Autolus Therapeutics plc (AUTL) Earnings Call Transcript & Summary

Hello, ladies and gentlemen, and welcome to the Autolus Therapeutics ASH AUTO1 and AUTO3 Data Update. As a reminder, this conference call is being recorded. I would now like to turn the conference over to your host, Dr. Lucinda Crabtree, Vice President, Investor Relations. Please go ahead.

Thank you. Good morning or good afternoon, everyone, and thank you for taking part in today's call on the ASH AUTO1 and AUTO3 Data Update. I am 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 Head of Clinical Development; Brent Rice, our Chief Commercial Officer; Dr. Martin Pulé, our Chief Scientific Officer; and Andrew Oakley, our Chief Financial Officer. Before we begin, I would like to remind you that during today's call, our discussion 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, December 7, 2020, regarding future events and should not be relied upon as representing the speakers' or 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. So turning to Slide 3, you will 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. Nushmia Khokhar to run through the AUTO1 data, with Brent, again, providing an overview of the adult ALL market opportunity subsequently. Christian will then summarize the key messages for today and provide concluding comments. And of course, we will welcome your questions following our remarks, which will be taken by the panel outlined here. So with that, I'd like to turn the call over to Christian.

Thank you very much, Lucy, and we're moving to Slide #5 and move -- look at the -- have a quick look at the team today at this call. As already introduced by Lucy, obviously, with me are Martin Pulé, the Chief Scientific Officer; and Andrew Oakley, the CFO. But the presentation, obviously, will be carried by Rob Chen on AUTO3, Nushmia Khokhar on AUTO1 and Brent Rice on the positioning of the programs. Moving to Slide 6. Our data update for AUTO3 is based on an October 30 data cut. We're excited about the consistency of the safety profile for AUTO3 between the inpatient and outpatient cohort. We see limited cytokine release syndrome and neurotoxicity. There is no need to take any prophylactic measures, and the product is well manageable in the outpatient setting. Efficacy is consistently high, showing a high CR rate of 51% across all patients and conditions evaluated in this Phase I study. Subsequent analysis of dose levels of 150 million to 450 million cells showed a 73% CR rate in patients who received a 450 million cell dose. We are pleased with the differentiated product profile and plan to update our next steps in Q1 2021. Moving to Slide 7. Switching gears to AUTO1. We're very excited about the updated durability data with first patients reaching 24 months in molecular remission with AUTO1 as a single therapy. We confirm the well-tolerated profile and a high level of clinical activity of the program and point to the substantial commercial opportunity. Now let me hand over to Rob, who will take you through the AUTO3 data update presented at ASH. Rob?

Hello. Good evening. So I'll be presenting the results of the Phase I/II study of AUTO3, the first bicistronic chimeric antigen receptor targeting CD19/22 followed by anti-PD-1 in patients with relapsed/refractory DLBCL of the ALEXANDER study. Moving on to Slide 9. We know that although the currency netting CARs are active, there's still a high unmet need. First, the durable CR rate can be improved. Also, the occurrence of severe CRS and neurotoxicity limit the use of CAR-T in patients. Dual-targeting CD19 and 22 may reduce antigen-escape mechanism and PD-1/PD-1 interaction between the tumor and CAR-T can inhibit the CAR-T function and by giving pembrolizumab, which is a PD-1 inhibitor, may prevent this. Turning to Slide 10. So AUTO3 is the first CD19/22 dual-targeting CAR. It has 2 independent CAR delivered in a single retroviral vector. Each CAR is optimally designed to independently target CD19 and 22. Additional features include humanized binders and pentameric spacer on the CD22 CAR and OX40 as a costimulatory domain on the CD19 CAR. Slide 11. The ALEXANDER study design is a Phase I/II study. The Phase I portion has 3 components. There's dose escalation cohort, an RP2D cohort and an outpatient cohort. In dose escalation, we tested 3 doses of AUTO3, 50 million, 150 million and 450 million. We also tested 2 different regimen of pembrolizumab. Initially, 4 patients were treated without pembrolizumab to evaluate the toxicity of AUTO3 by itself. Then pembrolizumab was added on day 14 post-peak CAR-T expansion for a total of 3 doses. Low rate of toxicity allow pembrolizumab to be moved to day minus 1 dosing regimen as a single dose prior to CAR-T expansion as a preconditioning regimen. After the -- that was declared safe, then we declared RP2D to be 150 million to 450 million AUTO3 and day minus 1 pembrolizumab. And then this was expanded for approximately 17 patients. And all patients have been built in this cohort. The third component is the outpatient cohort and 17 patients have also been dosed in this cohort so far. I'm moving to Slide 12. The outpatient expansion cohort was added to look at the feasibility of giving AUTO3 in outpatient study. There is no difference in inclusion or exclusion factors except for social reasons. Patients who do not have caregiver support or patients who live greater than 60 minutes away from the trial site are excluded. In terms of monitoring, this was very simple. Patients were required at a minimum to be seen every 2 to 3 days for 10 days for AUTO3 infusion. Turn to Slide 13. The table shows you the baseline patient characteristics of the study. This trial includes relapsed/refractory DLBCL patients. As you can see, it's a very high-risk population due to majority of patients having refractory disease, stage IV disease and high-risk molecule features such as double-hit, triple-hit and double-expressor lymphoma, and it's also very heavily pre-treated population with a median number of prior therapy of 3. Also, the median SPD shows that a tumor burden in our trial was similar to the other CD-19 CAR-T trials. Moving on to Slide 14. These tables show the treatment-emergent adverse events greater and equal to 25% of patients, and then the seriously adverse event greater and equal to 5% of patients. So as you can see, majority of the Grade III or higher adverse events are hematological in nature. And the majority of the SAEs are related to fever or infection. And these type of AEs and SAEs is expected of a CAR-T trial in third-line setting in DLBCL. Turning to Slide 15. Based on predefined study cohort of the dose escalation and then the RP2D and outpatient cohort, we actually saw a very low rate of CRS and neurotoxicity. Overall CRS rate was 35% and overall neurotoxicity was 6%. Turning to Slide 16. Looking at CRS in closer detail, with respect to the dose of cells received by the patient. Number one, no prophylactic measures was used in this trial; two, majority of CRS were Grade I only; three, only 1 case of Grade III occurred, and this was not at a dose at 300 or higher, and only 16 patients required use of tocilizumab for the treatment of CRS. Looking to Slide 17. Examining the neurotoxicity in detail, again, with respect to the dose received, overall neurotoxicity was low and consistent with the prior observations reported. We did not see neurotoxicity of any grade actually at doses of 300 or higher. The 3 cases of neurotoxicity are all atypical in the context of tumor progression with multiple confounding factors. And as per Dr. Ramakrishnan's ASH video presentation today, based on his experience, this profile appears to be better than the current approved [ treatment ] in CARs. Turning to Slide 18. This is the efficacy analysis based on a pre-planned cohort. The overall response rate is 65% and the CR rate is 51%. And we see CRs at every single dose level. And at the RP2d cohort with 150 million to 450 million AUTO3 cells with pembro day minus 1, the overall response rate is 66% and the CR rate of 55%. Turning to Slide 19. In the post-hoc analysis, we looked at the responses based on the cell dose received. We observed a CR rate of 62% when AUTO3 cell dose of 300 million and higher and then CR rate of 73% at AUTO3 cell dose of 450 million, which is very high. Turning to Slide 20. Looking at the disease assessment of CR patients, our CRs are durable, with 16 out of 22 patients remained without progression. Of the 6 patients who have relapsed, 1 did not get pembrolizumab and 5 patients received 1 dose of pembrolizumab. All the patients who received 3 doses of pembrolizumab did not have disease progression, and the median duration of CR was not reached in that group. Turning to Slide 21. Cellular kinetic was associated with the response. Patients who achieved CR or PR appear to have higher expansion and persistence based on and Cmax and AUC. Turning to Slide 22. An important feature of this ASH update was addition of the outpatient cohort. This was done to assess the feasibility of AUTO3 in outpatient study. 17 patients were dosed in the outpatient cohort. Among the 17 patients, 4 patients received AUTO3 inpatient due to reasons such as social, bulky disease and complication of bridging therapy. 13 patients out of the 17 received AUTO3 as outpatients. And among the 13, 5 patients were admitted for fever, febrile neutropenia or CRS. Important to note that no patient was admitted for neurotoxicity. The median duration hospitalization was 5 days, and no patient required ICU care at all. Turning to Slide 23. So in conclusion, AUTO3 is tolerable and has a best-in-class safety profile. AUTO3 also has a high CR rate with a CR of 73% in patient receiving 450 million AUTO3 cell dose, and CRs are durable with ongoing CR observed beyond 24 months. The outpatient demonstrated that AUTO3 can be given safely in the outpatient study with low rate of admission. Now let me hand over to Brent, who will touch on the potential commercial opportunities in DLBCL.

Next slide, please. Thank you, Rob. Good afternoon or good evening, everyone, and happy to be with you. So while we're on the topic of AUTO3, I'd like to take a minute and walk you through some of the commercial considerations. If we could turn to Slide 25. Data from the outpatient cohort as presented by Rob reinforces the feasibility of AUTO3 as a true outpatient therapy. As I've stated previously, the current therapies have been primarily relegated to academic centers of excellence only and in the inpatient setting due to the high rate and severity of toxicities and intense patient management that's required. This limits the size of the market and available patients to approximately 20% of the total opportunity. Based on AUTO3's clinical profile and the data from the outpatient cohort, it is positioned well to allow treatment across all settings of care, thus growing the size of the market and reaching the full addressable population while enhancing the available reimbursement options. In fact, over 80% of third-line-plus and second-line patients are treated outside of academic centers of excellence. Turn to Slide 26. As we further build upon the outpatient opportunity, 97% of patients currently receive approved CAR-Ts as inpatients in centers of excellence due to the need for intense 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 setting such as liso-cel, we see increasing challenges with 63% of patients requiring hospitalization, mainly due to CRS and other adverse events, including an ICU admission, as presented on December 5 at ASH. AUTO3's best-in-class clinical profile positions it to be the go-to solution of choice for the outpatient setting. Turn to Slide 27, please. In conclusion, AUTO3 is uniquely positioned to penetrate the outpatient setting, including academic, nonacademic and community oncology clinics in the ALEXANDER trial. It should be noted that the majority of second-line patients are treated outside of academic centers and community clinics, which generally do not refer to centers of excellence, potentially mitigating challenges with referral networks, and accessing more flexible reimburses. AUTO3's product attributes and potential to reach the full addressable second-line and third-line-plus population make it poised to be best-in-class. I would now like to turn the presentation over to Dr. Nushmia Khokhar, who will walk us through the AUTO1 clinical data. Turn to Slide 28, please.

Thank you very much, Brent. Good afternoon, and good evening, everyone. As Brent mentioned, we will switch gears now to the AUTO1 study. This is ALLCAR19 study, and updated data using AUTO1, a novel fast off-rate CD19 CAR in adult patients with relapsed/refractory B-ALL. I will be highlighting the data that was presented by Claire Roddie at ASH on Saturday. If we move to Slide 29. Prognosis in adult patients with B-ALL is poor. About half the patients that achieve an initial CR will relapse. In these relapsed patients, the only curative option is an allogeneic stem cell transplant after achieving a second remission. The patients achieve second remission -- have to achieve a second remission to be able to proceed to this transplant. The newer options like blinatumomab and inotuzumab are available, and they have high response rates. However, these are short-lived, and these therapies are mostly used as a bridge to transplant. Historically, CD19 CAR-T cell therapies deliver excellent response rates but at the cost of considerable toxicities, especially in the elderly. Currently available CD19 CARs use a high-affinity binder. AUTO1's CAR-T cells are different. They are designed to have a lower affinity binder with a fast off-rate, thus allowing a more physiological T-cell activation, improved engraftment and potential for long-term persistence. If we move to Slide 30. This slide shows the ALLCAR19 study design. This is a Phase I non-randomized single-arm study in adult patients with ALL. All patients that were enrolled onto the study underwent leukapheresis. They proceeded to receive bridging therapy as necessary. Then patients got standard preconditioning regimen with fludarabine and cyclophosphamide, subsequently followed by AUTO1 infusion. The target dose for all patients was 410 million cells. This was given as a split dose on day 0 and day 9. The fractionation of the dose, though, depend on the disease burden at baseline as assessed by the blast count in the bone marrow. Patients that had a lower disease burden of less than 20% blast got an initial dose of 100 million cells, followed by a final dose of 310 million cells given on day 9. Patients with high disease burden, that is a blast count of greater than 20%, got a dose of 10 million cells, followed by 400 million cells given on day 9. In all patients, the second split dose was not to be given in case patients had a Grade III or higher CRS or neurotoxicity. Moving on to Slide 31. As this is a Phase I study, the key primary endpoints were around safety, namely rates of the Grade III to V adverse events, also feasibility of manufacture. Some of the key secondary endpoints included the response rates and the depth of response after treatment, persistence of the CAR-T cells, disease-free survival and overall survival. The key eligibility criteria are also listed here on this slide. Notably, this is a study conducted in adult patients with relapsed/refractory disease. And also there's no exclusion for prior blinatumomab or inotuzumab treatment. Slide 32, please. Overall, 26 patients were registered, 25 patients underwent leukapheresis, and product was made for 24 patients. As of the clinical cutoff date, 20 patients were treated. 100% of successful leukapheresis resulted in a product being manufactured. During the course of the study, the manufacturing process moved from an open-manual process to a closed semi-automated process with most products being manufactured with this closed process. Advantages of this closed process are more rapid and scalable manufacturing and also a favorable phenotype enriching for central memory and naive T cells. Overall, the mean transduction efficiency for all products was 66.5% and the range being 50% to 83%. Moving to Slide 33. Of the 20 patients treated, these are baseline characteristics. Few things that I would highlight, the median age here is 43 years for these patients. These patients were heavily pretreated with a median of 3 prior lines of therapy. However, the range goes up to 6 prior lines of treatment. A significant portion of these patients had received prior blinatumomab and inotuzumab. Also, interesting to note that 65% of these patients had failed a prior allogeneic stem cell transplant. I would also like to highlight that about half of these patients had very high disease burden in terms of more than 50% blast in the bone marrow at the time of treatment. Slide 34, please. Looking at the expansion kinetics and the persistence of the CAR-T cells, all patients had a robust expansion, and most patients had detectable CAR-T cells at their last follow-up. And it's important to note that patients have long-term persistence, with CAR-T cells being detected now up to 24 months. Comparing this to published data from Kymriah in pediatric patients, where the cells may be more robust and fit, it is remarkable to see that the area under the curve, seen with AUTO1 product, is almost double that of Kymriah, and the maximum CAR-T levels detected are also significantly higher. Next slide, please, 35. The safety data for the study is as follows. 50% of patients had CRS. However, all of this was Grade I and Grade II. Notably, no patient had Grade III or higher CRS. Grade II CRS was primarily seen in patients with high disease burden, and overall about 35% of patients received tocilizumab to manage CRS. Neurotox of any grade was seen in 20% of the patients. Only 3 patients had a Grade III neurotox, and all of these patients had very high disease burden with more than 50% blast. Again, I would note that these cases were manageable with steroids, and most cases of neurotoxicity resolved to Grade I or better within 24 hours, and all of them resolved to Grade I or better within 72 hours. Grade III neutropenias are seen at baseline, and about 7 of the 20 patients had Grade III neutropenia that predated their AUTO1 treatment. After AUTO1 treatment, Grade III neutropenia was observed at day 28; however, most cases resolved by month 2 or 3. As for the deaths seen on the study, overall 7 patients died on the study: 3 due to disease progression or complications post progression; 4 patients died from infection as listed on this slide; 2 were prior to their day 28 evaluation; 1 was MRD-negative CR at 6 months; and unfortunately, 1 patient passed away due to COVID. Moving on to Slide 36. The efficacy and the duration of response is highlighted here. The first thing I would like to mention is that overall the response rate was very high at 84%. So this was a complete response rate with MRD-negative CR seen at day 28. Of the patients that have relapsed, 3 relapsed with CD19-negative disease and 2 with antigen-positive disease. Another important thing to highlight here is only 3 patients received a transplant while in remission, and most patients in CR continue in CR with MRD-negative disease without subsequent therapy, including transplant. The median follow-up for the entire population is about 17 months, but if I can draw your attention to the patients with the longest follow-up now at 24 months and beyond in MRD-negative CR. Moving on to Slide 37. As mentioned previously, the overall response rate at MRD-negative CR rate is 84%. The EFS for all patients at 6 months is 69% and 52% at 12 months. The median duration of response for the entire population has not been reached, and the median EFS is not reached. Next slide, please, which is Slide 38. The ALLCAR19 study has also included small cohorts to evaluate AUTO1 in indolent non-Hodgkin's lymphoma, a cohort in high-grade lymphoma and also a cohort in CLL that is highlighted here. The cohort that has enrolled patients thus far is cohort 1 in indolent B-non-Hodgkin lymphoma, and I will present some of that early preliminary data from that cohort. Slide 39, please. So this cohort in indolent lymphomas is enrolling robustly. As of the data cutoff, 8 patients had been enrolled and 4 patients had received treatment. The product characteristics and baseline characteristics are listed on the slide. Few things to highlight that the patients enrolled have MCL and follicular lymphoma. They are heavily pretreated with a median of 3 prior lines of therapy, and most of them have advanced stage disease. Moving on to Slide 40. Of the 4 patients that have been treated, all are evaluable for safety and efficacy. 3 of these 4 patients have a Grade I CRS. No patients had Grade II or higher CRS, and no patients had neurotoxicity of any grade. All 4 patients had robust CAR-T cell expansion, and at month 1 evaluation for all 4 patients showed a complete metabolic remission based on the Lugano Criteria. Just as an example, the PET scan of one of the patients is shown here. They had diffuse disease at baseline. And as you can see, at month 1 scan, the disease is cleared giving a complete metabolic remission. Similarly, serial lymph node biopsy showed lymphoma cells as seen by the brown staining in that slide before treatment and subsequent clearing of the disease with treatment. Moving on to Slide 41. So to summarize for AUTO1, in conclusion, AUTO1 has a tolerable safety profile that has been observed. Despite high disease burden and despite patients being heavily pretreated, there's no Grade III or higher CRS seen. 3 of the 20 patients that had a Grade III neurotoxicity or ICANS resolved rapidly with steroids. Robust expansion is seen across all patients, and now prolonged CAR-T cell persistence is observed all the way out to 24 months, which happens to be the last data point and the longest follow-up we have. Efficacy in adult patients with relapsed/refractory ALL is impressive. MRD-negative CR rate is achieved in 84% of the patients as assessed at month 1. The EFS at 6 and 12 months is 69% and 52%, respectively, in all treated patients. Responses are durable and ongoing. CRs are observed beyond 12 months, supporting the development of AUTO1 as a stand-alone therapy. And as I highlighted, most of these CRs are without needing autologous -- or allogeneic stem cell transplant. Also, as seen, the early data from the indolent non-Hodgkin lymphoma cohort is promising. And the last thing to highlight is that a global Phase IB/II AUTO1 study, which is a potentially pivotal study, is ongoing in relapsed/refractory adult ALL patients. That was the last data slide. And with that, I will hand it back to Brent to discuss some of the commercial opportunities in adult ALL.

Thanks, Nushmia. If we could move to Slide 43. I'd like to take you through some of our commercial considerations in adult ALL. As you know, despite current treatment options, adult ALL patients have significant unmet need associated with both clinical and economic consequences. And there are no CAR-Ts currently approved. ALL patients are generally more fragile with more co-morbidities, while CAR-T toxicities in this setting have been notable with high incidences of severe CRS and fatal neurotoxicity. AUTO1 represents a potential new choice for patients with an opportunity to conduct further clinical study for second-line treatment, increasing the total addressable population. And as a reminder, the FDA has granted AUTO1 orphan drug designation for adult ALL. Turn to Slide 44, please. I'd like to take just a few moments to highlight the challenges and key features needed for a successful therapy in adult ALL. As you know, adult ALL is a fast-proliferating disease with poor patient outcomes. The need for very high levels of sustained anti-leukemic activity and good tolerability are key. The ideal CAR-T candidate will have rapid CAR-T-mediated pill with appropriate cell expansion coupled with long CAR-T persistence and minimal tox profile. Turn to Slide 45. When we take a closer look at AUTO1's clinical profile, it has a potential superior efficacy profile when compared to standard of care. AUTO1's CR rate is 84% in all patients, and 92% in patients treated with the closed process, while blinatumomab's CR is 44%, respectively. Furthermore, 6-month and 12-month EFS was quite promising at 69% and 52%, respectively, across all patients. It is important to note approximately 50% of blin and ino patients received subsequent transplants unlike AUTO1. Turn to Slide 46, please. The commercial opportunity for Autolus is significant with relapsed/refractory adult ALL being 3x the size of relapsed/refractory pediatric ALL. And let's not forget that in the last-line setting, autologous CAR-T therapies are the only therapies with curative potential and not much competition and no other CAR-Ts are approved in this space. Turn to Slide 47. As we look to capitalize on AUTO1's unique profile beyond adult ALL, we have 4 Phase I trials enrolling by Q1 next year. And these are an indolent NHL and CLL, primary CNS lymphoma and pediatric ALL with our bicistronic dual-targeted formulation. Turn to Slide 48. AUTO1 has been designed for potential best-in-class use as a stand-alone therapy and not a bridge to transplant with high rates of durable complete response. The potential for a more manageable safety profile in patients with low disease burden will inform the select feasibility of hospital outpatient administration in both academic and nonacademic transplant centers, which should open access to a larger market opportunity. All of this, coupled with the opportunity to pursue in earlier lines of therapy and indications outside of adult ALL, potentially positions AUTO1 as a truly transformative therapy. I will now hand the presentation back over to Christian.

Thanks a lot, Brent, and we're headed for Slide #50 for a summary. We're excited about the emerging profile for AUTO1. We're starting to see long-term molecular remissions in patients at 24 months of observation and see an overall high level of 52% event-free survival at 12 months across the trial with a median follow-up of 16.9 months. Combining this high level of clinical activity with good tolerability points to an emerging transformational profile. The commercial opportunity in third-line ALL is significant and can be expanded by moving to earlier lines over time. In addition, we're starting to explore the profiles for AUTO1 in indolent lymphoma and primary CNS lymphoma. And finally, we just started exploring a novel AUTO1 22 in pediatric ALL, as you just heard from Brent. The key update on AUTO1 demonstrated feasibility for administering and managing AUTO3 in the outpatient setting. Low rates of high-grade CRS and very low levels of neurotoxicity are the basis for the favorable safety profile. Complete remission rate is high across all doses and conditions evaluated. Analysis of dose activity relationship points to elevated CR levels at higher dose levels. We are assessing the development strategy and believe the profile may expand the utility of CAR-T in DLBCL. The next update is planned in the first quarter 2021. So with that, let me take you through the upcoming milestones and moving to the last data slide, 51. Our key focus is on moving AUTO1 forward in the Phase Ib pivotal study, expecting to enroll through 2021 with data in 2022. AUTO1 program is being broadened into NHL, and we expect data updates on those exploratory trials in 2021. In addition, the new pediatric program has started with the next-gen version of AUTO1 called AUTO1/22. As indicated, AUTO3 next update is planned in Q1. Moving to AUTO4, the program is progressing, and we expect to present data in 2021. Several additional programs are being progressed towards Phase I studies, including AUTO5, AUTO6NG, AUTO7 and AUTO8. And with that, I would like to close the presentation and move to the Q&A session.

[Operator Instructions] Our first question or comment comes from the line of Mara Goldstein from Mizuho.

Just a couple questions on the AUTO3 data that was presented. I know that you spoke to that outcomes were correlated with higher levels of expansion of the cells. Were there any differences also by dose? And then secondarily, on the outpatient setting, are there any -- are you contemplating any prophylactic measures going forward for that outpatient setting just to minimize any risk of CRS or inpatient admission?

First of all, thanks a lot for joining, Mara, and thanks for the good questions. So starting out with the -- whether there's a relationship between outcomes and expansion related to dose, obviously there is a relationship between dose and outcomes that Robert was walking us through. I don't think there is a clear-cut correlation between the dose and expansion itself. But what we do see is the correlation between outcomes of responses and expansion of the CAR-T cells in vivo. The second question related to the outpatient setting, as first Rob walked through and then Brent alluded to in more detail as well, the program -- the product obviously has a very good profile. We have a relatively low admission rate. And what was very important is actually to understand what does it take to manage these patients, for those patients that actually have to be admitted. And as Rob pointed out, the patients were well manageable, predominantly managed for fever and basically an antibiotic's cover. So there is probably possibilities to consider some prophylactic treatment, but you want to be careful because you want to also make sure, particularly as it pertains to potential mitigation around CRS is that you actually don't want to actually impede the mechanism of action. So we don't foresee to use agents like steroids, just to be very clear. What we might want to consider is to actually give some prophylaxis with regards to actually protection against infection. I think that's probably covering the question. Thank you, Mara.

Our next question or comment comes from the line of Gil Blum from Needham & Company.

Congratulations on all the progress. So now that we see some feasibility for AUTO3 in the outpatient setting, what do you guys think about potential for earlier lines of therapy, especially considering it appears to be very safe and is feasible for administration?

Gil, thanks a lot for your question. I think a very good question because one of the challenges, I think, we see in non-Hodgkin's lymphoma in general is that, obviously, the patients that are treated through the early lines of treatment are predominantly treated in outpatient setting and safety profile of the therapies does matter a lot in that particular setting. We have seen that CAR-T therapy can be very active in these early lines with some of the first -- early programs in the space actually moving towards second and high-risk frontline settings. But of course, you need to combine that with an attractive safety profile. We believe that the safety profile for AUTO3 is very attractive in that regard and, I think, would bode well for an opportunity to over time move into early lines of therapy.

All right. Could you perhaps share some of your thoughts on the duration of response in the longer-term for AUTO3? So there's some recent presentation for 4-year data from Yescarta showing around 32% patients remain in response. And we're currently seeing about 45% of responders with over 6 months' response. How do you see this evolving moving forward?

I think that is -- frankly, it's too early to call because obviously our observation time, with the exception of the early patients in the study, is still very limited with a lot of the patients obviously enrolled over the last 6 to 12 months. So I think we just need more data, more follow-up time to understand kind of the overall profile from a durability perspective. I don't think there is more, I think, we can say at this point. We need more observation.

That's fair. And kind of a last one on AUTO1. So we're seeing the potential for development in non-Hodgkin's lymphoma. How does this fit in with your development plans for AUTO3? Is there any like cross-talk here at all?

I think what we want to make sure is we want to get a good feel for the program in a broader set of non-Hodgkin's indications because one of -- the program obviously has some interesting features. It obviously, as demonstrated in both pediatric ALL and adult ALL now, has a very good safety profile, is an enormously active CD19 CAR that also does have an ability to put long-term pressure on disease. The longest follow-up we have is in pediatric patients of more than 3 years of follow-up with CAR-Ts measurable in the blood. So those are very interesting features. And what we're trying to get feel for is as we're looking at a set of indications from follicular, mantle cell, CLL, DLBCL, get a sense for the feature of the -- how the feature fits with those particular settings. And as pointed out and just as you asked before with early lines of therapy, if you go into more indolent settings as well, it becomes very important to actually have a product that has a very good safety profile, not only very high level of activity. And there may be some interesting sort of profiles that may emerge over time. But that's what we're exploring with the program and, frankly, be guided by the data.

Our next question or comment comes from the line of Matt Phipps from William Blair.

Christian, a few questions, but I'll try to be brief. So obviously we are seeing some progressions from the last update at ESMO in the 1-dose pembro cohort. Have you been able to look at these anymore? Are you guys considering going back and adding another dose of pembro or 2? I know it's looking at small numbers of patients to make those comparisons. But what is your current thinking on the, I guess, the number of doses of pembros and maybe reasons for these relapses?

Matt, thanks for joining. I would say, what we've done in the trial is we tested 2 schedules of pembro. The first schedule we tested was a sequential use of pembro where we first spoke to the full activation of the CAR-T cells, go through the full peak of the activation, and then start pembrolizumab after that with 3 doses is the first regimen we tested, which gives us about a 3 months cover. The second dosing we tested is actually to add pembrolizumab to the preconditioning regimen and have a full overlap of pembro activity and CAR-T activity. And what we're basically demonstrating with both of those regimens is that both of them are safe. And that gives us actually an ability and a range to use pembrolizumab, either in a single dose or actually 3 doses, including starting 3 doses at day minus 1. It is interesting, as you pointed out, that the patients we have longest observation for are patients that have received 3 doses of pembro, and they did fare well. It's a small number, as you pointed out, but it is interesting to see that. And obviously we'll want to get more information also from the additional final patients in the outpatient cohort and then from there actually deduce kind of the best path forward in terms of the overall dosing regimen for the program.

Okay. So still moving there. Can I also ask how consistently can you manufacture 450 x 10^6 cells? Is that a limitation in some of these patients? And anything you can do to try to increase that since it does seem to have higher CR rate?

It's a very good question, Matt. So what we were doing in the recommended Phase II dose cohort is we were producing between 150 million and 450 million cells. And we're exploring a number of parameters also within the manufacturing process. And we did basically produce 150 million, 300 million and 450 million doses. What we do see is, obviously, for those patients that we managed to go to the upper end of the range by growing the cells to that level, that we do see an improved outcome. And that obviously gives us a very nice guidance in terms of refining and focusing on the manufacturing process that we're using going forward.

Okay. And last one from me. How -- I'm sorry if I missed this, in the outpatient cohort, what was the time from infusion to admission for those 5 patients? How many days from the duration of hospitalization, by the time between infusion in the outpatient setting and requiring admission?

Rob, do you want to take that?

Sure. So the median was 2 days for the 5 patients that were admitted. But obviously it's a very low number at the time. So that can change.

Our next question or comment comes from the line of Jim Birchenough from Wells Fargo Securities.

It's Nick on for Jim this afternoon. Just one question. Can you comment on the mechanism of relapse you're seeing in the ALEXANDER trial?

Nick, thanks for joining. In terms of mechanism of relapse, I don't think we have a good sense at this point what mechanism is at play. And I think it takes more -- frankly, more events to start to actually see a picture. What we're not picking up is we're not picking antigen losses as a driver, as you would expect with the tool targeting. That's not something we're picking up. But in terms of the reasons for the relapses that we're seeing, I don't think it's -- I don't think we have a good handle on that at this point. We'll need more follow-up information and frankly a larger data set.

Okay. And then just going back to the question on pembrolizumab dosing. Is the 400-milligram dose allowed or is the 200-milligram dose being used for the day minus 1?

It's the 200-milligram dose used.

So the obvious follow-up then is, is the 400 allowed or would you look at that in sort of separate cohort as it were?

Well, what we've seen is we've seen, obviously, in terms of the safety information that we have at this point is that we know that using either 3 doses of 200 milligrams sequentially starting on day 14 and onwards or to actually have a 200-milligram dose overlaid with CAR-T infusion, both of those approaches are safe. So we do know that we can safely combine a 200-milligram dose, either single or 3 doses with a CAR-T activity. We do not at this point have experience actually going to 400-milligram pembro.

Okay. And then in terms of the 5 outpatients that were hospitalized, did any of those received toci?

Rob?

Yes. Some of them did receive toci, but not all of them, because some were admitted just for febrile neutropenia.

And then just last one for me. On the AUTO1, these data are really tremendously impressive and in the context that I think Gilead saw a 41% rate of Grade III neurotoxicity in marginal-zone lymphoma, and that is one of the tumors allowed in the expansion cohorts. Have you treated a marginal patient yet? And if so, obviously, can you comment on if you saw any neurotoxicity?

So we -- obviously, we have not seen neurotoxicity in the patients, but I do not recall top of my head. Nushmia, whether we had a marginal-zone in there?

Christian, I'm afraid, Nushmia has dropped off.

Okay, to my knowledge, we had mantle cell lymphoma and pre-follicular lymphoma patients in. We didn't have a marginal cell lymphoma -- marginal-zone lymphoma patient.

And you could expect severe neurotoxicity in the mantle cell lymphoma patients as well, and we didn't see it.

Our next question or comment comes from the line of Biren Amin from Jefferies.

Christian, I guess, on AUTO3, you're planning on an update to investors in Q1 of 2021. Is that more of a data update? Or are you potentially -- is that more of a go/no-go decision on whether to move the program forward into pivotal studies next year?

Biren, we seem to have lost, Christian. So let me just sort of step in and answer that one at this time. Yes. Look, what we expect to be able to do is to update the Street in terms of where we are with the program in Q1. I don't think at the moment that we can say too much more on that, whether it's a go/no-go decision. But we've got a little bit of analysis to do. We'll do that and sort of update everyone in Q1 as to where we are.

Got it. And then can you just maybe talk about the manufacturing fail rate with AUTO3 currently?

We were able to manufacture all the cells in AUTO3 at this point. There was no manufacturing failure.

Got it. And then maybe just on the outpatient setting, were these patients sent home? Or were they instructed to remain close to the academic center where they receive the cells? And how much of -- I guess, it seems like if the median was 2 days on admission to the hospital, I'm assuming that these patients were being monitored on a daily basis. Can you just talk a little bit about your process for monitoring these patients in an outpatient basis?

So number one, these patients always require that they live within 60 minutes of the center for the first 10 days post-infusion. And whether that could be the home or a hotel close by, after that 10 days, there is no requirement that they have to stay close by. And for that first 10 days, the requirement is that they need to be seen at a minimum every 2 to 3 days by a physician, okay, not daily, every 2 to 3 days. We do recommend a daily verbal communication between the patient and the qualified medical personnel from the site. But in terms of the requirement, just every 2 to 3 days seen once by the physician or a qualified medical personnel.

Our next question comment comes from the line of Eric Joseph from JPMorgan.

The first one related to the outpatient cohort study, can you just clarify what some of the medical reasons were for the 4 patients that had to be treated or infused with the product in the hospital and just sort of how that compared.

Yes. So sure. For example, a patient that had bridging therapy and had neutropenic fever or infection, they just stayed in the hospital. They did not get sent out to get outpatient therapy because they've just had a major infection from complication from bridging therapy. Okay. So there's one scenario. Another scenario is very refractory disease, bulky disease, the physician just decided that this patient would do better inpatient.

Got it. Okay. And maybe just contrast that with sort of expectations sort of in sort of a real-world or commercial setting as you think about potentially transitioning this for outpatient commercial use, with the experience here what you'd anticipate in a setting outside of a clinical trial.

Eric, this is Christian. I'm actually back. I managed to dial back in. So apologies for having dropped calls a little while back. I think probably Brent will probably be well positioned to answer this question.

Yes. Thanks for the question, Eric. I mean as we continue to treat patients in this setting, it will further inform the feasibility and the actual patient-monitoring protocols that were put into place in the commercial setting, both in the hospital outpatient setting, which would include nonacademic and community clinics. And so as we put those measures into place, and there are some already going into place with, for example, liso-cel kind of setting, setting that up for their products, we see a really smooth transition for AUTO3 based on the tox profile, the low hospitalization rate, to be able to administer in the outpatient setting, have those protocols in place. And the feedback that we're getting from those sites that would like to participate in the Phase II study is very -- they're very excited. They really want to be able to participate because of the data that we've been able to put forward and the promise that it has for patients.

Got it. And just a follow-up question, if I could. Given that we're kind of seeing the difference in progression pattern based on the density of -- or the extent of pembrolizumab use, is there any reason to think that pembro might be having some non-CAR-T-mediated contribution to response or durability of response? And to the extent that, that is the case or you think that might be the case, are there any considerations or implications for a pivotal study design that takes into account -- that might address combination roles?

Eric, it's a good question. When we look at the use of either pembro or nivo in DLBCL, there's virtually no activity that was reported in the trials that were conducted in the space. So there is not an expectation whatsoever to actually have activity. And this is -- was actually in the context of continued ongoing therapy with the PD-1 monoclonal, and it still wouldn't actually get to any significant level of activity. So to see complete remissions is something you wouldn't expect at all based on pembrolizumab and nivolumab in that setting.

Our next question or comment comes from the line of Graig Suvannavejh from Goldman Sachs.

Congrats on the progress as well. I just have a few. One, just on the hospitalization rate where you had 5 patients, I'm wondering with that 38% figure that you cited, is there ways to optimize that? Is that an acceptable percentage of hospitalization? I just want to get your thoughts around that just on a go-forward basis so we can think about the outpatient opportunity. Also, just maybe a question on AUTO1. I think that there's been a change in when top line data would be available, and it's now 2022. I just want to confirm if that's simply related to kind of getting sites open or COVID-related delays? And then how do you think about with the different trials that you've got ongoing, how we should be thinking about your ability to mitigate kind of COVID and the timing of the starts or progress with your clinical trials? And then maybe just a last question, if I could. We've had a change in administration or one that's anticipated relatively shortly. So are there any kind of changes in reimbursements that you would expect might be coming that might be more favorable for CAR-Ts or any programs that you're aware of?

Well, thanks a lot, Graig. Thanks for joining. The first question relates to the rate of hospitalization, whether that would be acceptable. We actually believe that there's 2 aspects in terms of understanding whether it's -- what is a good profile in that space. The first, obviously, is you want to make sure that you can actually manage the patients well and the majority of the patients in outpatients, I think we can clearly do that. For those patients that have to be admitted, you want to make sure that the effort that has to go into managing these patients is minimal so that the burden on the hospital, the burden on the system is minimal. And we believe actually what we're seeing in the trial actually is very favorable. As pointed out, nobody had to go to ICU. There was limited intervention primarily actually managing fever and ensuring that there is no infection ongoing in these patients. But that's basically the extent of the management that was required, which is very minimal and, frankly, can be done in any hospital in any setting. So that was the first question. The second question, the AUTO1 time line. Very clearly, we did start to actually accumulate issues related to -- or delay related to COVID. We did highlight that, that was a risk in the Q3 earnings call, and we pointed out if things would actually start to further develop that in a negative way, that that could actually start to become an issue. What we are seeing is obviously, I think, a very broad impact across most of the areas in the U.S., obviously all across Europe, where we see various degrees of lockdowns and other types of limitations that we see in terms of the not only daily life but, of course, any aspect from logistics all the way through to actually the capacity within hospitals. So we have to assume that this is not going to go away over the next few months, and we took the decision to change the guidance because of that. And I think that is just -- I think, it's important just to be mindful about it. Now the AUTO1 study is particularly vulnerable in the sense that it is obviously enrolling or expected to enroll at a higher rate than the other studies that we have currently ongoing, particularly the Phase I studies. And with that as well, having a patient population that has very little time to spare. So disruptions that it would have in supply chain, et cetera were particularly challenging. So we're going to slow that down, and we're going to run at a slower rate until we got sort of into safer ground and can sort of accelerate from there forward. The last question was related to the U.S. government change of administration and potential impact on reimbursement. I think that is probably too early to actually have any good sense around. But we would think that there's going to be a good level of continuity in terms of the general government policies as we go forward. And I think we just have to see kind of what the new administration is planning to do once it actually starts to be in office and operating.

Our next question or comment comes from the line of Ingrid Gafanhão from Kempen.

I just would like to come back again to the point of the decision on AUTO3 in Q1 '21. You were originally thinking about moving quickly into the Phase II portion of the trial, which could potentially be registrational. So I'm just trying to understand how the data has maybe changed your mind in that if you think you actually may need to do -- to look more into the data or you actually think you may be able to get to a bit of a quicker way to the market.

Yes. I mean we were pointing to an opportunity to move the program forward in the first half of next year. And we're pointing to the fact that the decisions around designs, et cetera will be made, obviously based on the ASH data, and we're consistent in that regard to providing an update in Q1 on the path that we're planning to take.

All right. And should we expect then some additional data to come with that update?

No. Because obviously this is a major update in terms of data that we've given. We're close to 50 patients now. There's obviously a bit more follow-up on the outpatient cohort but up to those data points will be presented obviously at upcoming conferences. We're not planning sort of interim updates as we go through the course of next year.

I'm showing no additional questions in the queue at this time. I'd like to turn the conference back over to management for any closing remarks.

All right. Well, thank you very much all of you for joining. I know we've been in all sorts of time zones at this conference. I'd like to thank those of you who stayed up very late to sort of listen to the call and obviously everyone else in the U.S. who obviously are still operating at a reasonable time of the day. We'll keep you updated, obviously, as we go into next year, and we're looking forward to continue the conversation. Thank you very much.

Ladies and gentlemen, thank you for participating in today's conference. This concludes the program. You may now disconnect. Everyone, have a wonderful day.