, the European leaders here, said it has we have to now see it work on a larger scale. We are committed to build this out, first in Europe and the U.S., and do the next pivotal studies over starting in the course of next year. And hopefully, then we can, this product, project, product, and also the production can be distributed across the entire world.
There is no limitation to where this can go because transportation is out of. It's all local, and we as a company will set up to be able to support and make a huge difference, bring CAR- Ts to many patients and make a lot of difference in the world. So with that, thank you, and we'll go and have the floor open for questions. So Sofie, if you can moderate the questions. Thank you.
Thank you.
Yes, you can get that.
Yes. Phil, go ahead, please. Thank you.
Hi, Phil Nadeau from Cowen. Two questions from us. First, on the CLL poster yesterday, there was a mention of three patients who had to have dose level one because they didn't have adequate cells for dose level two. We're just curious what happened with those patients. Was it a manufacturing issue or variability just in the patients themselves? And then second question on the regulatory process. Can you give us some understanding of what the FDA looks for to validate a point-of-care manufacturing paradigm for cell therapy? Thanks.
Yeah.
Would you like to make a start, Jeevan?
Yeah.
Yeah.
I can make a start to the first part of the question. The recollection that I have is all the patients received treatment. Yes, it was lower than the dose that we expected, but this goes back to that translational data, whereby quantity is not as relevant as quality, because we actually ended up seeing responses in those patients that got a lower dose of treatment. So in a sense, this is something that we need to continue to observe. And yes, there is an element of this, which is really about what is your starting material? So the starting material, the patient's starting material really determines a lot. This is what we're discovering. So this is something that we need to continue to interrogate, but it goes back to that piece of, well, we continue to see responses in those patients as well. With regard to the regulatory point, maybe Paul?
Yeah, in the regulatory, the way we will implement the model is that we will take full end-to-end responsibility for the manufacturing onsite. So, and that will follow normal regulatory requirements, GMP, full validation of the product, an NDA with an approval, and then, for us, being able to standardize and implement the manufacturing across these centers in a very, in a very consistent way. And that's where the team is working on, the. As you can see, it's almost fully automated model, and at this moment, there is still a lot of work ongoing on the standardization and the automation of the quality release. That all can be captured in the electronic data systems and be central released by us as the final approval of the release.
So we will use industry, pharmaceutical industry-grade standards to do this entire process, but we'll have to pioneer on do this in a decentralized way. We think that, and the benefit risk, which we address here by being able to do it decentralized with fresh cells, requires a lot of attention, and we will work together with the FDA. So far, so good. We're doing this in Europe, in three countries, five hospitals, and expanding. We are in very close connection with the regulators over this, with the local in the countries, but also centrally with EMA. We have initiated a discussion with the FDA, but there, we couldn't submit our IND before we had a first manufacturing site on the ground and data produced from that.
That's ongoing, and in the first half of the year, we'll be able to submit an IND and start working in the U.S. Our teams are in discussion with the FDA, but submitting the IND will require our first manufacturing site up and running, and that will the one in Boston, which is currently being validated.
Yeah, we have the next question from Pete, from Citi.
Thanks, Pete with Citi. Just a few topics to hold in mind, given that we've got four KOLs in front of us. But just sorry to harp on the point. So the data that's been presented, was that done over the five hospitals that you mentioned, Paul, or is that. Okay. So in terms of reproducibility, how many times have you done this process? And I suppose just being at the poster board yesterday, I mean, I'm just earwigging, hearing what everyone else is saying, but I mean, there's a healthy dose of skepticism that the FDA is gonna be relaxed about this decentralized process. So just how do you sort of push back to the pushback?
Well, I'm not relaxed at all about it. I've been 30 years in the business. I've been dealing with the FDA for a long time. We will meet. We'll need to meet the standards, need to meet the quality, and we are not going to undershoot. We are going to overshoot with what we do here. So that is, yes, just the, I think, and Luis can respond, but we probably have done more than 100 runs, laboratory-wise, in our cells. Luis, why don't you answer the standard, the question on manufacturing and-
Hi, my name is Luis. I'm the head of manufacturing at Galapagos. We have actually performed more than 300 runs in overall, including our central facility in Leiden, where we have a vast experience in healthy donor production. That helped us to increase the understanding of the process and also how comparable the process can be across different sites. Comparability is at the core of our work, as we have a consistency by design approach, by standardizing, automating, and making everything digital. We are able to really have all the sites performing under comparable conditions, and that's also what the FDA is expecting from us, and we are ready to present the data to support our first IND with comparable sites also between U.S. and Europe.
Everything is standardizable, except, of course, the apheresis from the patient, and that's the biggest variable. And like you hear in CLL, for example, the variability of that and the viability of CLL is very well known that it's not that easy, but it has been shown that with our process, we can do it and with the fresh cells. So more to learn. We have to do this times 10, times 100, but I think a good start for where we are today. Mm-hmm.
Paul, is the plan just to have one U.S. site next year, or how many are you hoping for?
No, no, no. First one will be started up as we speak; it's ongoing. We have already two others in view, which we are contracting with, and probably at least five in the first year, but if not, we try to shoot for 10, to have a good presence in the U.S. for the clinical trial, as well as in Europe, to run a clinical trial in the European/U.S. context. Yeah.
Now, actually, I want to reconnect also to the first question, meaning that the surprises should not come from the fact that the three patients did not get to DL2, but the fact that all three patients having DL1, they expanded. So that's the... I think, what is also the beauty of the system, that again, we were used to inject a lot of cells because we were expanding a lot of cells in vitro, and then those cells we did not expand, and they were dying only. Instead, but it's very nice what you said, so the patient is the incubator, the real incubator, so you just have to shoot some cells, and probably they will expand because they are so alive and so not manipulated that I think that's the key, and we will see with data, of course, but that's what is attracting me as an investigator.
Thank you. But to describe this, the key innovation is probably that, yeah? Having very high memory content, very fit cells, getting into the patient, and the patient is the incubator. Much better incubator than a Cocoon to keep the cells for a long time. And also.
Especially, especially because the cells will be specific against the target, and we know you can put one cell, and that theoretically, it should expand and become a.
And then just rounding out to the four docs, thanks for your time, but just two questions for you. As it stands today, just that whole bispecific cell therapy story, I mean, we're seeing it playing out in myeloma, but how. You know, I'm asking you to crystal ball gaze, but how are you feeling about it in CLL and, and DLBCL? And then just topically, with the FDA's recent review of T-cell malignancies, just any views, on that? Thank you.
Yeah. So very, very early in CLL, 20 or so patients treated. There is some activity of bispecific antibodies, so it's early, but I think that is a potential competitor. You know, I think that certainly with bispecific antibodies, though, you still have the challenge where, you know, the cells are not being sort of manipulated at all. They're just staying in an immunosuppressed host, so you're relying on generating that initial immune response in that context. So there may be some advantages to sort of engineering the cells outside the body and then reintroducing them that I think CAR T can provide.
Yeah, I'd just like to address that. Again, when bispecifics can show the complete response rates that CAR-T cells, then they become a competitor. And I think that's fair. They're probably gonna be moved more in the front line, so what do we do after they relapse from that? So I think that's their intention. Coming back, and if I may, to address the T-cell lymphoma issue, it is important, and I'm glad. You know, every time we do CAR-T cell therapy, we do. That's why it's very, very important we report all SAEs.
But, you know, putting it into the context, I mean, when patients go through CAR T-cell therapy, there's an inherent about approximately 5% mortality rate, be it from whatever, infection, cytokine release syndrome, neurotoxicity, et cetera, and including secondary malignancies. But when we look at this incidence of T-cell lymphoma, and, you know, initially what was reported to the FDA was 0.15%, and that's among the SAEs. So if you put it in the context of how many CAR T cells are performed, the incidence becomes, less than 0.1%. Now, that's a significant 0.1%, and again, the studies are being done to understand what the biology is, whether there actually is an insertional mutation resulting in this proliferation. But I think we have to study it hard.
You know, would that prevent me from moving forward and presenting this potentially curative option to my patients? The answer is no.
Yeah, questions from Brian, from RBC.
Thanks. Maybe two questions. First, for the CLL experts, I'm curious, how much data do we have on the correlation between T-cell expansion versus anergy, to response and to duration of response with some of the older CAR Ts, just to be able to project what we might see here over time, given some of the technical advantage, advantages of this process? And then for the NHL experts, do you envision using this broadly, in most of your patients, or just in certain patients where a shorter vein to vein time would be a potential advantage? And what would you want to see in terms of long-term data, to use this ahead of the more established centralized cell therapies?
Maybe I can start and just briefly mention an interesting finding from the ZUMA-8 study, which I presented at the ASH meeting last year, actually, which was that there were about 15 patients, and very generally, very poor expansion of T cells in these patients with axicabtagene ciloleucel. But there were three patients treated with low disease burden, where there was some expansion of the T cells, and those were the patients who had the best response. So to me, that was pretty suggestive, and actually, I encouraged the company to pursue that signal, which, which they didn't. But that would have been very promising, I thought.
Mm.
I don't know if you want to speak to liso-cel. Yeah. Yeah.
I think we don't know much in CLL about that. I mean, we are trying to translate too many, too much information from other lymphomas, and it's a completely different thing. Again, even the strategies to, for CAR Ts in CLL is like changing the ratio between CD4 and CD8. Do we know if that is relevant or not? We don't know. The phenotype, they are anergic, starting with. So that, again, to answer the bispecific question, with the bispecific, we are trying to stimulate cells that are not so able to be stimulated. And in fact, in CLL, again, another big failure is anti-PD-1 and anti-PD-L1 that revolutionized most of cancers, solid and blood cancer, not in CLL. They don't work because the cells that are sitting there are probably not responsive.
The CLL cells are inducing them into an anergic state. So we probably need to take the cells out to give a stronger antigen recognition capacity, because probably the anergy that is present in CLL patients is really impairing an immune response against the tumor. So we don't probably don't have so many cells and so specific against the leukemia, so we need to manipulate them, put an anti-tumor, anti-leukemia antibody. And then with a short time, probably they can recover a little bit outside the body, and then when they're injected, they can. They find their target, and they can be stimulated. So this has to be proven.
Maybe I'll take the question regarding which model to choose or which CAR-T to choose, because we're now doing both. We are doing commercial axicell and also participating to this trial. For me, of course, from an ethical perspective, when you have a commercial or regular CAR-T patient, normally that's superior over getting to a phase I or II clinical trial. So when the patient fulfills the criteria for receiving axicell, he or she will receive axi-cell. Unless, for example, it's a rapidly progressive patient, where we think that maybe this model where you can go faster can be better.
But the advantage here of this study is in lymphomas, we are also having a lot of NHL types, or this trial is getting into NHL types where axicell is not available. Let's for instance say primary CNS lymphoma, where there's a high unmet need. So actually, in this ATALANTA trial, we showed, I think, that this works. That is, CAR-T is highly effective, Galapagos also in the indications for axicell, but now we are moving into the other lymphoma types, follicular lymphoma, primary CNS lymphoma, maybe in the future also Burkitt lymphoma, and that's the exciting part here, I think.
Yeah, I just want to follow up on that because it's an interesting question. You know, I sit on a lot of ad boards and particularly where this early necessity for those more aggressive patients. And, you know, the other option in this would be an allogeneic CAR T cell, off quote, "off the shelf." And it's very funny, you know, just recently, my peers, they said: "Well, if I could get this immediate access, you know, I'd be willing to accept a lower outcome." You know, when we set the bar, like I say, for complete response rates. And the reason is because if they can't get a CAR, they're gonna die, right? So but in this situation, I mean, we're seeing very, very promising data in terms of response.
And so if the data holds true, and you know, if I had this available, why would I want to wait 28 days or 21 days? So would I apply it to all of my patients in the future? 'Cause you're talking about where right now, and if we'll be doing the really phase I, phase II of this, but if it became approved, this... And again, I had, didn't have to ship cells off. I didn't have to do the cryopreservation, etc. It's kind of, to me, a no-brainer.
As I, as I said, I was speaking with them a few days ago, and I said, "It depends how many Cocoons you can give to my hospital. That's the only limitation.
Maybe if I can just add, it's something, it's maybe intuition, but, for example, if we like, have like, an older patient that is quite, maybe frailer, more frail, in my opinion, the toxicity although the safety data need to be more mature, need to mature a little bit more. But from a neurotoxicity perspective, for example, there is a difference with this product versus axi-cel, where you can sometimes see severe grade 3 neurotoxicity, which in my hands, I haven't seen this with this product. So maybe that's something in the future that will also guide us.
Thanks so much. If that's okay, we'll take a question from Jacob Mekhael of KBC Securities, who joins virtually. So that's one for Paul, I think. "Your pipeline chart includes next-generation CAR-Ts. Will those be internally developed, or could they come from licensing or M&A?
Yeah, both. We have a very strong capability led by John Malis and our internal team in Pittsburgh are working on next generation CAR T. But we are very open to look at all possible outside options here. They're not invented here; it's not a thing. We will use the best possible option which we can bring for next gen CAR T to patients. And John is very active also with this whole team on looking externally what is evolving, including what we're looking at in China, Europe, and the U.S. Yeah. Mm-hmm. So, yes.
Thank you. And then maybe a second question: "How fast do you expect to complete the expansion cohorts and progress to a pivotal trial?
I think, for CLL, we are determined to start the critical study in the course of next year, pending the IND submission, the validation of the sites in the U.S., and being able to start it. It's a very attractive trial because we solve a real medical problem, so it's up to us now operationally to handle it all. But in the course of the first half of the year and get the sites, and the IND in, and then make sure we start in the second half of the year, the clinical trial in an extensive way. Europe and U.S.
Thank you. More questions from the room, perhaps? Then I think we can.
One there?
One question.
Oh, sorry. Excuse me.
Hi, Daina Graybosch from Leerink Partners. A question for the doctors using this: So you saved the logistics of cryopreservation, but what does it take in terms of space and people to actually do the Cocoon on site? So you're trading off one logistics to the other, and I wonder if you could talk about the trade-offs of both those things.
Yeah. So we have really a really small GMP cell manufacturing unit, which I think you can count the cell manipulation technologists on one hand. They are also doing other things in the hospital. They are doing the stem cell work and things like that. So it's from a personnel point of view, it's something that is. You don't need a lot of people actually to run this. And also from a space perspective, we have several clean rooms. We have six clean rooms, I think. But of course, you can envision that you can put a lot of clean rooms in a lot of Cocoons in one clean room.
Yeah, also.
Yeah. So even from a space perspective or room perspective, it's not that you need big or large infrastructure.
But we ourselves are doing an extensive exercise to be able to communicate to the centers what it takes. We know what it takes today in clinical trials, but it could be very efficiently organized in small clean rooms. Actually, at the moment, there are three people needed with three different types of capabilities to be available. But of course, in clinical trials, you don't do three, four, five cocoons at the same time. It's one, and so at the moment, the number of people to run it per product is still high. But if you can get to efficiencies with many cocoons and an organized lab, we'll be back with much more information on how that could function.
It is exactly the same question the centers who collaborate with us ask, and we have to work out as we speak now to, to build it out. But high interest, I can tell. Mm-hmm.
Then one more question, another regulatory one, perhaps more specific. When you. When the companies of two-day manufacturing have presented their results, they often say the actual vein to vein time is limited by the quality, testing. And I wonder what you're doing in terms of quality testing in these trials thus far, that you can get to seven days, and do you have to have new solutions to keep it there as you move forward?
Yes, we have existing solutions which make it happen today. We are further optimizing it. The fact that we use a sterile incubator end-to-end with no manual handling allows to start quality release testing during the process, and that is. That's one of the key features. There is no manual handling of the cells. It's a totally closed system end to end, and that allows, after the transfection, start doing evaluation. More to follow, more information to follow on this. It works today. We're working with the regulators to make sure we can standardize it on a global level, and we also further automating each of the different quality release tests, quality control tests, to make them also, how you say that? No human error proof, yeah.
That is all.
Foolproof.
Foolproof, yeah.
Mm-hmm.
Foolproof. Foolproof of full proof. Yeah. So that's all ongoing, but so far, so good.
Okay.
Would you like to give some concluding remarks?
Well, thank you very, very much for the crowd here in the room coming to listen to us, for your presence at some of you at the meetings yesterday. It was really encouraging for our entire IR team to have this type of motivation from the key opinion leaders. Showing the results is a big day for us, but a lot of work to do, and hopefully, next ASH, we'll be able to report even much more data, and hopefully very far advanced with the clinical trial. So thank you very much, and have an enjoyable stay in San Diego and good learnings at the meeting. So thank you.
Thank you.
And-