Autolus Therapeutics plc (AUTL) Earnings Call Transcript & Summary

Good day, and welcome to the Autolus Therapeutics ESMO Investor Conference Call. [Operator Instructions] Please note, this event is being recorded. I would now like to turn the conference over to Lucinda Crabtree, Vice President, Investor Relations. Please go ahead.

Thank you, Cole. Good morning or good afternoon, everyone, and thank you for taking part in today's call on the ESMO AUTO3 Phase I/II data update. I'm Lucinda Crabtree, Vice President of Investor Relations. With me today are Dr. Christian Itin, our Chairman and Chief Executive Officer; Dr. Robert Chen, our AUTO3 and lymphoma program lead; Dr. Nushmia Khokhar, our lead -- Head of Clinical Development; Brent Rice, our Chief Commercial Officer; and Andrew Oakley, our Chief Financial Officer. Before we begin, I would like to remind you that during today's call, our discussion today will contain forward-looking statements. All statements other than statements of historical facts on this call are forward-looking statements. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors including those discussed in the section titled Risk Factors in our annual report on Form 20-F filed with the Securities and Exchange Commission on March 3, 2020, which can be accessed on the EDGAR database at www.sec.gov and in subsequent filings we make with the SEC from time to time. The forward-looking statements on this call reflect the company's views as of today, September 18, 2020, regarding future events and should not be relied upon as representing the speakers of all the company's views as of any subsequent date. While the company may elect to update these forward-looking statements at some future point, the company specifically disclaims any obligation to do so even if the company's views change. These forward-looking statements should not be relied upon as representing the company's views as of any date subsequent to today. Please be advised that today's call is being recorded and webcast. On Slide 3, you'll see the agenda for today, and it is as follows: Christian will provide a brief introduction, and that will be followed by a review of the AUTO3 data by Dr. Robert Chen. After which, Brent Rice will provide an overview of the commercial opportunity before handing back to Dr. Christian Itin, who will summarize the key messages for today to discuss forthcoming milestones and provide concluding comments. And of course, we will welcome your questions following our remarks, which will be taken by the panel outlined. So with that, I'd like to turn the call over to Christian. Thank you.

Thanks a lot, Lucinda. I appreciate it. Well, welcome, everybody, and thank you for joining to our ESMO update call. With me today on Slide 5 are Robert Chen, who's our lead physician on the AUTO3 program, who will actually give us the clinical update. We're also here joined by Nushmia Khokhar, who runs all our clinical development; and Andrew Oakley, our CFO, that most of you know well. So with that, I'd like to just on Slide 6, briefly introduce, obviously, the 2 key areas of focus that we have this year, which are very much directed towards our lead programs, AUTO1, which we're developing for the treatment of patients with acute lymphoblastic leukemia with a particular focus on the adult patient population. And obviously, the topic for the call today, the AUTO3 program in diffuse large B-cell lymphoma, which we're obviously very excited about and are looking forward to sharing the updated data. When we then go on to Slide #7, you can see our current programs that are in clinical development. You can see beyond the B-cell malignancy programs, AUTO1 and AUTO3, obviously, there are further programs into T-cell lymphoma as well first indications into the solid tumor area, and in particular, in the case of neuroblastoma. So with that, I just would like on Slide 8 to briefly introduce you to the program. The AUTO3 program is really designed to achieve a high level of complete remissions and sustain those over time. And what we have seen with a number of programs that have already reached the market or close to the market is that reaching a substantial level of complete remissions actually has been feasible with CAR-T programs. What has been a lot harder, though, was to maintain those complete remissions over time. And there are particularly 2 reasons that drive that. On the one hand, it is the loss of antigen, in fact, the loss of CD19 antigen, which obviously creates a situation where, in fact, the CAR-T can no longer recognize the lymphoma cells and as a consequence, can no longer control the disease. And the second key mechanism actually is the upregulation of PD-L1, the checkpoint inhibition pathway, that actually allows the lymphoma cell to shut down incoming T cells and prevent the actual kill from occurring. And so in order to actually achieve -- create a product that actually has an ability to counteract those 2 key escape routes that the lymphomas have, we are -- we designed a product that has, in each one of its -- of the CAR-T cells, 2 different types of receptors, one receptor that recognizes CD19, one chimeric antigen receptor that recognizes CD22. What that does is that even if a cell would lose CD19, it would still be recognized through the CD22 targeting receptor, and it would still get killed. So we're basically shutting down that right of escape due to antigen loss. The second element that we introduced into the program is actually to have a cover using a PD-1 monoclonal antibody in our case pembrolizumab that we introduced in the recommended Phase II regimen actually at day minus 1 during the preconditioning regimen, and that provides us with about 3 months cover that gives us a window within which the lymphoma cannot escape even if it actually upregulates PD-L1, it would still actually become targetable for the CAR-T cell. So the goal for this program is, on the one hand, to obviously achieve a high level of complete remissions, but then also to sustain those over time. The third key objective that we have with the program is actually to have a favorable adverse event profile. The importance of that is, as you'll hear later on from Brent, is that the majority of patients are treated outside the academic hospitals. And in order to be able to do that, you actually have to have an adverse event to safety profile that actually allows you to manage these patients in those settings. And that is an area that we particularly also focused on. So in fact, when you look at this product, this product is differentiated from a molecular composition perspective, the different binders to the targets, different architecture, a different way of activation and then, of course, the mechanisms that we use is different as well from any of the other programs that actually has been tested so far in this space. So with that, I'd like to actually just briefly talk about the commercial opportunity on Slide 9. As we all know, DLBCL is a very significant indication, affects a quite a sizable part of the population. We look at approximately 24,000 patients that are diagnosed every year in the U.S. alone. So it's a very substantive population, and it is a very aggressive form of lymphoma. And the goal is really to actually get patients into durable complete remissions and actually get the patient to a cure. So this is a disease setting where buying time actually doesn't work. Obviously, buying time works in follicular lymphoma, it really doesn't work in diffuse large B-cell lymphoma. You actually have to get to the root of the driving cells in that disease setting and actually get to a transformational outcome. So with that, obviously, with regards to the positioning of the product, obviously, it's -- we believe, AUTO3 is with the profile that we see emerge now, very well positioned to address the high unmet medical need, but also have an ability to actually reach the patients across all the settings of care, which is one of the key areas that are key features that we're looking to work -- have worked into the program. And on Slide 10, obviously, when we look at the key lines of therapy in diffuse large B-cell lymphoma, we obviously have -- we start out with a classical monoclonal antibody, chemotherapy backbone, typically, R-CHOP as the first-line treatment. And if you get into -- if you get through that, you do not respond or you relapse from this initial treatment. There's a second-line chemotherapy that is fairly intense, that can actually be consolidated with a stem cell transplant. And if you fail after that, that is when you reach the third-line setting, and that is the patients that we're treating in this particular patient population we're dealing with for AUTO3. So what we're aiming to get to is actually get patients into long-term remission in a third-line setting, which obviously is a tough hurdle to take and is what the areas that we're active in. So with that, what I'd like to do is actually hand over to Rob Chen, who will actually run us through the actual clinical data update. And I'd like to hand over to you, Rob.

Thank you, Christian. I just want to make sure everyone can hear me, and then I will present the data as was shown at the ESMO conference. Let's go to Slide 12. So this was presented by Dr. Eleni Tholouli at Manchester University Royal Infirmary Hospital, we have the other investigators. Slide 13, please. So just want to remind you the ALEXANDER Study Design, this is a Phase I/II study. In Phase I, AUTO3 a dose CD19/22 targeting cohort study in a dose escalation manner starting with 50 million CAR-T cells, then go to 150 million and then 450 million. The first 3 patients were dosed without pembrolizumab, the preconditioning regimen has fludarabine and cyclophosphamide. After that, patients were treated with pembrolizumab starting day 14 for 3 doses in regimen. When the emerging data showed that this was safe, we then introduced pembrolizumab as a single dose during preconditioning on day minus 1. And this has shown to be safe as well. Then we added 15-patient at RP2D dose level, which was determined to be 150 million to 450 million CAR-T cells with day minus 1 of pembrolizumab. And this cohort has been finished. Currently, we're enrolling in outpatient cohort before we do the Phase II. Now Slide 14, please. And just to remind you, again, the -- our eligibility criteria for this trial, this is an adult patient. So patient grown equal to 18 years old. Patients had to have either chemo refractory disease or relapsed DLBCL after 2 lines of therapy or after stem cell transplant. And we took basically the -- all subset of DLBCL, including high grade with mixed BCL2, BCL6, your standard double and triple hit patients. We also took patients with transformed DLBCLs from follicular lymphoma and transformed from other indolent lymphoma. We exclude the patient with prior transplant, hematologic, prior allogenic transplant, also prior CD19 or 22 targeted therapy. And basically, our criteria are the same as the pivotal trial population for Yescarta and also Kymriah. Slide 15, please. So this table shows you the baseline patient characteristics. As of ESMO data cut, 35 patients being treated, majority were DLBCL, NOS or high grade, about 23% were transformed DLBCL patients. This is, again, a very high-risk population. Majority patient had stage 4 disease, have refractory disease or hybrid IPI and again, heavily pretreated median on prior therapy of 3. The -- our median SPD shows the tumor burden of the patient population is very similar, again, to the other trials done in the CD19 therapy. Next slide, please, Slide 16. This slide shows you that in our trial across all dose levels, we did not see any severe cytokine release syndrome. 23% of patients developed Grade 1 CRS and 11% of patients developed Grade 2. Again, no Grade 3, 4 or 5 CRS was seen with the primary infusion. Only 5 patients required pembrolizumab for the treatment of CRS. We did not use prophylactic tocilizumab of any kind in the study. Slide 17. We only saw 3 cases of neurotoxicity, 2 were rated as severe. Again, important to know that we did not use any prophylactic steroids. Also, the 3 neurotoxicity were very atypical, all occurred in the context of tumor progression with 0 to minimal CAR-T expansion in peripheral blood. And of the patient that achieved at CR, we do not see any neurotoxicity of any grade. And also among the patients have robust CAR-T expansion, we did not see any neurotoxicity of any grade either. All 3 neurotoxicity, all had compounding factors as well. For example, sepsis, narcotic use, metabolic acidosis and ill altered abnormalities. Slide 18, please. We saw CR across all dose range. Overall, the overall response rate was 68% and CR rate of 54%. However, in our dose range, the AUTO3 dose range of 150 million to 450 million CAR-T cells with day minus 1 pembrolizumab. The overall response rate was 71%, with a CR rate of 64%. You see here that the total N here is 30 as compared to 35 for the safety analysis. That's because we only are reporting on the cohort of patients that have completed treatment and evaluable. Slide 19, please. Most interestingly, our CRs appear to be durable. You can see here, only 1 patient has relapsed after achieving CR. And this patient was treated at a lower dose level with 50 million CAR-T cells without pembrolizumab. All the other patients treated at higher than 50 million CAR-T cells or with pembrolizumab have either -- have not developed progression after achieving CR. And 93% of patients again that achieve CRs are without progressions with a median follow up of 6 months. Next slide. In summary, as reported by our investigators, AUTO3 has a tolerable and also best-in-class safety profile, 0% of patients had severe CRS syndrome with primary infusion. Also 0% of patients achieved had neurotoxicity in patient achieving CR with detectable CAR-T expansion. Overall, the study had 6% severe neurotoxicity rate, however, again, all cases of neurotoxicity reported were in the setting of disease progression, minimal CAR-Ts detected and with compounding factors. In the complete RP2D cohort, overall response rate at 71%, with a CR rate at 64%, and our complete response appeared durable, 93% without progression. And again, according to our investigator Dr. Tholouli at ESMO, this product does appear to be differentiated from approved CD netting card out there. And due to the improved safety profile, we do have an outpatient cohort that's enrolling at this time. Next slide. I wanted to introduce Brent Rice, who is our VP of the -- and also Chief Commercial Officer of Autolus.

Thank you, Rob. Good morning, everyone, and happy to be with you today. I'll be walking you through the commercial opportunity for AUTO3 based on its innovative design. Please turn to Slide 22. It's important to take a moment and highlight again the innovative mechanism of action that truly differentiates AUTO3 from other CAR-Ts that are being developed. It's a first bicistronic chimeric antigen receptor, first dual-antigen targeted CAR focused on CD19 and CD22. It has the OX40 and 41BB humanized co-stimulatory domains. As Christian highlighted, it's designed to address primary tumor escape mechanisms, PD-L1 upregulation and CD19 antigen loss. Its best-in-class safety profile with no Grade 3 or higher CRS and no neurotoxicity of any grade in patients that achieved CR. And 93% of patients achieved a CR with no progressive disease. Turn to Slide 23, please. On the next few slides, I'm going to walk through the current payer landscape and treatment patterns with the approved therapies to highlight the need for a product like AUTO3. These data represent all utilization from full year 2017 through year ending 2019. Due to continued Medicare Part A reimbursement concerns by centers with the current therapies, the majority of utilization is in the commercial setting. In fact, when we take a closer look at this on the right, less than 13% of all utilization is for Medicare beneficiaries, representing a significant untapped opportunity for AUTO3, which has been designed for use across all settings of care, including Medicare Part A, and Medicare Part B in the outpatient setting. Turn to Slide 24, please. As we take a deeper look into the outpatient opportunity, 97% of patients currently receive approved CAR-Ts is inpatients in centers of excellence because of the high rate and severity of toxicities and the need for intensive patient management. This represents significant upside for AUTO3, which can go where patients reside. When we look at other products helping to penetrate the outpatient studies such as liso-cel, we see continued challenges with 54% of patients requiring hospitalization, mainly due to CRS and other adverse events. AUTO3's best-in-class clinical profile positions it to be the go-to solution of choice for the outpatient setting. Turn to Slide 25, please. When we look at where CAR-Ts are currently being utilized from a center perspective, there's a high level of concentration in a few centers, reminding us of the referral challenges from physicians in the community. In fact, over 70% of all patients are treated in only 17% of the accredited centers of excellence certified to administer these therapies. AUTO3 mitigates referral networks by going where patients reside and provide centers, physicians and patients more choices and the needed flexibility to administer any outpatient or inpatient setting while democratizing used across all settings of care. Turn to Slide 26. The ALEXANDER expansion cohort is designed to further assess the feasibility in the outpatient setting, driving early adopters for a potential pivotal study in 2021. The expansion cohort will, one, allows centers to broaden their experience with AUTO3 and gain confidence in use as outpatient therapy; drive early adopters in a potential pivotal study, which could start the first half of 2021; allows us to build an understanding of healthcare resource utilization, facilitating the design of the pivotal study; and enables early exploratory metrics to be considered, which may be relevant to supporting an outpatient profile. I hope you share in our enthusiasm for the promise of AUTO3 for patients as we look to advance the clinical program. I will now hand the presentation back over to Christian. Please turn to Slide 27.

Thanks a lot, Brent. Much appreciate it. Moving to Slide 28. Let me briefly summarize kind of the key points for this update presentation. First of all, we see that AUTO3 continues to show a very high level of clinical activity with the CRR in excess of 60% in the recommended Phase II cohort. And it looks like, when we look across the whole safety profile, obviously, that we have a very favorable safety profile. What's quite compelling is that patients that do respond with a complete remission actually have not seen high-grade cytokine release syndrome or have seen any grade -- any neurotoxicity of any grade. When we look at the complete remissions, as I indicated in the introduction, the importance is to actually have sustained remissions. Obviously, the recommended Phase II cohort is still early on in observation. Looking at the totality of the data, obviously, it looks like the complete remissions we can induce are durable, and we're obviously looking forward to complete the data set on durability on the recommended Phase II dose cohort. And I think that's going to be one of the key updates that we're obviously looking for at the end of the year at the ASH Conference. And then finally, when we look in terms of the next steps of the program, you heard both Brent and Rob referred to the outpatient cohort. Obviously, that's a substantial additional set of data that we're collecting and almost fully enrolled in that cohort and are planning to give an update on that experience at ASH in the -- as the next conference update. So we expect by the end of this year, a very substantive set of data with around 50 patients experienced around the program, obviously, a large part of that at the recommended Phase II dose level. And with that, we'll have a very, very solid basis for the program and move forward into a pivotal phase. With that, I'd just like to remind you quickly on the final slide here, Slide 29, the upcoming events. Obviously, key events that we're preparing for next is going to be the ASH Conference with updates both on the AUTO3 program as just indicated as well as longer observations, and particularly on our Phase I experience with the AUTO1 program, which start to reach now up to 24 months of follow-up at most of the patients at about 12 months follow-up or more. So it starts to give us a very good view on the impact that AUTO1 has on these patients with acute lymphoblastic leukemia. And then obviously, as we move into transition into the next year and through the next year, several programs that will move into clinical development and will continue to obviously drive news events in the upcoming 12 to 24 months. So with that, I'd like to actually open up for questions.

[Operator Instructions] And our first question today will come from Jim Birchenough with Wells Fargo.

Congrats on the data update, looks terrific. A couple of questions. I guess just first, looking ahead to ASH and thinking about durability response. I guess, is there a certain target CR rate you'd like to have maintained at the time of ASH in terms of your target product profile? And I guess, similarly, on the outpatient cohort, are you looking just to keep any CRS to Grade 1, Grade 2, with no neurotox? Is that the profile that supports outpatient use? Or what do you view as the profile that will support -- go forward on the outpatient basis?

Tim, thanks a lot for joining. When we think about the -- what we're looking for and aiming for with this program is that this 3 months mark for the recommended Phase II dose, we'd like to see a CR rate at 50% or above, which we believe is very meaningful and gives us sort of a very clear direction with regards to the future opportunity here for the program. And when we look at the outpatient cohort, one of the key things, as Brent pointed out in his remarks, is that it gives us an opportunity and I'd assent as an opportunity to actually gain experience with a CAR-T program in outpatient setting. There are not an awful lot of who do have experience doing that, that's the first thing. Secondly, we obviously want to make sure that reproducing the clinical safety profile that we've seen up to now in the inpatient setting. And then finally, we also want to understand that should patients be admitted, what is the reason for the admission? What is the time that the patient would actually have to admitted? And also, is there any need or any use of ICUs required? So that's kind of the range and understanding of the resource utilization that you would have would be associated should there be an admission, but also understanding the level of patient management that is required. As a backdrop to that, I think it's important to understand that the patients we're dealing with here are obviously very advanced in their disease. Many of them have significant tumor mass. That tumor mass does often affect vital organs and can actually lead to a wide range of adverse events that are tumor related. So it is not uncommon that these patients do require intense management to get through these particular episodes and to get managed through that. So that is sort of one of the things that obviously as the backdrop that I think we're all working on. But it's important, obviously, that we have a very low level of immunological type of adverse events or neurotoxicity-related adverse events, which are the ones that are typically associated with the CAR-T therapy itself. And that is obviously giving us an ability to then actually have a therapy that is similar or in many cases, probably favorable over the current standard of care, which most of it is based on combination chemotherapy with either antibody or ADCs.

And then maybe just one other question just on CD19 and CD22 antigen expression. How well is that being characterized in the study? Are you seeing CD19 and CD22 positivity at baseline? And are you seeing loss of one of those antigens over time? And is the other pathogen expression driving the durability? Just trying to understand what you're seeing over time in terms of the antigen expression.

Very good question. It's an area we're studying quite intensely and obviously depends to quite an extent also on the availability of biopsies from those patients. What you -- what we do know in general about the CD19, CD22 expression is that with CD19, in particular, the cell -- the disease when you look at it, tends to be homogeneously positive. And with CD22, the vast majority are positive for CD22. When you look more carefully, what you do see with any antigen expression is that it can be variable. It can be variable over time or it can be variable also with regards to location. And so one of the nice things used in 2 chimeric antigen receptors in 2 different antigens is you can actually -- basically filter out or equalize these differences in levels of expression that you will find across tissue and give you a much better chance of actually having a very high probability of identifying the cell and being able to kill it.

And our next question will come from Eric Joseph with JPMorgan.

Just a couple in following up to the additional neurotoxin events that were observed here. You noted that these cases were seen in the setting of disease progression or other compounding factors. And so I'm just curious to know whether neurotox is an expected sequela of progressive disease or if these are, in fact, treatment-related events. Can you talk a little bit about their time of onset? And then sort of practically speaking, when you look towards development or commercialization in the outpatient setting, would you anticipate any, I guess, restrictions or by patient performance status? Are you seeing any correlation, I guess, in the emergence of this -- of neurotox with a patient's baseline characteristics?

Thanks, Eric, and thanks for the question. So first off, I think it's important to understand that what we're looking at in those patients are patients who have very high disease burden and very rapidly progressing disease, that is impacting multiple organs. As Rob was basically pointing to patients having acidosis, having all sorts of imbalances that are a consequence of major impact on vital organs in these patients. And unfortunately, those types of effects that are triggered by the late stage of the disease and, frankly, the disease burden in these patients can drive these types of adverse events and is, unfortunately, an observation we make across the field in these types of patients. In general, I think it is fair to say that the types of patients that actually did experience this adverse events were patients that you would never actually consider treating in an outpatient setting, frankly, because their condition is such from a disease burden and progression perspective that they do need very intense management fight through their very final stage of life. And so this is a patient, nobody would ever actually anticipate wanting to treat them in outpatient setting. I mean, that's why what we're observing here has no consequence as far as we can tell for the profile and the ability to actually treat patents in outpatient setting. So we don't think there is a connection there, and we don't think there is an impact. Rob, anything you would like to add?

No, you summed that really well. So in terms of trying to answer your question, the time line the neurotox. So patient #1 actually developed around day 53. So that's very atypical. And there's also around the time of tumor progression. So that's not going to affect the outpatient management of the patient because the patient would have been discharged long ago. The other 2 patients, basically the neurotox occurred around the time of disease progression, and those 2 are already inpatient to begin with. And again, rapid tumor progression, all these, like Christian said, multiple organ dysfunctions. So again, not what you just think of a 2 outpatient patient. In terms of outpatient cohort, we don't have any specific eligibility criteria that additionally, they have to fulfill. But investigators do have a choice of putting a patient on outpatient or not depending on how sick the patient is to begin with.

Got it. That's helpful. And maybe just a housekeeping question on the efficacy data in the Phase II dose cohort. Are -- should we, I guess, just reconciling patients that came on to study, ITT versus those who are valuable, are there -- should we expect additional efficacy follow-up for the patients that were not available at this data cutoff?

Absolutely. Obviously, we've completed, obviously, the recommended Phase II cohort, which is what we're presenting the data for or have presented here at ESMO. The outpatient cohort, obviously, will be reported in full, and obviously, all patients were reported on that.

Our next question will come from Ingrid Gafanhão with Kempen.

Congrats on the results as well. I have 2 questions, if I may. So first of all, I was wondering if you can give us a little bit more color on what are you seeing for those patients. You mentioned the patients that had neurotox didn't see any CAR-T expansion. So I was hoping you could elaborate on that. And the second question is can you remind us of which kind of prophylactic measures are being used in the other trials with CAR-T?

Thanks for joining. Ingrid. Rob, do you want to take those 2 questions?

Sure. So what we can say is from the other CAR-T programs such as Yescarta, Kymriah, they do associate higher rate of neurotoxicity with higher CAR-T expansion. And this is why we said that in our study, the 3 cases of neurotox are very typical because we basically saw almost no CAR-T extension in those patients. Whereas in outpatient that had robust CAR-T expansion, we did not see any neurotox of any grade. So I think that's the one differentiating factor. And what was your second question? If you can repeat that?

Yes, sure. I was wondering if you can just remind us what are common prophylactic measures or coming close to being prophylactic measures that are you in other CAR-T trials?

Sure. So the initial pivotal trial for Yescarta and Kymriah, they did not recommend prophylactic measures. However, later on in ZUMA-1, I think it was either cohort 304, they did introduce earlier use of steroid for neurotox prevention and early use of tocilizumab for CRS prevention. We just want to highlight that we do not use that at all.

And our next question will come from Mara Goldstein with Mizuho.

Just if you wouldn't mind a little bit more color around the subject of neurotoxicity. And given that the neurotox, these cases that you did see occurred in patients who did not have high levels of expansion, is there something comparable in a late-line population of background sort of demographic that we could look at in terms of understanding the rate that neurotoxicity could occur in a normal population? And then secondarily, on the outpatient trial. Is it anticipated -- on the outpatient arm, is it anticipated that you would fold that within a broader program? Or would it be a wholly separate registrational program? And then just lastly, on your allogeneic program with the anticipation of initiating trials in the fourth quarter of this year, are you any closer to disclosing what that indication might be?

Well, thanks for joining, and thanks for the questions. Starting with the second question on the outpatient cohort or whether that should be considered going forward as sort of separate entity. The answer is no, what we would like to do is actually include patients in outpatient setting into a pivotal study and actually have this as part of the actual experience in a pivotal study. So that is what we're planning for. So not as a separate approach. When we think about baselining as sort of the question you're asking there, I think, first of all, I'd like to remind you of the slide that Brent actually was showing before, and he was basically highlighting just basic neurotox rates across programs, just to basically put things a bit in perspective here. And what we basically showed is that what we've seen to date is 9% of the patients that have shown any form of neurotoxicity, and that compares between 30% and 64% with competitive programs. So that, I think, should give you at least some baselining at that level. When it comes to actually late-stage types of adverse events linked to organ failure, acidosis, et cetera, I would like to actually defer it to Rob and see whether you have any kind of particular type of studies that he might want to point to.

Well, I mean, it's very hard to differentiate that. I mean, what I want to point to is, if you look at our population of patients that achieved CR with robust CAR-T expansion, we're not seeing any neurotox. So you can assume that patients that have no exploding disease or would not -- would also not experience neurotox at all.

Okay. And then just ALLO program?

And then the last question, Mara, related to the ALLO program, that is obviously a program we're running in collaboration with our academic partners and is expected to start at the transition -- end of this year, transitioning to next year.

And our next question will come from Asthika Goonewardene with Truist Securities.

And congrats on the update to the data. I was wondering if you could give us maybe a little bit of color on ICU admissions for CRS and neurotoxicity. If I remember right, previous data, you didn't have any patients admitted to the ICU side of those. And I just wanted to double check and see if that was the case with the latest update? And then, Christian, you mentioned that you want to include an outpatient -- outpatients in the pivotal study. Do you also envision that your label at launch will carry sufficient data to make physicians comfortable with outpatient use? And then I have a follow-up.

Asthika, thanks for joining. I'll start with the second question. So there are 2 elements there. One is to include patients in -- that are part of an outpatient cohort in a pivotal study and have this part of the data package that we would plan to -- the answer to that is yes, and we'd like to actually do that. The second part of the question you asked about was about the confidence for the physicians to actually be able to do that. And I think confidence is, frankly, a question of experience. So what you have to do and what we'll see, I think, with every new modality that physicians have to get comfortable with and actually build experience on it, it requires actually having treated patients, having gained experience with the product. And I think that is going to be one of the key things that we're obviously doing with the current cohort to provide the first group of physicians, the ability to actually get experience with the product in outpatient setting and get confidence because of that. And then very clearly, as you would move a product that exist with this profile onto the market, obviously, you'd also have to also expect that physicians will need to sort of gain confidence and actually will use it more broadly over time. But I think there is development and there is a confidence built that is part in that process. I don't think that a pivotal study on its own does per se address because it is not necessary a question of data, but it's a question of your own personal experience, I think, as a physician as well.

Excellent. And then a question I had on ICU admissions on CRS and neurotoxicity? And then I have one more.

Sure. So I can answer that question. So as I've shown here, we did not have any serious CRS. So there were no patient admitted to ICU for severe CRS. In terms of neurotoxicity, only 1 patient while he got to ICU, and that was for multi-organ failure as well, okay? So only 1 of the 3 required ICU admission.

Got it. Great. And then I wanted to touch a little bit on kinetics. For AUTO3, I think I don't see maybe one slide where you showed the expansion, the in vivo expansion and I'm sure you're looking at this extensively. So Christian, hate to put you on this spot here, but maybe I was hoping you could tell us a little bit about what you're seeing that's differentiating in terms of in vivo expansion, persistence and engraftment versus other CAR-Ts on the type of analysis that you're doing at Autolus?

Obviously, we're running a broad set of analysis on that data, and then we'll report once the complete data set is together. I think more generally speaking, what we're aiming to do with this product is to have an ability to build to a significant level of activity without basically over having a period where the activity overshoots. Because basically, what you see with products that are very active very early on where the activity tends to overshoot, you also see alongside that, a very significant accumulation of cytokines and as a consequence, very significant cytokine release syndrome. And you can also actually have in that profile, you're much more prone to actually develop neurotoxicity as well as their CAR-T cells expand and redistribute across the body, which is sort of going along typically from a timing perspective with the onset of neurotoxicity. So what we're doing -- what we're looking to with our product actually, and this is how we also originally screened for it, is to actually have a very high level of cells with a limited amount of cytokines release associated, and we did present some of that data actually in the context of the ASCO presentation. So those were actually screening criteria. It goes back to the design that we put in with the particular types of cost inventory modules, that we're using as well. So it's really looking to actually get to a very high level of intensity of clinical activity, but avoiding and overshooting of that activity, and that's sort of what we're looking to do. So in general, what we're seeing is a delayed onset of -- from an expansion perspective, slightly delayed compared to some of the other programs. And clearly, from a cytokine release perspective, obviously, much, much reduced levels of cytokines that we actually do see produced in these patients.

And our next question will come from Biren Amin with Jefferies.

And congrats on all the progress. So Christian, I think you mentioned that the 3-month CR rate that you would hope to target with this is around -- is about 50%. What's your target for a 6-month CR rate, given that seems to be more predictive of a durable remission?

Biren, thanks for the question. And it's very interesting what you're pointing out, and that is actually that the CAR-T programs depending on the ones -- depending on which ones you look at, have slightly different profiles. What we saw, which is initially a fairly pronounced drop to 3 months and then actually less of a drop between the 3 months to 6 months mark and then between 6 months and actually 2 years almost a flat line, very, very little, very, very few events at that point in time. And some of the other programs looked a bit different. Kymriah also dropped relatively quickly, but we continue to drop beyond 6 months. And obviously, overall, having a less robust sustained CR rate than what was observed with Yescarta. And the liso-cel base, as presented, suggests sort of a similar behavior somewhere between the Yescarta and the Kymriah data. So when we look at it, obviously, what we believe is very indicative is actually, if we don't have early relapses in the first 3 months, we believe that is a very positive sign. But you have to be right, obviously, you want to see a sustained over time. Having the profile that we're seeing at this point in time, we believe, is very encouraging. But of course, we're going to continue to watch very carefully as these patients develop. What we would like to see is basically a sustained CR rate from 3 to 6 months. And that's obviously what we'll have to observe. And so far, in the patients that are longer -- have longer observations time, obviously, all patients seem to be able to make it from 3 to 6 months that we have enough observation time on. But the data at this point, of course, is still relatively small and obviously needs to sort of mature further.

Okay. And then just a question on the CRS that you present today. I think you reported the median duration of CRS in 35 patients was 3 days. I think in your last update earlier this year, just a few months ago, the median duration of CRS was 5 days. So you're seeing about a 2-day drop from the last update. Is there anything related to 12 patients that you've added from the last update that's changed that's driven that?

I don't think so. I think the challenge with every data set you look early on with relatively limited number of patients is that any kind of trends average, et cetera, get influenced significantly by individual events. And I think what you're seeing is that as we're adding more patients to it, that some of those early events get basically equalized over time. There is no difference that we're picking up in the patients nor is there any difference in the way that the patients are being managed.

Okay. And then I have a question on the outpatient cohort. How are you monitoring these patients for adverse events? Is there a nurse or someone that calls these patients on a daily basis to see how they're doing? Are there instructions being given to their caregivers? Or are they asked to stay within close proximity to the clinical site?

Rob, do you want to take that?

Sure. In terms of our protocol, we just require that the patient need to visit with the physician at least every 2 to 3 days, okay, in the U.S. We do recommend that somebody calls the patient daily, but it is not absolutely required. Does that answer your question?

Okay. Thank you.

And our next question will come from Matt Phipps with William Blair.

First, Christian, can you provide any more details on the patients that died at CR like 2 or 3?

Again, I'm handing over to Rob on that one since we have you on.

Sure. So this is a -- yes, this is a 83-year-old patient that had a horrible abdominal lymphoma disease. So prior to treatment with AUTO3, this patient had developed abdominal fistula from the lymphoma. The patient did achieve a CR with AUTO3, however, the fistula has not healed and eventually died due to complication infection from the fistula.

Got it. Okay. And Brent, how much would, I guess, the clarification and establishment of CMS reimbursement helps some of this commercial CAR-T landscape?

Yes. It's a great question. The CMS reimbursement landscape, as you know, is evolving with every rule-making cycle. So we now have some new rules in place for fiscal year 2021 with the MS-DRG 018, which is essentially a case rate replacing the NTAP. So that is a change on the Part A side. But I think that centers still have some concerns of reimbursement. And so that's why you're seeing a small percentage of the Medicare population being treated. The real opportunity on the Medicare side is the outpatient setting, where the reimbursement is more favorable, centers don't have to worry about being under reimbursed and the existing therapies just can't be utilized there because of the severe neurotoxicity CRS and the rate of those adverse events.

Got it. And can you just remind me, if a patient is treated outpatient, what's the time line for where they -- if they get readmitted within a certain number of days, you lose that outpatient reimbursement? Isn't there -- is it 3 days? Or I can't remember exactly what it was?

Yes. Yes, there is -- it's a good question. Again, that's specific to the Medicare population. And so if we look at the PPS exempt centers of excellence, which are the comprehensive cancer centers, it's 1 day. If we look at the nonexempt hospitals, then it would be 3 days. So if the patient is not admitted within 1 day in the exempt centers, which is where the vast majority of the use we're seeing right now, then it would stay outpatient. If it was a nonexempt center, then they couldn't be admitted within 3 days or that would revert back to an inpatient Part A claim.

And then liso-cel did have about 10%, I think, patients treated in an outpatient setting. But I can't say I've really heard much push for more use there for liso-cel based on that. Is that a function of the data itself? Or is that a function of not enough patients specifically in that outpatient setting? And I guess, does that impact maybe what you hope to enroll in a pivotal trial?

So when you look at -- obviously, at the disease population, the vast majority of patients are outpatients. They are about 80% of the patients are outside the centers of excellence and then a large proportion of the patients that are outside of centers of excellence also would actually be treated in outpatient setting. So I wouldn't expect this to be anywhere to be close to being short of patients rather the contrary. The exact reason for what you described, I don't think we actually would have the information on that. And what is obviously one of the elements, as I pointed out before, is obviously adoption in that setting will take some time because it takes physician experience every time, and that will take a bit of time to build up. And that may be a contributing factor, but I don't think there's any particular additional information that we have on our side.

Okay. Last question, Christian. Just to confirm what you hope to show end of this year, hopefully, at ASH for AUTO3. Is it just longer follow-up of these early CR patients here? Or we actually have some data on outpatient already available by the ASH update?

We will have both types of data available by the end of this year. And obviously, first things first, which is that the therapy has to be durable. So durability information matters a lot in this disease setting. And so that's an important part of the update at the end of the year. But secondly, obviously, we'll have experience from the outpatient cohort that we will share at the conference as well.

And our next question will come from Graig Suvannavejh with Goldman Sachs.

Nice on the data, a really great profile. Three questions, if I could. One, could you remind in terms of if there are any plans to think about moving the program into higher lines of settings, whether you feel you even need that for the commercial opportunity perspective? So that's my first question. Second, with the comments around moving the program into a pivotal, just wondering when you might be able to share more details around what that trial design might look like? Is that something we could expect at ASH? Or is it something that might be a 2021 event? And then my last question is, have you sized in terms of revenue what the potential opportunities for AUTO3? So if you could share that?

Thanks for that. So obviously, with regards to revenue, I think what we're pointing to is the fact that there is a very substantial patient population in last line setting looking over 10,000 patients, and that is going to give you a very sizable opportunity. With regards to moving up the life, I think it is very interesting, obviously, to -- when you think about the development path, you want to take with a program like this. If you have a back end of the disease, the level of CRs we're seeing in patients that are really heavily beaten at that point in time, I think, it is -- and do that, be able to get there with a good overall safety profile, I think, it is very enticing to actually look at moving to second-line setting in this indication. So very clearly, it's something we think about quite a bit, we think about the sequencing, et cetera, of those activities. But clearly, way too early to have a more detailed conversation around that. But very generally speaking, would you want to move up the line in this particular disease setting? I think the answer is clearly yes. And you see that actually also with as an example, the program that the KITE program, where you see the third-line setting initially and then the second-line data coming along quite imminently. So there's very clearly a push to do that, and there is every how to do it. Because clearly, the immune system of the patients are going to be in better shape earlier in earlier line setting than in late-stage setting. So I think there'd be an expectation that you might actually further improve outcomes for patients. And then with regards to, obviously, the path we're going to take with the program. As I indicated, clearly, the durability of the response, critical component, but in terms of the trial design, obviously, the experience on the outpatient setting, I think, will be an important part to include in a trial design and inform the house when that data matures to the point where that can be properly defined.

And ladies and gentlemen, this will conclude our question-and-answer session. I'd like to turn the conference back over to Christian Itin for any closing remarks.

All right. Well, thank you very much for joining today to this update. Obviously, we're very excited about where we are. We're excited about the consistency of the data we do see across the dose cohorts. And we're really looking forward to giving you the next key update just in a few months' time at the end of the year at ASH. Thanks a lot, and all have a great day. Thank you.

And ladies and gentlemen, the conference has now concluded. Thank you for attending today's presentation. You may now disconnect your lines at this time.