Good morning, everyone. Thank you for joining Jefferies Healthcare Conference. My name is Kelly Shi, one of the biotech analysts here, and we are very pleased to have Christian Itin, CEO of Autolus Therapeutics, for this fireside chat session. To start off, maybe we can talk about the overview of the Autolus cell therapy platform and the pipeline.
Happy to do that. Thanks for having us, and thanks for all of you coming to a very early session here in New York and making a try into the room. So, real pleasure being here. We are a CAR T company. Our lead program is currently under FDA review for patients that have acute lymphoblastic leukemia. What we're looking to do with that program is really create a product that allows us to get a high degree of activity, but at the same time, have a good safety profile, which is important to be able to actually reach a larger number of patients, and frankly, safely treat those typically very sick patient population.
There's quite a bit of opportunity beyond that with that particular product, which has a very unique set of properties, and we'll talk more about the clinical data certainly later. And are currently looking into a range of indication, both at the hemato-oncology side, but also at the autoimmune side. Behind obe-cel, there are a set of programs that employ dual targeting as one of the approaches to sort of limit one of their key routes of escape that we have seen with T-cell mediated therapies. There's a product called AUTO1/22, as well as AUTO8. AUTO1/22 is targeting B-cell malignancies more broadly, and AUTO8 is designed to target multiple myeloma and related plasma cell-related diseases.
And, what we're very excited about is a product that we just started actually work in the clinic, in London, is a program on the solid tumor side called AUTO6NG, where we're treating kids with neuroblastoma with a very sophisticated, way of cell programming. Which had basically at its heart, an ability to change the ability, of the CAR T cell to survive in a very hostile environment. The number of, modifications that we made to that program that allow us to sort of deal with, typical evasion mechanisms, but also, very challenging microenvironment, situations that you find in many of the solid tumors. So those are kind of a range of, of the activities.
One of the things that we obviously had to do, as we're sort of maturing our lead program, is actually fully integrate the company. So we have our own commercial manufacturing facility, which is a key asset, but also an absolute necessity in this space if you're delivering autologous CAR T therapies. And are also in the process of setting up the commercial infrastructure to support a commercial launch once we have achieved an approval in the U.S.
Terrific. For the lead program, obe-cel, in adult ALL, over time, you have presented a very compelling efficacy and a safety signal, especially the durable response and the survival benefit, and also a very low-grade CRS and neurotox. And at this ASCO, you also presented a consolidative transplant data. Could you share with us the key learnings?
Yeah, happy to do that. So maybe a word about obe-cel before I get into the detail. First of all, what we were looking to do with obe-cel is really create a product that can engage tumor cells in a way that resembles a physiological T-cell engagement. And the importance of that is that it would give us an ability to have obviously a very high level of activity. We would see a lot of proliferation of the CAR-T cells, so there's a lot of active agent in these patients.
But at the same time, we were looking to avoid overactivation, and technically the way we solve that is by actually engaging those cells with an ability to recognize specifically, but at the same time, once the kill actually occurred, have an ability to disengage rapidly, so we would avoid this overactivation. This comes down to the actual way in how we constructed the chimeric antigen receptor, and within the properties around its binding, around the binding. Particularly, we're designing a product with a fast on-rate, which gives you specificity, combined with a fast off-rate, which avoids the situation where the cell can get stuck, and then subsequently overactivated.
That has actually played out extremely well in the clinical studies, and what we're able to show is that initially in pediatric patients, that we were able to show in kids equivalent to the ones that were in the approval study for Kymriah, that we actually had a high degree of clinical activity without inducing high-grade cytokine release syndrome. This would compare to about 47% high-grade cytokine release syndrome with Kymriah in that particular study. So it gives us a very strong, a very strong level of safety benefit. But also what we did see is that we had about between 3- and 5-fold the peak of CAR T cells.
We had a lot of CAR T cells formed in vivo, and obviously over time, we had a very high level of, in terms of area under the curve for presence of the CAR T cells over time. And in fact, that went out to 3-4 years, where we can measure these cells in circulation in children. We then transferred that into the adult patients, could replicate that data. We have now more than 5 years of follow-up on these patients and see about 35% of those patients in ongoing remission, and you would consider those patients likely cured.... Now, we, based on this data, we then ran the pivotal study, which is the FELIX study, which we ran through the height of the pandemic, with most of our clinical centers in the U.S.
As you can imagine, that was a time when logistics was pretty hairy, as well as the challenge that you couldn't actually go to the centers, and you were basically running a real-world study from an inclusion perspective. Now, in that study, we replicated the data that we had in our prior adult study before. So we were basically replicating the safety data, and Kelly mentioned that. We had 2% high-grade CRS, we had 7% high-grade ICANS, which is substantially less than any other CAR T in the space, but also substantially less than Blincyto, which is the standard of care in the space today. For this ASH now, what we're starting to look at is really what is happening to these patients longer term.
What was quite compelling with the 22 months of follow-up, median follow-up, is that we do see the event-free survival stabilize at 40%, going horizontal, where we're seeing the survival stabilize at 40%, again, going horizontal, indicating that indeed, that we have a proportion of our patients that have a real opportunity for a long-term benefit. That is a first actually in adult patients. We've seen it in pediatric patients, with Kymriah. We haven't been able to replicate that to date in adult ALL patients.
This is the first time that in a registration study, and this has been the largest study actually conducted with a CAR T in this indication, with 127 patients dosed, gives us a very strong view in terms of the ability of the product to induce not only high levels of responses, and do that at a very good level of safety. But at the same time, give us a chance for a long-term outcome without any subsequent therapy. And I think that is certainly a different quality about the product.
Mm-hmm.
And it's not one that you see reflected in medians. We all like to see, you know, median survivals, median this and that. The problem is, when we look at medians, we assume we have linear relationships, and the median value actually represents what the clinical outcome is. When you have actually a study like this one that stabilizes at 40%, that's where the clinical benefit is, and that is obviously not expressed in the medians, but it's expressed in the shape of the curve. And then the final part that Kelly was referring to is that we had looked at the impact of subsequent transplant.
Up to now, the only way that you could actually induce a longer term benefit in these patients is to actually treat them to a point where they would have complete remission. And in fact, not just the standard complete remission, but one where you're MRD negative, so there's no residual cells measurable. And at that point, if you were able to transplant these patients with a stem cell transplant, you had a chance to consolidate that outcome and get a longer term benefit. What we were seeing in our study was actually that the patients that received a second transplant, if anything, were certainly not better off than if they hadn't received it, but possibly worse off.
In fact, when we're looking at the curves with and without transplant, the patients that received the transplant actually did worse on the event-free survival and overall survival, indicating that indeed, the transplant doesn't actually support the longer term outcome. And mechanistically, the link is that we're seeing in the patients that have long-term outcomes in general, we see that there are persisting CAR T cells. So the CAR T cells are actually present over one, two, three years' time, and we see that that longer term persistence is actually correlated with long-term outcome.
Most of the patients that were transplanted actually had still active CAR T cells in them, and one of the things that happens with the transplant is you remove those cells and then replace them with new stem cells, obviously, taking out the activity that you had in, and that is highly likely the reason why we see a worse outcome in these patients, in addition to treatment-related mortality that is typical for transplant, particularly if it's a second transplant the patients receive.
Terrific. And we know another CD19. Tecartus also got FDA approval and launched also in adult ALL, the ZUMA-3 trial. Maybe you could share your insights on the difference of available clinical profile for both on safety and efficacy. And also regarding your post-CAR-T transplant discovery for obe-cel, has Takeda shown similar data in the past?
Yeah. So there's an approved CAR T program in this space from Kite Gilead called Tecartus. That program was approved based on a study called ZUMA-3. That study was conducted prior to the pandemic, and the patient populations are actually quite different from the patients that we had seen in our study. I indicated we had sort of real-world population just because of the fact that within the pandemic, frankly, there was a lot of concern for the patients. There was very little options that the patients had and a very high medical need in that population. So, whenever you had a patient show up at the hospital, it tended to be at a very late time point with very advanced disease and very high tumor burden.
ZUMA-3, like, the prior studies I had conducted on Blincyto, that were done, obviously, outside the context of a pandemic, and that has allowed much more selective patient inclusion. So there's a fundamental difference in the underlying patients. In terms of outcome, what I think stands out is a fundamental difference in safety, certainly between the programs. The baseline activity is similar, probably not the same, but similar. And what we certainly did see in the context of Tecartus is that adding or having patients go onto a transplant improved outcome, as it would for Blincyto . So what we were observing with obe-cel was the contrary and was very unusual in that regard.
One more point I think is that when we look overall at the patients that we have treated, one of the key things that we obviously did observe is that we do have this long-term persistence, which is also a fundamental difference that we're seeing between the products. That frankly, actually something that you wouldn't see with Tecartus and the work that was then done subsequently post-launch, and that was actually then during the pandemic in what's called the ROCCA study. Looked actually at sort of the real-world experience with Tecartus, and it certainly indicated possibly a higher degree even of neurological toxicities. We're talking up to 38%.
But what was very interesting was the conclusion of the presentation end of last year, which indicated where the authors or presenters indicated that they believed that the product needed consolidation to actually get a longer term outcome, which is fundamentally different from what we have just shown.
Thank you. Very helpful. And, as it gets close to the regulatory decision in both U.S. and Europe, could you share the commercial strategy in both regions?
Right. So we have filed a BLA at the end of last year. We have a target PDUFA date at November 16 this year, so towards the end of the year. We also did file with the European Agency. That filing was accepted at the end of March, so that's also ongoing. So we have about a quarter difference in terms of the time point of the respective filings. What we're looking to do in the U.S. is starting out, first of all, as a background, in the U.S., you have about 60 centers that cover approximately 90% of all patients treated in that state or that advanced state of the disease. We're expecting to launch out of 30-36 centers-
Mm-hmm.
... from the get-go, and these are the centers that actually are all being onboarded now. So you go through all the various activities to make sure that the centers are in a position to be able to accredit them. And then once the label is actually granted, that's when you do the last part of that activation part of the process, and then within probably 2 weeks to up to 3 months, those centers will actually come online. In parallel, we'll continue to actually add centers so that we will reach the 60 centers in a relatively short period of time during the first year of launch.
In Europe, the way that you run through the approval is obviously it's a central approval through the European Agency, but then you have the negotiations with each individual country on pricing and reimbursement, so there's a second leg to that. And the typical sequence that you run through Europe actually goes through basically a group of countries that sort of you follow through. Most launches would start in Germany, go to France, and would actually from there actually move forward. And obviously, since Brexit, the UK obviously is a separate approval, and that obviously will be run separately, and obviously as our home market, it's a important market for us as well.
Terrific. As manufacturing is always a pivotal step for the commercial launch for cell therapy product, could you also comment on the manufacturing preparedness for obe-cel-
Mm-hmm
... and specifically, capacity and predicted out of spec rate in commercial phase, and maybe also any like logistic steps you have to think about?
Yep. So clearly, when you have an autologous product, where you manufacture individually for each patient, obviously you need a very bespoke manufacturing setup to do that, and you need to think pretty hard about how you're gonna build economies of scale, to support attractive cost of goods, but also to give you a level of consistency in the manufacturing output and the consistent delivery to the patients. We spent a lot of time on that, and this probably was the single most involved aspect of building the company and building the program. It starts out with the need for a very robust manufacturing process, that can deal with a high degree of variability of incoming material from the patients.
As you can imagine, if you have a patient with acute leukemia, you can have, you know, up to 90, 95% leukemic cells, when you collect cells from a patient, and which obviously creates a very, very tough starting point and starting material. So you have to be able to actually create a process that can deal with that high degree of variability and translates this high degree of variability into a very consistent output, a very consistent product that, to Kelly's points, meets the specification and actually stays within them. If you're out of specification, obviously you cannot sell the product. The patient may still be treated under an exception, but you cannot sell the product, so commercially, you take a pretty significant hit.
It is also disconcerting for the patient, it's disconcerting for the physician, and it's a lot of administration, administrative burden because that patient needs to be moved from a commercial patient to either an expanded access or an exceptional, basically a med, a clinical, trial type of setting. So there's a lot of ramifications there. So first, get the product as robust as possible. I mean, to give you a sense, we did hundreds of runs at full scale to actually determine, characterize the process, getting as robust, as stable, as consistent as possible.... We then actually work on a platform which is highly automated. So each patient obviously is on an individual piece of kit that actually provides that, gives you a lot of the manufacturing you can run on it.
So it's a high degree of automation that obviously takes human error down to the extent possible. Third, you need to actually then actually build the relevant level of capacity. Now, for adult ALL, you have about 3,000 patients on the back end of the disease. We're looking to capture or be able to serve at least 2,000 of those 3,000 patients between the U.S. and Europe, and that's what the initial capacity reserve we made at our, at our facility. Now, you have then the question to ask, well, once you have established a process, are you gonna manufacture yourself, or are you gonna actually have a third party manufacture for you?
The challenge you have is you have, if you go to a CDMO, is first of all, there's nobody that actually has capacity at that level. It doesn't exist. It has to be built even at CDMOs. The second is that it's virtually impossible to be economic. So there's a very high chance that you'll actually not reach profitability if you actually farm manufacturing out for these type of very bespoke products. So we took the decision to actually set up our own commercial manufacturing facility, which we built in the U.K., in Stevenage, which is north of London, about half an hour, and very close to where we actually manufactured for the clinical trials from. Has a lot of benefits. The location, it gives us actually a global reach.
Surprisingly, through the pandemic, we realized it gives us more reliability in terms of access from an air travel perspective or air freight perspective. And for those of us who travel a lot in the U.S., we all have made the experience that when you're on a domestic flight, and it's getting to the afternoon, it's kind of hit or miss whether your flight still goes or gets delayed, et cetera. The international flights actually tend to go on time because that's where the airlines are making their money. So even through the pandemic, that was actually true, and we had highly reliable, with all the limitations, highly reliable product delivery. So between that and the high degree of work of process development work we did, our out-of-spec rate in the trial was around 5%.
So it was very low, and we expect to be able to go even further, further down on the commercial side. So the facility we built gives us that capacity of 2,000 earmarked for adult ALL. It has a total capacity of 3,000 products. We did manage to build this within 22 months, from groundbreaking to BLA filing. Fully validated facility, which is a record time in the industry. It's probably 40% of what anybody else ever did. In order to do that, we had to do a lot of things differently. The importance of it, it's a highly modular build, it's a very unique startup process that we designed, which gives us now an ability also when we think about expansion, to actually trigger decisions for expansion at a time when we have visibility on growth of demand.
Mm-hmm.
And with that, actually can make much more sensible, much more economical decisions on investment, downstream as the opportunity starts to build. So those are a few points I think I just wanted to make. It's really important to have control over manufacturing. And when we think about the logistics time, which is one of the things, relating to delivery time, you were asking as well, in the study, we're at 21 days. We will be at 16 days at launch, and the reason why we're at 16 days at launch is twofold.
First, we've entered into an agreement with Cardinal Health, which allows us to actually use their logistic centers, and that allows us to actually move product while we're in the release part of the process, move the product already close to the center, and then as soon as the release is in, have a very short distance from the actual depot to the center itself.
Mm-hmm.
That cuts about three days out of the turnaround time. And secondly, we had introduced towards the later part of the pivotal study, a set of analytical methods that were substantially faster, and those cut another three days out. So overall, we're gonna be at 16 days or below at the time of launch.
Terrific. Maybe moving to another very important development, direction for Autolus in autoimmune space. Based on very promising data from academic center in Germany, in lupus, now we have more than 20 cell therapy programs or have started trials in lupus, and Autolus is pioneering in this space. And could you actually share with us the trial status, and also how does Autolus differentiate from other CAR-Ts?
Yeah. So this goes back to, I think a very exciting set of clinical experiments, basically a set of compassionate uses that were done at the University of Erlangen, which showed for the first time that if you treat patients that are kind of in a very, very advanced stage for autoimmune disease, that it can actually not only improve the trajectory of the autoimmune disease, but it could reset those patients. In fact, reset to the point where the patient would sort of get back to a normal B-cell compartment without actually having autoimmunity come back. So it's a rather remarkable set of data, and I can only encourage you to have a look at that. It's published in Nature Medicine and at a few other publications.
What was very remarkable from a biology perspective is that this is the first time that anybody actually could identify the type of plasma cells that were driving autoimmunity, and to our surprise, it was not mature plasma cells. It was plasma blasts. It's early-stage plasma cells, and in fact, those cells do not actually are not in this typical only BCMA-expressing late stage kind of phenotype. They're actually cells that are much closer to B cells or late stage B cells, and in fact, carry CD19 on the surface. And so this allowed them allowed the team in Erlangen to use a CD19 CAR, which is in essence is Kymriah with a different manufacturing process to basically reset these patients. And what they could see is that within 30 days, the autoreactive antibodies were gone.
Within 3 months, these patients had no disease scores anymore. They were going from, you know, disease scores that were in the 8-16 and above, for, and these are SLEDAI scores in lupus, to 0. So these patients also had reversals of fibrosis, which started to build in organs like the kidney, lung, or the heart muscle. Very unusual, transformational data, absolutely stunning. First time we've seen a reversal for autoimmune disease with any modality. Now, the property of that product is, as I mentioned, it's, it's in essence Kymriah as a receptor with a different manufacturing process. The reason why this center actually had that CAR, which they were producing themselves, was that it was part of a pediatric ALL program. So they have plenty of data on pediatric ALL.
The kids were dosed as you would dose Kymriah, at 1 million cells per kilogram. What that allowed us to do is actually do a straight comparison with our own data, where the kids are treated with 1 million cells per kilogram. It's same, exact same dose, and we could compare the data. Andreas Mackensen, who is the hemato-oncologist at the center, who did obviously the dosing of the patients, as well, is somebody that we have known for a long time. He was one of the first people who ever treated a patient with Blincyto in my old life, so 20 years ago, more than 20 years ago.
So we compared the data, and it was very clear the data that we have and the data that they have is very comparable, with the exception that our product is substantially safer. So we know we got long persistence, you know, with their product, 2-3 years. We're in the 3-4-year range. We got exceptional safety. We got very high level of activity and an ability to induce long-term outcome in kids. That product, when put into autoimmune patients, had now a much shorter persistence-
Mm-hmm.
Because it's an active immune system, and the cells get cleared more rapidly, but it provided this very unique outcome. The reason why obviously we have a lot of confidence in our product here has a lot to do with the fact that our product matches, obviously, all the key properties, except it's safer. And also, it's obviously a product that will have a label, in another place with a full-fledged BLA package, CMC capabilities.
Mm-hmm.
All of those things sorted out, and that puts us in a very strong position in the space.
Terrific. I see time's up. Let's wrap up our session here, and thanks again, Christian, for spending time with us. Thanks, everyone, for attending.