Precision BioSciences, Inc. (DTIL) Earnings Call Transcript & Summary

Good day, and thank you for standing by. Welcome to the Precision BioSciences' CAR T Program Update. [Operator Instructions] I would now like to hand the conference over to your speaker today, Alex Kelly, our Chief Financial Officer. Please go ahead.

Great. Thank you, Cindy, and good evening, everyone, and welcome to our webcast to discuss the progress we're making with our allogeneic CAR T pipeline. Before we begin, I would like to remind you that some of the statements that we make today are forward-looking statements within the meaning of the Private Securities Litigation Act of 1995. Such forward-looking statements involve known and unknown risks, uncertainties and other important factors, including risk factors, which are included in our quarterly report on Form 10-Q. With -- you can find our SEC filings on the SEC website or also on the Precision BioSciences website. All forward-looking statements speak only as of this date, and except as required by applicable law, Precision has no obligation to update or revise any forward-looking statements made today. This evening, we are joined by Michael Amoroso, our CEO; by Dr. Alan List, our Chief Medical Officer; and Dr. Derek Jantz, our Co-Founder and Chief Scientific Officer. We're also fortunate that Dr. Bijal Shah, Associate Professor of Malignant Hematology Department at H. Lee Moffitt Cancer Center and Research Institute and the principal investigator in our PBCAR0191 clinical trial will join us for the Q&A. With that, let me turn the call over to Michael Amoroso.

Thank you, Alex, and welcome to our investor community during the 63rd Annual ASH Conference of 2021. We appreciate you sharing your Saturday evening with us. Today, we plan to talk to you about Precision BioSciences. Starting with a bit of background on our identity as a gene editing company. Based on the wholly owned proprietary platform known as ARCUS, created by our very own Derek Jantz, Chief Scientific Officer; as well as another team member, Jeff Smith. We believe ARCUS is the most advanced gene editing platform in the world today. ARCUS is unique as it's the only gene editing platform whose foundation is a natural homing endonuclease, versus other platforms built from bacterial restriction enzymes which have a much higher rate of cutting. What this means, is we are able to replicate precise gene editing as it evolves in nature. And why this matters with our first main differentiating point around Precision, ARCUS is precise. It gets to the target DNA site, makes it edit and turns itself off, the nature of the homing endonuclease to minimize off-target cutting. In addition, ARCUS leaves a unique signature in the genome due to a 4 base 3 prime overhang cut that allows our world-class protein engineers to tag ARCUS edits in the genome and ameliorate any minimal off-target editing to make it inconsequential. This is incredibly important for patient safety and is the backbone of the focus of our gene editing process at Precision BioSciences. Next, ARCUS is unique and biologically evolved due to its versatility, and this advantage is twofold: one, not only can ARCUS knock out a gene, but it's also designed for a high sophistication edit such as gene insertion and/or gene repair. Second, ARCUS' unique size. It's small, 364 amino acid chain, much smaller than any other gene editing technology. This allows ARCUS to be delivered to a wider range of cells and tissues using any viral or nonviral gene delivery method. Today, we will focus on the application of ARCUS in our ex vivo allo CAR-T programs, where we knock out the TCR and insert the car in our allogeneic CAR Ts. Next, I'd like to take a moment and share with you my first 50 days and the privilege of being the Chief Executive Officer of Precision BioSciences. What I have found has been really fortifying for the reasons I've joined, world-class team, top scientists, a world-class gene editing platform, ARCUS, as we've discussed. Our approach to first and best-in-class allo CAR Ts, which is the focus of today's call and our time together, creates a very exciting time in the evolution of Precision BioSciences as well as for our patients. The sharing of data to drive thoughtful evidence-based decisions going forward, more of which you'll learn tonight from Dr. List and Dr. Shah as well as Derek Jantz. And last but never least, our exciting portfolio of in vivo programs, 3 of which we intend to file INDs over the next 3 years. Lastly, I will outline tonight's agenda. PBCAR0191 update, Dr. Alan List, our CMO, will further expand upon Bijal Shah's presentation from today, earlier this afternoon. Then we will move into an update as we had promised at ASCO for our myeloma and BCMA programs. Finally, we aim to give further clarity on our path forward and milestones for clinical data that can be expected from the external community as we move forward. Thank you again for joining us, and I'm now going to turn it over for our first-in-class approach in our next slide, where Dr. List will talk to you about PBCAR0191, the overall results and our path forward. Alan, please?

All right. Thank you, Michael. The update that I'm sharing with you today is focused on our experience with what we refer to as our Enhanced Lymphodepletion or eLD regimen. This includes both the data presented earlier today in the oral presentation by Dr. Shah as well as additional updates since the October 10 cutoff for the ASH presentation. As I'm sure that most of you are aware, this is a Phase I/II study, evaluating escalating doses with PBCAR0191, ranging from 3x6.0 cells per kilogram to 3x6.0 cells per kilogram at dose level 3 in patients with relapsed/refractory lymphoma and B-ALL. The eLD regimen was developed to achieve a longer, albeit limited duration of leukopenia to ultimately improve expansion and persistence of PBCAR0191 to increase both the rate and durability of response. As you can see in the scheme of slide, this includes 4 days of fludarabine at a dose of 30 milligrams per meter square, beginning on day minus 6 and cyclophosphamide at a dose of 1,000 milligrams per meter squared on day minus 5, through day minus 3, a dose that is double that used in our standard Lymphodepletion regimen. All patients received the 3x6.0 per kilogram cell dose, which is dose level 3, which allowed us to directly compare the results to patients treated with the standard Lymphodepletion regimen. The objectives of this approach were to reduce host immune rejection sufficiently to increase cell expansion and persistence in order to improve clinical outcomes while maintaining a manageable safety profile. The results we are sharing today include both relapsed/refractory lymphoma and B-ALL patients. So expansion kinetics are shown on this slide, Slide #9, if you're following along, as measured by PCR. As you can see, peak expansion with eLD, shown here in purple, was profoundly higher than our experience with standard lymphodepletion in blue, reaching a 21 fold increase in peak expansion accompanied by a 47 fold increase in the total area under the curve with good persistence evident at day 28. I might point out that subjects were able to begin treatment quickly with all subjects beginning lymphodepletion within 24 hours of completing eligibility assessment. The vast majority of patients had very poor risk features and advanced disease, with 14 of the 18 or 78% of the lymphoma patients having aggressive histology. Overall, the median lines of prior therapy was 5, but range as high as 15 lines of prior therapy. 3 of the 5 ALL subjects are 60% and 7 lymphoma subjects 39% had a prior allogeneic or autologous stem cell transplant, respectively, whereas 5 lymphoma and one ALL subject also progressed following an auto CD19 directed CAR T cell therapy. I want to emphasize that this is a very different population compared to that that's enrolled in the prior auto-CAR T cell trials. Select adverse events with eLD and maximum grade are shown here according to disease type. Despite the robust cell expansion, there were no cases of grade 3 or greater CRS in subjects with lymphoma or ALL. There was one grade 3 ICAN in lymphoma subject that resolved the grade 2 or lower within 72 hours. There was no evidence of graft-versus-host disease, which is consistent with the known insertion of our CAR into the track gene locus. The longer depth and duration of neutropenia was associated with grade 3 or greater infection in 44% of lymphoma patients and 8 or 80% of the ALL subjects, which is not unexpected in this heavily pretreated patient population. There was one infection related death at day 54 that was deemed possibly related by the treating physician. There were a total of 3 other infection related deaths again not related to PBCAR0191. The best response to PBCAR0191 occurring at day 28 or later is shown here, among all 22 evaluable eLD study subjects, 16 or 75% had an objective response and 13% or 59% achieved a complete response. I want to point out that one patient did not have a day 28 response assessment because of cardiac arrest related to a choking incident. The overall and complete response rates are comparable between both the auto-CAR T naive subjects and those that received a prior auto-CAR T treatment. 3 of the 6 auto-CAR T treated patients also had received a prior autologous stem cell transplant. Comparison response rate and death according to the disease type, appears similar, as you can see on this slide. Among 17 lymphoma, day 28 evaluable subjects, the overall response rate was 71% with a CR rate of 53%. Among the 5 ALL subjects, the overall and complete response rate were both 80%. The similar plot for the lymphoma patients is shown here, illustrating response depth, the duration and time of progression or death. The color coating for outcomes and prior auto-CAR T treatment or allo cell transplant is shown on the right-hand side of the slide. Overall, core responders reached 180 days, which is illustrated at the top of the figure. Subject one reached day 280 before disease progression and subject 5 with lymphoblastic lymphoma underwent an allogeneic stem cell transplant while in CR at day 148. 2 responses are ongoing, one approaching day 250. On Slide 15, the similar plot for the ALL subject as shown. Patient '18 at the top of the figure achieved an MRD-negative CR that has now extended beyond a year. This patient was not evaluable -- was not eligible, excuse me, for an allogenic transplant. 3 of the 5 subjects overall achieved MRD-negative CRs, one died in complete remission, one received an allogeneic stem cell transplant while in CR around day 90, and #18 remains an ongoing response. To summarize the data that I've shared so far, we found that Enhanced Lymphodepletion successfully mitigated the rejection of PBCAR0191 cells as evidenced by the marked improvement in peak cell expansion and AUC compared to standard Lymphodepletion. Despite the significantly increased peak, there was no grade 3 or greater CRS events and one self-limited Grade 3 ICANS. As might be expected in this heavily pretreated patient population, prolonged cytopenias were associated with more grade 3 or greater infections. And as a result, moving forward, we will adjust the lymphodepletion regimen and consider further escalation in cell dose. Although this is a more advanced population compared to the third line use of auto-CAR T, eLD yielded high rates of overall response 73% and CR rates of 59% that rival response rates achieved with commercial auto-CAR T products in a less heavily treated patient population. What may differ is durability of response, which at the current cell dose of 3x6.0 cells per kilogram appears lower. Consistent with the advantage of an allogeneic CAR T product, all of the subjects began with a depletion within one day of eligibility determination. What I'm excited to share with you next is what we consider a compelling signal for PBCAR0191 in patients who have relapsed falling response to treatment with an auto-CAR T product. We believe that positioning PBCAR0191 as potential salvage following disease progression from auto-CAR T treatment provides a differentiated path forward to be the first-in-class allogeneic CAR T product. There's no doubt that auto-CAR T cell therapy has transformed the landscape for patients with lymphoma. And as we heard earlier today, in the transform trial here at ASH, and we will here tomorrow in the plenary session, it has now overtaken autologous stem cell transplant as second-line therapy. These successes have also created a rapidly growing population of patients who progress following auto-CAR T cell therapy that lack effective salvage therapies. These patients have a poor prognosis with a median survival of only 3 plus months and therefore have a high unmet need. Overall, as many as 40% of patients do not respond to treatment with an auto-CAR T, and 60% of patients who do respond will ultimately relapse. Retreatment with cryopreserved auto-CAR T cells or a new product is not affected, given the poor functional attributes of CAR T cells from these patients who relapse. A total of 6 subjects treated with Enhanced Lymphodepletion have progressed following response to an autologous CAR T cell product, including 5 with lymphoma and one with ALL. PBCAR0191 was the first salvage therapy after auto-CAR T in only one patient. And the lines of the salvage therapy after CAR T ranged as high as 5. Each of the 6 patients responded to PBCAR0191 with 4 complete responses and 2 very good partial remissions. Included in this plot is the estimated duration of response to the auto-CAR T for each subject as estimated from the interval from the date of infusion to the date of next salvage therapy. The top arrow for each subject represents duration of response to the auto-CAR T and response to PBCAR0191 is represented by the second arrow. You can see that the response duration to PBCAR0191 exceeded the original response to the auto-CAR T in 3 of the 5 evaluable subjects that are captured within the purple box at the top of the slide. One patient who achieved CR experienced CNS progression, and there was one infectious death in CR. The ALL patient at the top of the figure remains in an MRD-negative complete response that is now beyond a year. This particular patient had relapsed following 2 prior allogeneic stem cell transplants in the auto-CAR T and is therefore not a candidate for another allogeneic stem cell transplant. To understand why this population of patients may be uniquely suited to benefit from an allogeneic CAR T, we are sharing with you plus of CD3-T cell recovery following Enhanced Lymphodepletion. This figure compares CD3 counts in subjects that are auto-CAR T naive in blue, with those subjects who relapse following a prior auto-CAR T treatment shown in purple. What you see is that auto-CAR T relapse subjects, not only a deeper CD3 cell mater, but also delayed CD3 recovery, which together could impair rejection of PBCAR0191. This particular population of patients who relapsed or failed a response to auto-CAR T cell therapy typically have poor product self-fitness that contributes to failure of the auto-CAR T treatment that relates to chemotherapy-induced reduction in early lineage T-cells that's necessary for expansion and to optimize cytotoxicity. In other words, these particular patients who progress following auto-CAR T cell therapy -- these patients do progress following auto-CAR T cell therapy because of inherently impaired immune integrity arising from the prior lymphoma therapy that may also mitigate PBCAR0191 rejection. This slide illustrates PBCAR0191 cell expansion kinetics in auto-CAR T naive subjects in blue compared to those who relapse filing on auto-CAR T, which, again, is shown in purple. Consistent with the CD3 recovery we shared in the previous slide, auto-CAR T relapse subjects experienced earlier cell expansion, higher peak expansion and more prolonged persistence compared to auto-CAR naive subjects. The area under the curve in the auto-CAR T subjects was 3.2 fold higher compared to the auto-CAR T naive subjects. Data that are consistent with the notion that these patients indeed have impaired immune capacity for Allo-CAR T rejection. Although our data are limited, we feel that these encouraging results suggest that PBCAR0191 with eLD may offer an effective salvage approach for patients who relapse following auto-CAR T therapy, where suboptimal product cell fitness contributes to treatment failure. PBCAR0191 offers a product with assured fitness that is generated from a healthy donor, using a single gene edit to optimize expansion potential and cytotoxicity. The impaired immune integrity that contributes to failure of the auto-CAR T product also appears to reduce PBCAR0191 rejection to improve cell kinetics, including both expansion and persistence. Each of the 6 subjects who progressed following auto-CAR T responded to PBCAR0191 with a CR rate of 66%. In 3 of the 5 evaluable subjects, the duration of response to 0191 exceeded the duration of the prior response to auto-CAR T. The ALL subject experienced a prolonged MRD negative CR but now exceeds one year after failing 2 allogeneic stem cell transplants and auto-CAR T. Going forward, we will prioritize lymphoma patients who relapse following auto-CAR T to validate the activity and safety of PBCAR0191 in this growing population with high unmet need. Okay. Now I'd like to share a clinical update on our PBCAR269A or the BCMA targeting program. The PBCAR269A Phase I study involves 2 separate cohorts, beginning with cohort A, which is monotherapy, followed by cohort B, which is in combination with the Gamma Secretase Inhibitor nirogacestat and relapsed/refractory patients with multiple myeloma. Patients received our standard lymphodepletion regimen, followed by a single infusion of PBCAR269A with a starting cell dose of 0.6x6.0 cells per kilogram and escalating to a maximum dose of 960x6.0 cells as a flat dose at dose level 4. The combination in cohort B begins at dose level 2, which is 2x6.0 cells per kilogram. Cohort A monotherapy cell kinetics that were assessed by flow cytometry are shown on this slide, which shows a dose-dependent increase in peak cell expansion as well as AUC. The overall response across dose levels was 29%, which included one very good PR at dose level 4 and 3 partial responses. PBCAR269A kinetics and Cohort B in combination with nirogacestat in 5 patients at dose level 2 are shown here compared with dose level 2 and dose level 4 cell kinetics with monotherapy. Peak cell expansion in AUC and the gamma secretase inhibitor -- with the gamma secretase inhibitor dose level 2 mirrored the expansion kinetics seen with dose level 4 monotherapy, indicated that nirogacestat combination for family improved cell expansion. To summarize our experience with PBCAR269A to date, we observed a dose-dependent increase in cell peak expansion with monotherapy with no grade 3 or greater CRS or ICANS. One monotherapy subject achieved a deep response at very good PR at dose level 4. Monotherapy had a favorable safety profile altogether, however, activity is below the high threshold of autologous CAR T. For that reason, we will focus on PBCAR269A in combination with the gamma secretase inhibitor, which is ongoing with 5 subjects dosed to date that has yielded much greater expansion compared to monotherapy. We anticipate be able to share this data on the combination by mid-2022. Finally, we will await more mature data from the GSI combination before proceeding the filing of the BCMA Stealth to IND. Now I'll turn it over to our Chief Scientific Officer, Dr. Derek Jantz, to share our best-in-class allogeneic CAR T cell products.

Thank you, Alan. So Alan just told you that we think we have a potential path to being first in allogeneic CAR T by focusing on patients who have relapsed following a prior auto-CAR T. But in parallel, we continue to be very interested in developing a best-in-class allogeneic CAR-T platform. And what we mean by this is shown on the next slide. What we're aiming for is a therapy that is administered as a single dose that is made using a single gene edit, and that's to avoid the possibility of chromosome abnormalities, resulting from making multiple gene edits in the same cell. And importantly, we want a therapeutic index that is as good or better than the on market autologous CAR Ts. So in other words, we want a therapeutic platform that will displace autologous CAR T. As Alan just told you, we're seeing very good response rates with our first-generation platform, but we're not sure we're quite able to match the durability of an autologous CAR T yet. And in fact, we don't think anybody in the Allo CAR T field has demonstrated durability equivalent to an autologous product. The reason for that, we think, is that nobody has yet shown that they can overcome the challenge of the allogeneic CAR T cells being rejected by the patient's immune system. So with these last few slides, I want to give you a quick glimpse into some efforts that we have underway to avoid rejection. The first of these is shown on the next slide, Slide 30. This is our second-generation platform that we call the Stealth Cell. Stealth Cell differs from the first-generation CAR Ts that Alan just showed data for in that it has 2 additional modifications aimed at avoiding rejection. The first of these is an shRNA that represses expression of beta-2 microglobulin, which is intended to mitigate rejection by the patient's T cells. And the second is a transgenic copy of HLA-E, which is intended to prevent rejection by the patient's NK cells. We believe that both of these modifications are necessary to prevent rejection in a patient. And in preclinical studies, we've shown that Stealth Cell CAR Ts are, in fact, able to avoid rejection by both cell types, T-cells and NKs. Next slide, please. PBCAR19B is our anti-CD19 CAR T built on the Stealth Cell platform. It incorporates an anti-CD19 CAR as well as the 2 additional Stealth Cell modifications. Importantly, all 3 components, the CAR, the B2m shRNA and the HLA-E transgene are carried on a single vector that is introduced using a single gene edit. That's really important. We've been saying for a really long time that making multiple edits to a CAR T cell at the same time is a bad idea because it introduces chromosome abnormalities, which could lead to cell transformation. So we have gone to great pains to ensure that both of our CAR T platforms are based on a single gene edit. Next slide, please. Our Phase I study for PBCAR19B started in June. Unlike the first generation study that Alan just talked about, in 19B, we are dosing at a flat dose and using standard Cy/Flu lymphodepletion. The first dose level in the 19B study is approximately equivalent to dose level 3 in the first generation study that Alan just described. So dose level 1 in the 19B study is potentially an efficacious dose. The first 3 patients have been enrolled in the study, because the FDA allowed us to start at a higher dose, we had to build in a significant time delay between the first 3 patients, but are now able to enroll more quickly. We're actively enrolling at multiple sites and expect to be in a position to give a meaningful update on the program around the middle of next year. Next slide, please, Slide 33. I wanted to wrap up with a new tool that we have in our toolbox that we haven't talked about much. Earlier this year, we announced a licensing agreement with Tiziana to access their anti-CD3 monoclonal antibody, which is called foralumab. We're interested in using foralumab as a lymphodepletion agent that is specific for T-cells and that's because we know that at least for our first-generation CAR Ts, the patient's T-cells are the primary driver of rejection. CD3 is a component of the T-cell receptor and the T-cell receptors already knocked out in all of our CAR T cells. So we don't need to worry about foralumab binding to our CAR Ts. So the antibody binds to the patient's T-cells, but it leaves the CAR Ts alone. Next slide, please. Foralumab could help us avoid rejection of our CAR Ts in 2 different ways. First, it can cause direct elimination of the patient's T-cells through CDC or ADCC. But foralumab has also been shown to induce CD3 internalization, which causes tolerance. So it may be possible to at least partially tolerize the patients to the foreign CAR T cells. This approach of using an antibody for lymphodepletion is somewhat analogous to the use of an anti-CD52, but with a few very important differences. First, we don't need to knock out CD52 in our CAR Ts, which requires a second gene edit, which as I just mentioned, is something we've worked really hard to avoid. Second, foralumab is highly specific for T-cells, so it only engages the cells we're concerned about driving rejection. CD52 is expressed on a wide range of immune cells and causes widespread immune suppression. Lastly, foralumab has a shorter half-life. So by controlling dose and dosing frequency, we think we can control the depth and duration of lymphodepletion to avoid prolonged immune suppression and the associated infection risk. So overall, it should be a much safer approach than anti-CD52, because all of our CAR T cells lack CD3 foralumab should be compatible with all of our PBCAR therapies. We intend to investigate it first, in combination with an anti-CD19 CAR T, but have not yet decided if that will be the first generation PBCAR0191 or the second-generation Stealth Cell. If you would please turn to the concluding slide, Slide 35. We believe that we have a potential path to a first-in-class allogeneic CAR T in our first-generation PBCAR0191 product, and we'll focus our enrollment on patients who have relapsed following prior auto-CAR T. Expect the next data for that around the middle of next year. And around that same time, middle of next year, we expect to give an update on the first patients treated with our second-generation CD19, that's PBCAR19B, which is the Stealth Cell. And we will give an update on our first-generation BCMA in combination with the gamma secretase inhibitor nirogacestat. So that's a lot of data being generated in the first half of 2022. And then lastly, we do expect to update one of our 2 CD19 INDs next year to include the use of the anti-CD3 antibody foralumab as a means of delaying CAR T rejection as part of our best-in-class CAR T strategy. And with that, I thank you all very much for your attention, and we can take any questions you might have.

[Operator Instructions] And first question from Soumit Roy of JonesTrading.

Congratulations on the very robust data. Could you expand a little bit on the approach to target the prior CAR T relapsed patient? Is the focus really to establish a 19 or 19B as superior to affiliate CAR T and compete there or really be a sequence product? Or you're just focusing it as a faster path to market. And the second…

Sorry go ahead please.

The second question is, could you elaborate a little bit on the 3 deaths with the complete responders, 3 unrelated and one related, is it infection based anti-CD3 and enhanced lymphodepletion would actually increase the infection chances?

Soumit, it's Michael. I appreciate the questions. Before I turn them over to Alan, I would say, just to answer your first question, 0191 on a first-in-class approach, we believe there's a patient population post autologous CAR T right now, a growing population as Auto-CAR T in NHL will move from third line plus to the second line standard of care for fit and healthier patients. This is a growing population with a high unmet need. We think that the combination of 0191 as well as with the tailoring approach of our lymphodepletion and the immune system of this patient has potentially an option, again, I'll remind you, the median survival in this population is a little better than 3 months. These patients have dire and urgent need. So we believe 0191 has a place in the lymphoma relapsed/refractory setting treatment paradigm today. In parallel, Soumit, to your point, in parallel, we will not give up on the fact that autologous CAR T is complex. It's make per order for patient. And that is a profile where we see response rates and complete remission best response today with 0191 on target with autologous, but our durability is not quite where it needs to be yet for that. So we will not give up on that entire population. We're going to continue to pursue an option there and that's where our best-in-class approach is always looking for the bar to be as good, if not better, than our autologous profile in totality. So the answer to your question is both. I'm going to let Alan expand a little bit on why the post autologous CD19 population is such an urgent need at the time as well as on the infectious deaths. Please, Alan.

Sure. Happy to talk about that, Soumit. It's a good question to ask. And so overall, the one that was deemed possibly related, was a patient that had a pneumonia at day 54, and this occurred back in December. It was believed actually to be at fungal pneumonia. But what this patient has in common with the other 3 deaths in the trial is prolonged myelosuppression. So delayed neutrophil recovery. The others had bacterial infections that contributes to their demise. So I think the other thing to remember about these subjects, they were heavily pre-treated. These were a median, and these patients who die, the median of 7 lines of therapy in as high as 15 lines of prior therapy. So they had very poor bone marrow reserve. We've done a few things to help to mitigate that. One is we have some parameters for eligibility, such as having a low or normal CRP level to indicate there's no cold infection. Secondly, they have to have a platelet count above 50,000. And going forward, they can have more than 2 additional therapies beyond their CAR T cell therapy, less than 7 overall. So we hope that these changes will help in managing it going forward. But it is a concern for us, and we think that we can do more to help to mitigate that. And one of those things is to adjust the lymphodepletion regimen itself. But I also pointed out, there was no grade 3 CRS in any of the lymphoma subjects with enhanced lymphodepletion. That means we have the opportunity for dose escalation in our cell dose, which we think, together with a modification with the depletion will put us at or above the peak expansion in AUC that we saw with eLD in dose level 3.

Thank you, Alan. And before we move on Soumit, if it's okay, Bijal, if I could come to you and ask maybe your thought process on the evolving landscape for the post auto-CAR T unmet need as well as what we see from the transform data, please?

Absolutely. I think what you're seeing right now is Zuma-7. But what is Zuma-7? It was an attempt to identify primary refractory large B-cell lymphoma after they had completed chemotherapy. Zuma-12 is going to take a very different approach. Patients who are pet positive after 2 or 3 cycles of chemo will now go directly to CAR T cell immunotherapy. And I think that, that readout is going to be coming soon. With that background, we can anticipate what's going to happen next. CAR T cell therapy is going to be progressively integrated into front line therapy. As that happens, the big question then is what do we do next? Is it sufficient to go back to chemo? Probably not, especially as we identify these very high-risk patients, we're going to need novel options and novel alternatives. So I think that having a product that I can call upon in that space is going to be critical to cases reach forward.

Thank you, Bijal. Hey, next question please.

And your next question from Eric Joseph of JPMorgan.

The post CAR T strategy here with PBCAR0191 is pretty intriguing. I'm just wondering if you could define a little bit better where the clinical opportunity is with this approach, whether it is all of those that are -- is it -- sorry, is it limited to just those that are relapsing post response to an initial response to autologous CAR T? And then in the data that you're presenting here, I'm wondering whether you have a sense of how CD19 positivity or the antigen loss might have contributed to whether duration of response with 0191 surpassed that prior auto-CAR T.

Sure. Eric, thanks for the questions. So I think 2 questions here. I'm going to go to Alan in a moment here, but if we could elaborate a little bit on the post CAR T strategy, the clinical opportunity and if this is just relapsing versus, for example, patients who might have been refractory to the auto-CAR T? And then as well as Alan, if there's any thoughts on the inversion remissions having CD19 loss, why they might have progressed? So I'd love to have you weigh in on that. Thank you for the questions, Eric.

Yes, Eric, thank you for the question. All the patients or the 6 patients that we had with Auto-CAR T failure, all by protocol have to be CD19 positive. And so these were all patients that when they relapse, we're still show CD19 positive. And as Michael mentioned, there are 5 of those 6 patients are evaluable for response duration compared to the response duration to autologous CAR T. And 3 of those patients exceeded their duration of responsive to auto-CAR T as you saw on the slide there. That -- those, what we call remission inversions are what we see as a very important signal that this could be an opportunity in this population. And I think the other slide that I share with you gives you some biologic rationale for why that should be. When patients fail in auto-CAR T, if you look back at the fitness of the cells, they usually have poor fitness. And that's because the patient himself had foramen integrity. That also means they have a difficulty in rejecting our allogeneic CARs. So we're in a perfect spot to be able to help these patients. So going forward, we are going to continue to evaluate patients with lymphoma that responded to the auto-CAR T cell therapy. It doesn't mean we're not interested at some point testing patients who never responded or we could manufacture an allogenic CAR. I would expect those patients are in the same situation where they have impaired a mean integrity, which is why they couldn't manufacture the CAR.

Thank you, Alan. Thank you, Eric, for the question. Cindy, if we could go to the next question.

The next question is from Ben Burnett from Stifel.

And congratulations on these updated data. I wanted to ask about -- so you mentioned initial Stealth Cell data in mid-2022. I guess, do you expect to have enough follow-up by that time to sort of interrogate just like the main hypothesis being tested, like the persistence of PBCAR19B? And I guess, also, would you expect to have a decent understanding of clinical durability at that point?

Yes, Ben, it's Michael. Good to hear your voice. Great question. So I think when you think about 19B, and I think you nailed it. When you talk about best-in-class approach, it's not only ORR and best CRS in line with autologous, but that 6 months CR super important that remission in relapsed/refractory lymphoma patients. So I think when we think about the middle of next year, we've got the first 3 treated, as Derek spoke about, those were treated in a stepwise approach so that we could start at a higher dose. So there's about a month to 5 weeks between each patient. And if you get a pre-screen failure, it basically resets that month. So it took us about 5 months to dose the 3. Now that we've dosed the first 3, we can move a lot faster. And if we move up a dose level, we only have about a 14-day lead-in. So I think our expectations, as I explained that to you operationally are, the first month will be an important inflection on how 19B doing in any patient, the pharmacokinetics, our peaks, our first response and our first scan. And then 6 month durability will be super important in any best-in-class approach, like Stealth 19B. So I think by the middle of next year, you could think some of the early runners that we've dosed this year, we could potentially have some data on. But whether we'll happen on all of our patients at that time, we know there'll still be some folks that you're looking at the end of '22 as you dose the middle of next year for that 6-month period. So Ben, I think you hit that on the head. There's kind of 2 ways to think about best-in-class. It's the overall response rate, the best response rate, but then the continuation with the durability. So that will be kind of a staggered rolling of results that I'd expect to see by the midpoint of next year, but also end of next year, too, depending on as we continue to roll those patients. Alan, is there anything you would add there?

No. I think you summarized it well. We're not going to have 6 month follow-up on all those patients by midyear. But I think we'll have most of these patients that we're targeting to treat enrolled by -- certainly by the time of ASH. And I would hopefully, maybe we'll be fortunate to present that data at ASH next year.

And Ben, the last thing I would just conclude on there. It's a great question is, I think we'll have enough patient data where we're able to see where we're going. And at this approach, Derek talked about our optionality for a best-in-class to displace an auto-CAR T. I think we'll have some good information to make facts and best decisions on the next path forward, very similar to what we did here with 0191 and the population we're continuing in versus the larger population where we'll put another approach on that.

Okay. Super helpful. I really appreciate it. And if I could just squeeze one more question. Regarding the nirogacestat results with the BCMA and the BCMA CAR T, interesting, the expansion difference that you saw with that agent. I guess can you maybe just expound upon why adding increase the degree of cell expansion to that amount? Like what's the hypox there?

Yes. Go ahead, Alan. Please.

So Ben, it really comes down to cell density. The BCMA is an engine that shed and the gamma secretase inhibitor will block a shedding of that antigen, so you're going to increase the density on the cells. We have some biologic correlate data that will be coming back from that. We don't have that analyzed yet. But I think that improvement that you saw in the expansion gives us a good insight that it's -- we're actually accomplishing that. Just like with CD19, we see better expansion we have -- when we have more targets in front of us.

Thank you, Ben. Cindy please next question.

And your next question is from Raju Prasad, William Blair.

Curious to know your thoughts on consolidation regimen. Obviously, with the strategy here, it seems you're going to go maybe an enhanced lymphodepletion regimen with 19 and then the self-cell technology with your second class or second gen. And then the CD3 adding to the lymphodepletion regimen. So just wanted to hear your thoughts on whether consolidation has been ruled out at this point? Or are you looking to see more data with your different preconditioning regimens.

And Raj, just to confirm, when you say consolidation, you're asking about repeat dosing there, correct?

Yes, repeat dosing within the initial lymphodepletion window?

Yes, very important here, and I'm going to ask Alan and Bijal to weigh in in a moment here as treating clinicians. I think very important to Precision BioSciences' what Derek spoke about. We have kind of defined what we believe best-in-class is. And we believe best-in-class to displace an autologous CAR T is a onetime treatment. So I will open it up, though, just so maybe Bijal, you'll start here of the ability to dose with an auto-CAR T and have that onetime long-term outcome. And how important do you think that is in the market? And then, Alan, maybe you can chime in also, please.

Absolutely. It's a lot to go through to take a patient through CAR-T. I mean, that's a simple answer. I mean, just logistically. Now again, I'm speaking about autologous CAR T of a patient who's got for now, relapsed disease, you're trying to coordinate that outpatient follow or the consultation. So that's an insurance approval step, then you're going through the process of getting the apheresis coordinated the timing for that, then by the time you get to the infusion, you're about 4 weeks in, actually, about 6 to 8 weeks in, I'm sorry, it's a long time and a lot to go through. So to take a patient through that journey, you really want it to be a onetime shot. You want to be able to know that you can get that disease into a meaningful and durable remission. So that's how I think about autologous CAR T. I don't know -- I can elaborate more if you like.

No, I think that's great. And Alan, I think we could maybe talk about repeat dosing and what that would mean with an allo of possibly eLD.

Yes, Raj, I think that the -- with repeat dosing, particularly with an allogeneic CAR, we're up against rejection. And we've done repeat dosing at day 10 on dose level 3 in our patients. We saw no expansion, and that's without repeating lymphodepletion. So I think in the allo CAR setting, that repeating another dose is going to be challenging without repeating the immunosuppression that's needed. Now it's possible in the future when we can titrate the tolerance and the lymphodepletion with foralumab, maybe that's something we want to look at. But our goal early is to match up with autologous CAR T cell therapy at this point.

Yes. So Raj, I would just conclude saying it's our stance today that we believe it's important not to have to introduce folks to another round of lymphodepletion. And best-in-class to us means a onetime treatment with an allo that could potentially displace what we're seeing with the auto-CAR Ts today. So we've got some other shots on goal in the future if we need them, optionality, things like flu resistant CARs and maybe we would talk about those approaches, but I think it's really important to a patient not to reexpose them to LD. That's our feeling from a clinical standpoint at this point.

Great. If I may ask just one more. We're going to see kind of an updated data set, I think, tomorrow or Monday on GSI plus CAR T, but the abstract kind of showed kind of a distinction between some subgroups there. So just wanted to get your thoughts on how you're looking at auto-CAR T plus Nirogacestat -- or sorry, of GSI compared to some of the expansion data you're showing here with your Allo product?

Raj, just to clarify. So we've got some more data coming up Monday. It's actually the drill down of our B-ALL or adult population. You won't see any combo with our GSI at this conference. We're not submitted here. Like Alan showed you, we've dosed 5. We'll be waiting on some of those results. We're continuing to enroll. But you'll see our GSI combo data somewhere Q1 to Q2 of next year, by the end of Q2 of next year. So you will not see that at ASH. What we have here on Monday is the further drill down in the adult ALL population. Is that your question?

No, sorry to clarify. There's some data on auto BCMA with a GSI that's shown some clinical data. I was just curious to hear maybe your thoughts on the expansion you're seeing with the Allo 269A.

Raj, I think I'll frame it. So I think when you look at our kinetics, Alan, with the combo with the GSI for an Allo, how do we potentially compare to an auto profile of Kinetics PK? Raj, am I hearing the question correct?

Yes. Yes, that's correct.

It's a good question. I haven't gone back to compare at that dose level to see how we compare. I know there's some data tomorrow going to be from the Fred hutch on their experience with GSI. So maybe we'll get an idea from their data. The data that I saw in their abstract was done by PCR. And of course, our data was by flow cytometry. And that's kind of a hard thing to compare. But I remember them getting to levels of 10 in the range of around 2,000 or 1,000 to 2,000 per microgram by PCR. So I don't -- just don't know how well that translates into the flow cytometry.

Yes. And Raj, obviously, the…

Really helpful.

This is just a key part of that. So we'll look for -- I know we're trying to get a pre read on kind of what the clinical outcomes could look like, but we'll see what that data looks like in H1 next year. Thank you for the thoughtful question.

Your next question from Andrea Tan from Goldman Sachs.

Two for me, please. First, Alan, just wanted to follow up on your comments for the PBCAR0191 program, where you mentioned that you're planning on adjusting the lymphodepletion regimen and exploring higher doses for the cells. Just would love for some additional clarity here on what else you could be thinking about as it relates to the lymphodepletion.

Andrea, okay, Alan, go ahead.

Well, Andrea, I don't know how much more specifics I want to share at this point.

Alan, just the difference between higher doses of CARs we were talking about to Andrea and lower doses potentially of eLD is still higher than SLD. Alan can you just discuss…

Yes, that's what I wanted to share. But Andrea, very, very good pickup. What we want to do is improve the safety. While not losing any bit of the benefit. So increasing the cell dose, we feel we can do very safely. And we've used a higher cell dose called the dose level 4B. Some of that data will be presented on the ALL presentation on Monday, and you can take a look at that. But that was well tolerated. We hadn't had any grade 3 CRS with dose level 3. So we feel there's room to go up. We also think we have room to adjust the dose down in what we consider are our most myelosuppressive component of the lymphodepletion regimen we're currently using. And we feel by doing the 2 things, increasing the cell dose and reducing some of the or adjusting dose downward in the lymphodepleting regimen that we're still going to be able to maintain a great peak, if not higher, and greater AUC and make it safer. Does that make sense?

Got it. Sorry, go ahead.

Go ahead, question 2, please.

Okay. Yes. Just hoping that you could maybe speculate on what you believe is different with CD19 maybe compared to the CD20 or BCMA that explains why that program, in particular, has seen success as monotherapy approach? And how does this impact your thinking on the forward as you think about additional programs?

Yes. So I think it's a good question, and I think the question is, if I'm hearing you correctly, Andrea, it's kind of comparing some of the early phase ones of Precision, whether we looked at CD20 and I think we could talk to you a stepwise why we think CD19 was the more robust antigen and then versus maybe a BCMA. Why do you think with this tailored enhanced lymphodepletion regimen as a monotherapy, we're seeing the best results thus far, if I'm hearing you correctly, in CD19? Is that the question, Andrea?

Yes.

Okay. I think the difference -- a couple of differences, Andrea. One is CD20, obviously, is the target of rituximab and lymphoma patients consistently get repeated doses of that as a selection against the antigen. It's also not an exophytic antigen. So it's not going to be one that is robustly bound by antibodies. So that's some of the reasons why we thought that CD19 is a better target. And of course, the question is, how many different products do we need for lymphoma or B-cell malignancies in general? We've never done with CD20 like we've done with CD19. That's going to enhanced lymphodepletion and it's possible that, that may have made a difference. But I think at this point right now, we have to be more focused in our development.

Yes. And then, Andrea, the only thing I would add to conclude on that is when it comes to BCMA, I think it's still a little too early, right? You've seen the monotherapy. We see that we're altering the peak of that dose with the GSI. We'll get a read in on our CD19 Stealth program. While we await the GSI combo data for BCMA before we make the decision to go forward sequentially with the BCMA Stealth, for example. So I think it's still a little early on BCMA to compare. But I think Alan's point about some of the learnings from 20 that we really apply to 19 give you an idea of how we're thinking about it.

Your next question is from Maurice Raycroft from Jefferies.

Congrats on the update today. I was going to ask one on the Stealth program. I guess, based on your preclinical data, can that help predict was clinical cell persistence could look like? And I guess you should know pretty quickly if your self-cells are lasting longer. So can you generally comment on whether you're seeing differentiation versus the first gen?

Maury, it's Michael. Good to hear your voice. Thanks for joining us on Saturday. I'm going to turn that question over to Derek. Derek, could you catch the question? Or do we need to repeat that?

Yes. No, I got it. You're right, Maury. If the Stealth Cell is doing what we wanted to do, we should be able to see that relatively early on because we should see -- we would expect both greater peak expansion of the CAR Ts and maybe equally importantly, longer persistence of the CAR Ts in the patient. So we're going to see that in more or less real-time over, say, the first month or 2 following treatment. At this point, we have 3 patients worth of data, which we feel like that's not enough to really draw any meaningful conclusions for particularly with respect to whether or not anything we might be seeing in terms of cell expansion is actually contributing to greater durability and responses, which obviously is what we're trying to achieve.

Thanks, Derek. Maury, the only thing I would add there, and again, that's at the first dose level, right? So that's -- to your point, I kind of know where you're going with that question, what are we seeing after day 28 that makes us feel like we can predict persistence and therefore, outcomes at 6 months. I mean, I think we have to look and see is the first dose level, the right dose level or if we have to dose that up. So I think that answers kind of TBD, but it's a great question, Maury, and we'll be looking at the same things.

Got it. And just a quick clarification there. What is dose level 2 for this program?

Alan, dose level 2 of the CD19B program, we could actually pull back up the slide. We are starting -- as Al said, we're starting at the dose level 3 from 0191 is the first dose for 19B, but I'll let Alan take you through the dosing in that Phase I. It's one more back actually. Keep going back, guys. Yes, up to.

Dose level 2?

The BCMA. I'm sorry, Maury, was it BCMA or Stealth 19B?

Yes. For the Stealth program because I think you guys have the range on the slide.

Okay. I thought we're talking about 19A -- I'm sorry, 548 million. It's a flat dose. It's not weight based.

And your next question is from Patrick Trucchio of H.C. Wainwright.

This is Jason speaking for Patrick. Congrats on the new really impressive clinical data. So my first question is, when should we be expecting the start of dosing for Level 2 and 3 for the 19B? And the second question is, will you observe any kind of possible infections just because it seemed like in the level 1 for 19B is the same dosing as your level 3 and the 19A? And will the patient selection criteria be the same with the new 0191 criterions. And that's all for me for today.

Okay. So a couple of questions in there. And Jason, thank you for joining with Patrick, and thanks for your kind words. A couple of questions in there. I'll turn it over to Alan and the clinical team in a moment. So the question is, if and when we'll go to dose level 2 or 3 with 19B, what would we see with dose level 1 that would make us want to go to the next dose level? I think we then also heard the question on should we expect, as we go up in dose level to potentially see some of the infections? And I think it's important to talk about standard lymphodepletion versus enhanced Alan, if you could. And then, Jason, I think there was a third component. Let me know so I could frame these right for Alan, if there is a third point, I might have missed it.

Yes. It's just -- will the patient selection for these other higher levels, what would be the same like the 0191?

How heavily pretreated versus what we've seen in 0191? So Alan, I'll turn that over to you.

Jason, maybe I can start with the last one. And we'd love to get patients that are eligible or just following comparable to what the auto-CAR T cell programs are getting, and that is getting as third line of therapy. But we don't have control of that. But what we are restricting eligibility to is to patients with lymphoma, excluding CLL -- ALL that was eligible for the 19B program. As far as are we concerned about infections when we dose escalate, and the answer is no, we're using the standard lymphodepletion regimen, which is not profoundly myelosuppressive or doesn't have long myelosuppression. That's what led to an infections that we saw with enhancement lymphodepletion. So we're not considered -- concerned about that at all. We'll make that decision based upon the kinetics of expansion that we see. And so if we're seeing a reasonable expansion, but not as good as we like and, obviously, the next step is to go up with dose escalation.

Yes. And then, Jason, the last thing I would just add there. I think the idea of the best-in-class approach that Derek and Alan and the team put together with Stealth was unlike 0191, to not have to pull the enhanced lymphodepletion lever, where you're looking at really the approach of knocking down the B2m as well as the HLA-E insertion, this is really an approach at the vector level at the CAR level to address peak and persistence. So that's why we're starting at a standard lymphodepletion. It's truly a unique and different approach.

Your next question from David Dai of SMBC.

So 2 questions for me. One is that, first of all, I see the durability data on Slide 14 do not break down by lymphoma subtype. So could you provide some color on what are the lymphoma subtypes are the subjects, number one? And #2, where we saw the longest durable response, are these considered follicular informed patients? Or are they the LPCR patients? And then second question, just help me understand what are your thoughts around prioritizing the 2 CD19 programs into the pivotal trials?

So David, I'll start with the last one. I'll take that one. And then what I'll do is I'll let Alan take you through the different lymphoma patients. I think he was asking the question about lymphoma patients with durability, so maybe it's a swimmer plot referral. But -- so first and foremost, the 2 approaches very important for CD19, on the first and best-in-class approach, to be clear. First-in-class for an allogeneic CAR T for Precision Bio, maybe potentially in the industry, is about helping an urgent patient need. Right now, it's where we've got following our science, following the best signal in the post auto. And this is a patient, again, with median survival right now is somewhere around 3 months, maybe a little better than 3 months. So I don't want to put the cart in front of the horse, David, but we'll treat the next 6 patients with potentially the next dose level of 0191 as well as a modification maybe to the eLD regimen, and we'll see what the data looks like. If that data looks good, we think it could warrant a conversation with regulators. But again, I don't want to put the cart in front of the horse. Let's see what that data looks like. There really is no comparator in that population. Again, think about the median population survival was about 3 months in this group post auto a little bit better. And it kind of likens me to really the landscape before the first auto-CAR T, was ever approved, where there really was no control or comparative. But that's a conversation we would have with the regulators if and when we've got -- we see the activity continue in the next enrollment of patients. I think the next question you had asked was about the different histologies of lymphoma in the swimmer plot here in Slide 14, so I'll let Alan address that.

David, the vast majority of these are diffuse large beat cell lymphoma with 4 exceptions. One is subject one, 3 and 4 are follicular. And we haven't had histologic review to know if they are follicular grade 3 or not. We also on subject 5 is a lymphoblastic lymphoma, and that explains why they went on to an allogeneic transplant in CR.

That's helpful. Just maybe just to clarify, what is the subtype for subject 2? Is that the DLBCL?

Subject 2. Is that DLBCL? Yes. Yes, it is, David.

Our last question from Justin Zelin of BTIG.

Congrats on the data here. I was just wondering from the data you generated, if you've identified an ideal window to treat with your Allo 19 program post autologous CD19 CAR T? And just on the BCMA program, are there any thoughts to address the lymphodepletion program there? Or are you set on the standard lymphodepletion program and the BCMA program?

Justin, it's Michael. Good to hear your voice. And again, thanks for joining us. Let me clarify before I go to your BCMA question and the different lymphodepletion possible approaches. Let me just clarify your first question. If we identified an ideal window post auto-CAR T, make sure I understand your question. Can you give me a little more color on that, please?

Yes. I was just wondering how soon -- just from the data you've generated with your CD3 cell recovery that -- I'm assuming sooner the better to treat with your Allo CAR T, but I was just curious on if you've identified a certain window for treatment that would provide ideal responses for patients?

Okay. Got it. So Alan, the question come in, I think it's important to know that these were not subsequently always getting PBCAR0191, in fact, only one of the 6. Justin is asking is there a time like the now that you'd want to treat as soon as possible versus later? Is there an ideal window when we would administer in the post auto relapse or 0191. And then the second question is around BCMA and whether we would ever have an approach of altering LD, and I think that's an important education on the myelosuppression in the marrow Alan. If you could take that?

Yes, absolutely. So Justin, it's an interesting question, particularly as it relates to the timing that we would want to capture patients that have failed on a CAR. My expectation is that the earlier, the better. We know the number of lines of prior therapy is problematic for autologous CARs for durable good outcomes. So we would want to get them as soon as we can after auto-CAR T failure. Unfortunately, this is all speculation right now because all 6 patients we treated had responded. So -- and some had had 5 prior therapies after auto-CAR T failure and others have had none, but it's a very good point. So our feeling and expectation is the earlier, the better, and that's what our preference would be. As for BCMA, we haven't thought about at all at this point to modify the lymphodepletion regimen. Generally, the patients with myeloma are fairly frail. They don't have very good bone marrow reserve. They have a bone marrow base malignancy. So -- and they also have hypogammaglobulinemia from the outset. So it's a setup for high-risk of -- for infection. We wouldn't want to dose escalate in that kind of a setting. It doesn't mean we wouldn't use something like foralumab, which may be where we can have a controlled lymphodepletion or tolerance from limited [indiscernible].

Thank you, Alan. So with that team, we appreciate the great questions. We appreciate you spending your Saturday night with us. We've gone about an hour and 15 minutes. So it is my pleasure to spend some time with you at my first ASH with the team. And I will just recap saying we're very, very excited on some of the first signals of the data. We're measured, we'll continue to be evidence-based and pursue the signals, as we've talked about right now. That's in the post autologous for PBCAR0191, that's in the post autologous relapsers for CD19. We'll talk to you next year about the combo data with BCMA and the gamma secretase inhibitor. And then ultimately, we'll continue to move toward our approach for a best-in-class profile to hopefully displace an auto-CAR T with our Stealth program. And we'll tell you more about that in the first half of next year. I want to thank again, Cindy, thanks for facilitating the call. And again, thanks to all the investors who have spent their Saturday night with us as well as the patients who have been willing and their families to be part of our trials. We could not do it without their courage. Have a safe and great evening. Thank you all.

And this concludes today's conference call. Thank you for participating. You may now disconnect.