CRISPR Therapeutics AG (CRSP) Earnings Call Transcript & Summary

Good afternoon and welcome to the CRISPR Therapeutics Clinical Update Conference Call. At this time, I would like to inform you that this conference call is being recorded. [Operator Instructions] I would like to introduce Susan Kim, CRISPR Therapeutics' Vice President of Investor Relations and Corporate Communications. Please go ahead.

Good afternoon and thank you for joining us as we report updated results from the CARBON trial, an ongoing Phase I study of CTX110, a healthy donor-derived, gene-edited allogeneic CAR-T therapy for the treatment of CD19+ B-cell malignancies. We recommend that you access the webcast slides on our website as you listen to this call. This conference call is being recorded, and a replay will be available on our website. During today's call, we will be making certain forward-looking statements. These statements may include statements regarding, among other things, the efficacy and safety of our product candidates, our research and development plans, regulatory plans and our plans to present or report additional data. These forward-looking statements are based on current information, assumptions and expectations that are subject to change and involve risks and uncertainties that may cause the actual results to differ materially from those contained in the forward-looking statements. These and other risks are described in our periodic filings made with the SEC, including our quarterly and annual reports. You are cautioned not to place undue reliance on these forward-looking statements, which are only made as of today's date. The company disclaims any obligation to update such statements. Joining me this afternoon are Sam Kulkarni, our Chief Executive Officer; Ewelina Morawa, our Vice President of Clinical Development; and Tony Ho, our Head of Research and Development. With that, I'm pleased to turn the call over to Sam Kulkarni, who will make introductory remarks.

Thank you, Susie. Good afternoon and thank you all for joining us today. This afternoon, we are reporting updated clinical results from our Phase I CARBON study of CTX110 for the treatment of B-cell malignancies. Before we discuss the data, I want to recap the tremendous progress we've made towards building the leading CRISPR company with 4 clinical programs, over 450 employees and a strong cash position of around $2.5 billion. We were the first to demonstrate the power of CRISPR gene editing in patients with genetically defined diseases with our lead program, CTX001. We have now treated over 50 patients with sickle cell disease and beta thalassemia, and the data show a consistent, functionally curative profile. We anticipate filing for approval of CTX001 in the next 18 to 24 months. Building beyond CTX001, we advanced 3 gene-editing allogeneic CAR-T programs into the clinic. With today's release, we show clinical proof of concept for CTX110, paving the way for our allogeneic CAR-T pipeline. In parallel, we have progressed our efforts in regenerative medicine and in approaches leveraging in vivo delivery. We expect to move multiple programs with these approaches into the clinic over the next 2 years, starting with an allogeneic stem cell-derived therapy for type 1 diabetes later this year. To meet the long-term demands of our growing pipeline, we plan to bring our own state-of-the-art manufacturing facility online in 2022. We could not have accomplished all of this without the right team. We have an incredible group of people at CRISPR. And together, we have created a sustainable innovation engine to develop transformative medicines using our gene editing platform. Today, we are excited to share data demonstrating that CTX110 could offer patients with large cell lymphomas an immediately available off-the-shelf option with similar efficacy to autologous CAR-T and a positively differentiated safety profile. Cell therapies represent the new frontier in the fight against cancer. We believe that our CRISPR platform is uniquely capable of precise, specific multiplex gene editing, which allows us to engineer best-in-class treatments for both hematological malignancies and solid tumors. Although current autologous CAR-T therapies have shown promise, room for improvement remains. Allogeneic CAR-T, in which T cells from a healthy donor are used as a starting material, could overcome many of the challenges of the first generation of approved CAR-T therapy. The advantages of allogeneic CAR-T includes immediate availability, flexible dosing, more consistent product attributes and more scalable manufacturing, ultimately allowing a much broader patient population to benefit from these therapies. We believe that over time, allogeneic therapies represent a whole new class of medicines that can become the first line of defense in the fight against cancer. We have built and continue to build a critical mass of expertise, capabilities and infrastructure in this area that we believe will allow us to lead the field in bringing new best-in-class medicines to patients. Creating a safe and effective allogeneic CAR-T therapy requires editing multiple genes within a T cell simultaneously and at high efficiency, a task for which CRISPR is ideally suited. To create CTX110, we make 3 simultaneous edits that are designed to avoid Graft versus Host Disease, target the CAR-T cells in the tumor and resist immune rejection sufficiently to enable durable responses without the need for more toxic lymphodepletion regimen. With today's data release, we believe that CTX110 has shown a safety and efficacy profile that can compete with autologous CAR-T in relapsed/refractory large cell lymphoma. A single dose of CTX110 at dose level 2 and above showed overall response rate of 58% and a complete response rate of 38%, which are in line with autologous CAR-T cell therapies. Moreover, our data demonstrates the potential for CTX110 to produce durable remissions as evidenced by a 21% 6-month CR rate, also similar to autologous CAR-T therapies. Importantly, CTX110 achieved this efficacy with a positively differentiated safety profile. We have not observed any Grade 3 or higher CRS, and ICANS and infection rates remain much lower than those reported for autologous CAR-T therapies. Based on this profile, we plan to expand into a registration-enabling trial in the first quarter of next year. This trial will incorporate consolidation dosing, which is supported by the safety, pharmacokinetic profile and clear dose response to CTX110. We believe that a consolidation dosing strategy will increase the rate of durable complete remissions already observed with CTX110. I will now turn the call over to Dr. Ewelina Morawa, our Vice President of Clinical Development, who will present updated data from the CARBON trial.

Thank you, Sam. The primary objective of the Phase I CARBON trial is to evaluate the safety and efficacy of escalating doses of CTX110. Dose escalation of CTX110 was performed in adult patients with relapsed or refractory large B-cell non-Hodgkin's lymphoma who have failed at least 2 lines of therapy. Patients who received prior autologous CAR-T cell therapy were not eligible. Patients received 3 days of lymphodepleting chemotherapy, consisting of fludarabine at 30 milligrams per meter squared and cyclophosphamide at 500 milligrams per meter squared, followed by a single CTX110 infusion. Some patients have completed screening in as few as 3 days, and the median time from enrollment to start of lymphodepleting chemotherapy was only 2 days. This time line was possible because there is no need for leukapheresis, bridging chemotherapy and CTX110 is available at the site before a patient is enrolled. Finally, patients who showed a response to the first CTX110 infusion could be redosed following disease progression. As of August 26, 2021, 30 patients with large B-cell lymphoma were enrolled in CARBON. At the time of data cut, 26 patients had received CTX110 and had at least 20 days of follow-up. Only 1 patient who was enrolled in CARBON did not receive CTX110. Historically, autologous CAR-T studies have reported primary efficacy results using a modified intent-to-treat or mITT approach. This methodology excluded up to 1/3 of enrolled patients from the analysis. The excluded patients are primarily those who experienced rapid disease progression or death during the manufacturing period or for whom autologous CAR-T cell manufacturing was unsuccessful. In contrast, the efficacy data we will show today with CTX110 are essentially unchanged when we applied an intent-to-treat or ITT analysis, which includes all enrolled and evaluable patients. It is important to emphasize that CARBON has exclusively enrolled patients with large B-cell lymphoma, including DLBCL NOS, high-grade double- or triple-hit lymphomas or transformed follicular lymphoma. We have not enrolled any patients with indolent lymphoma, such as follicular lymphoma, which progressed more slowly and historically have responded at higher rates to CAR-T cell therapies compared to large cell lymphoma. We focus CARBON on patients with the most aggressive disease presentation and high unmet medical need that can be directly addressed with an off-the-shelf CAR-T cell therapy. Notably, nearly 1/3 of patients enrolled in CARBON have received CTX110 within 9 months of their first treatment for large cell lymphoma, which speaks to the very rapid disease tempo and lack of responsiveness to prior therapies for patients treated on this trial. This table summarizes the baseline characteristics for patients who have received CTX110 in CARBON across the 5 dose levels. All patients were heavily pretreated, having received at least 2 lines and as many as 10 lines of prior therapy. 9 patients received prior autologous stem cell transplant, and the majority of patients had Stage 4 lymphoma and were refractory to their last line of therapy before entering the trial. Responses to CTX110 were assessed by trial investigators using the 2014 Lugano criteria. This table summarizes response rates to the first CTX110 infusion by dose level. As the dose increased from dose level 2 to dose level 4, we saw a higher percentage of patients respond to CTX110. Complete responses were seen in dose levels 2 through 4. Responses were seen in a variety of patients, including patients with refractory disease, bulky disease, or who had progressed after prior autologous stem cell transplant. When we look at the 23 patients who received CTX110 infusion at dose level 2 and above, the overall response rate was 61%, and a complete response rate was 39%. Those response rates remain nearly unchanged using an intent-to-treat analysis. [ This one line spot ] shows that CTX110 can produce durable complete responses. The longest response comes from a patient who will be discussed later in this presentation and speaks to the potential of 2 CTX110 infusions to produce an ongoing remission for more than 18 months. We are also encouraged by the 2 patients who are in an ongoing complete response approximately 14 and 11 months after a single CTX110 infusion. In addition, the fourth bar shows the patients that treated at dose level 3 who had a complete response at the day 28 and month 3 visits, but who also have a single small FDG-avid node in her arm at the 6-month evaluation. The lesion was excised, and the patient is clinically well and has not received any additional anticancer therapy. Finally, the fifth bar comes from a patient who was initially treated at dose level 3.5 and achieved a CR at the day 28 assessment but progressed at month 3. This patient received a second CTX110 infusion, and we recently learned is now back in CR. Together, we believe these efficacy data tell us that a single CTX110 infusion can produce deep and durable complete responses and redosing can safely extend its benefit to a greater percentage of patients. This table shows the frequency and severity of adverse events of interest. Average safety data for the 23 patients treated at dose level 2 and above are summarized in the far-right column. CTX110 was well tolerated across all dose levels. There are several specific aspects to CTX110's safety profiles that are important to highlight. First, there have been no cases of Graft versus Host Disease. Second, there have been no infusion reactions to either lymphodepleting chemotherapy or CTX110. Third, looking at the established class effects of CAR-T cell therapy, there have been no cases of Grade 3 or higher CRS with CTX110. Importantly, all cases of CRS were Grade 1 or 2 per the ASTCT criteria and either required no specific intervention or results following standard CRS management. Neither the frequency nor the severity of CRS has increased in patients who were redosed with CTX110. The only case of Grade 3 or higher ICANS was in a patient with concurrent HHV-6 encephalitis, who was discussed in depth during our last data release. There have been no new cases of ICANS in any other patients treated at dose level 3, dose level 3.5 or dose level 4. Finally, only 2 patients experienced Grade 3 or higher infection, the previously discussed patient with HHV-6 encephalitis and 1 patient who developed pseudomonal sepsis that resolved in 4 days. Overall, CTX110 has an emerging safety profile that is positively differentiated from autologous CAR-T therapy based on the lower frequency of severe CRS or ICANS and from allogeneic CAR-T therapies that require more toxic lymphodepletion regimens, which can result in prolonged immunosuppression and increased risk of serious infections. CTX110's ability to produce deep and durable remissions with a single infusion is highlighted in the case study of a 62-year-old woman diagnosed with DLBCL. She had a partial response to both R-CHOP and R-ICE before receiving an autologous stem cell transplant. The patient relapsed after transplant and enrolled in CARBON with a baseline 6-centimeter mesenteric mass that will still hold 5 on PET scan. She received a single CTX110 infusion at dose level 3 and had an uncomplicated clinical cohort without any CRS, ICANS, or infections. At her 1-year assessment, there was no evidence of lymphoma by PET CT. The patient remains clinically well with no ongoing toxicity from treatment. A second patient speaks to the safety and clinical benefit of multiple CTX110 infusions, which we have evaluated in patients who responded to the first infusion but subsequently progressed. This case study is of a 58-year-old male with refractory Stage 4 DLBCL NOS. The patient received 2 prior lines of therapy with a best response or partial response and upon trial entry has multinodal involvement in several areas as well as 30% lymphoma cells in the bone marrow. He was initially treated at dose level 2 and achieved a CR at day 28 post-CTX110 infusion. However, approximately 7 months after the first infusion, he experienced disease recurrence. The patient received a second CTX110 infusion at dose level 3 and has an ongoing remission with response lasting more than 9 months for a combined duration of clinical benefit of over 18 months. Of note, this patient did not experience CRS, ICANS, or infection after receiving either CTX110 infusion. We have observed deep responses with CTX110. The waterfall plot on the left shows the best percent change in target lesion diameter for the 23 patients treated at dose level 2 and above. The color of the bars reflects the best overall response inclusive of redosing. On the right is a similar plot of data from 95 patients treated with Axi-Cel in the ZUMA-1 study. What is immediately evident in both plots is the consistent evidence of antitumor activity and the ability to produce deep responses in a significant fraction of patients. Having previously worked on clinical development of autologous CAR-T therapies, I believe we are seeing efficacy with CTX110 that shares many key similarities, importantly, without the requirement for patient-specific manufacturing. And now, I'm going to hand it over to Dr. Tony Ho, our Head of R&D, to contextualize the CTX110 clinical data and share our plans for CTX110 moving forward.

Thank you, Ewelina. When looking at the CTX110 data we've shown today and the results of trial that led to the approval of the autologous CAR-T product, YESCARTA, KYMRIAH and BREYANZI, it's important to keep 2 things in mind. First, the publications and approved product labels report top line efficacy using a modified intent-to-treat approach, which only considers a subset of evaluable patients. Unfortunately, between 10% and 33% of patients who were enrolled and underwent leukapheresis in these trials did not receive autologous CAR-T cell infusion and are excluded from these mITT analyses. This subset includes patients with the most aggressive forms of disease, who experienced progression, toxicity or death or for whom autologous CAR-T manufacturing was unsuccessful. In contrast, because CTX110 is off-the-shelf and does not require patient-specific manufacturing, only 1 patient enrolled in CARBON did not receive CTX110 infusion. Using an ITT approach, the overall response and complete response rate in CARBON are similar to previous autologous CAR-T studies. Second, because autologous CAR-T can cause severe or life-threatening CRS or ICANS in a significant fraction of patients, their use is primarily limited to academic centers and require periods of mandatory in-patient admission. In contrast, CTX110 has a positively differentiated safety profile that may allow it to be used in the outpatient and community setting. We believe consolidation dosing can improve on an already competitive profile for CTX110 based on its pharmacokinetic profile and clear dose response. The PK profile for CTX110 showed significant and consistent expansion. CTX110 cells routinely expand over several long quarters of magnitude, with peak expansion typically occurring 8 to 10 days following infusion. In most patients, CTX110 levels decrease over the following 2 to 3 weeks and approached the limit of detection near day 28. Expansion profiles are similar for second infusion, with no evidence about anti-HLA or antidrug antibodies accelerate the recurrence of CAR-T cells. These data indicate that the standard dose of these drugs create a window for CTX110 activity and support consolidation dosing at 1 month. CTX110 has a clear dose response, which we believe is driven by the effector:target ratio. The plot on the right shows a correlation between clinical response and E:T ratio. There is an apparent threshold, as shown by the dotted line, that, if exceeded, has resulted 7 out of 11 or 64% of our patients achieving CR. Below this threshold, only 2 out of 12 or 17% have achieved CR. Simply put, if the CTX110 cells are administered when tumor volume is low, complete responses are likely. These data strongly support a consolidation dosing strategy, whereas second dose of CTX110 is administered at 1 month when the tumor volume is lower. This strategy has the potential to lead to a higher rate of durable complete responses by eliminating any residual tumor in patients who did not achieve complete remission following single dose. Let me turn back to Sam to conclude our presentation.

Thank you, Tony. We've shown today that CTX110 has the potential to be a best-in-class allogeneic cell therapy in patients with relapsed and refractory large cell lymphoma. CTX110 has overall and complete response rates that are in line with autologous CAR-T and can produce long-lasting complete remission. Importantly, this efficacy is achieved with a highly differentiated safety profile with reduced rates of severe CRS, ICANS and infections. Furthermore, we have the potential to improve on the efficacy profile with the consolidation dosing strategy. Supported by these data, we plan to expand the CARBON trial into a potentially registrational study in Q1 of next year and broaden its use to the outpatient and community settings. In parallel, we plan to further scale our manufacturing in our state-of-the-art manufacturing facility to support this expansion. More broadly, we are using the experience and insights gained from our ongoing clinical trials to engineer the next generation of CRISPR-edited allogeneic CAR-T cells, which will incorporate novel edits to further enhance the potency of these cells. Altogether, these data reinforce my belief that engineered cell therapies are the future in our fight against cancer, and we are well positioned to be the leader in the field. None of this will be possible without our investigators, site staff and above all patients and their families, who have participated in this groundbreaking clinical research. We thank them for their efforts and bravery. We are now happy to take questions. Operator?

[Operator Instructions] We'll move first to Joon Lee with Truist Securities.

Congrats on the data. The PK profile does differ a little bit from last year, and the CR does seem to erode a bit. Did you see any evidence of endogenous NK-mediated projection of CTX110? And would you consider using enhanced depletion methods or adding some other bells and whistles like HLA-E? And I have a follow-up.

Thank you, Joon, for your question. We're very pleased to see that our allogeneic CTX110 can produce durable responses and do it in this safe manner, which does have something to do with the fact that we have these consistent PK curves. I'm going to ask Tony Ho, our Head of R&D, to answer the specifics to your questions around the PK curve.

Yes. So from today's data, you can see that from a patient-to-patient basis, we do see a consistent expansion profile with CTX110. And this has given us from single-dose CTX110 a very durable response, as you can see from today's presentation. And we believe that with consolidation dosing, we can actually improve the durability even more.

Great. And for the edits that you're doing, are you doing them simultaneously or in sequential order? And tell us a little bit about your QC protocol to weed out any cells with any genetic anomalies, just out of curiosity?

Yes. Thank you, Joon. I think our manufacturing process using CRISPR is actually much more facile than many other platforms that are out there for cell therapies. And we are able to do multiplex editing to more than 5, 6 edits without causing any off-targets and minimizing translocations. I think we do rigorous analysis on our drug product to make sure that we pass all specs, and this is something we've discussed with regulators. I think to finish off on your previous question, I think the PK curve here is actually a feature, not a bug, of this therapy. The fact that we have consistent expansion and where we have all these cells expand at day 8, and that gives you a window where it kills the cancer cells, and then the cells are gone about a month later or reach that limit of detection, yields this beautiful balance between having the efficacy we're seeing, producing the durable responses yet minimizing the CRS. We haven't seen any Grade 3 CRS and also lends itself to the follow-up question you asked around the consolidation dosing, where, at that point around a month, we can have a second dose, which could completely eliminate the cancer and increase the percentage of durable responses that we see.

We'll move next to Maury Raycroft with Jefferies.

Congrats on the updates. First one is just if you can talk about what a registrational study could look like. And in order to start in 1Q '22, can you say if you have had any preliminary FDA buy-in on this and what next steps are?

Yes. Thank you, Maury. I think for our -- the data today are quite remarkable. 2 years ago, when people are talking about allogeneic CAR-Ts, if you said, "Are you going to get durable responses with a single dose of allogenic CAR-T?" People were not very confident of that. And here, we've seen that with one single dose of allogeneic CAR-T, we can get these durable responses. Not only that, we can get that in a safe -- with a very differentiated safety profile. And we can only improve upon these responses with consolidation dosing. All those factors point us towards -- and give us great confidence that we can start our pivotal trials. In fact, if not start our pivotal trials, we're going to expand into our registrational trials. Obviously, we have various regulatory interactions, both U.S. and ex-U.S., and we work hand-in-hand with regulators. But at this point, we feel well positioned to start the potential registrational trials early next year.

We'll take our next question from Geoff Meacham with Bank of America.

I also want to offer up some congrats on the data. I have 2 related questions and, Sam, they're mostly related to regulatory as well. Just do you see differentiation between allo and autologous therapies in terms of how the agency views them and what is required for registration? I wasn't sure if you had a different set of sort of guidelines for allo. And then just generally, what's been the dialogue with the agency on having safety and AE guardrails just in the context of the recent Allogene development as well as the AdCom panel a few weeks ago?

Yes. Thank you, Geoff. I'll start with the first part of your question and then have Lawrence Klein, our COO, add some comments about the second part of your question. I think as the agency would look at this, they would look at it as any other drug in oncology with the -- and they look at the risk-benefit profile. I think what you may end up here, as you look at allogeneic versus autologous, with this kind of safety profile and the fact that every patient gets treated, you may actually have a significant advantage of autologous therapies in getting approvals. Now one thing I'll point out is, ultimately, the data -- the gold standard for measuring efficacy data is ITT or intent-to-treat population. And in our case, as you look at allogeneic CAR-T, it's almost identical. There is no such thing as a modified ITT. Almost every patient that's enrolled gets the drug, gets CTX110. Here, in our case, 3 out of the 24 patients enrolled received the drug. And I think we've shown very good response rates and efficacy rates in line with autologous CAR-T. So overall, I think it's the same gold standard in terms of the regulatory agencies looking at it from an approval standpoint, which would be efficacy in -- on an ITT basis. Of course, from a safety standpoint, I think this looks like a relatively safe profile. In terms of the guardrails, we've worked with the agency for a while now to establish our manufacturing, to establish our release criteria and make sure we take all the precautions and have a high-quality product that we're putting into patients. As far as the comment on the -- in light of the recent events, I'll turn it over to Lawrence Klein, our COO.

Geoff, thanks for the question. I think the first thing I'd say with respect to the recent news from Allogene is, we have very little data at this point to say anything definitive or specific about that and the readthrough to CTX110. And that's understandable given how recently these things emerged. I think an important thing to establish will be whether there's any connection between the genetic abnormalities in the cells that they identified and the clinical course of the patient. And it may very well be that there's no connection there and that would, of course, be a good thing. But finally, what I'd say is there are a number of differences between what we're doing with CTX110 and what Allogene does with ALLO-501, with ALLO-501A. The first being that we use CRISPR versus Allogene using TALENs to edit the cells. And those 2 editing technologies have different profiles in terms of their efficiency of editing, their off-target profiles and their propensity to cause changes to chromosomes. That's one key difference. The second is that Allogene uses integrating lentivirus, whereas we use a non-integrating AAV to insert the CAR constructs. And it has been shown in previous CAR trials that integrating lentiviruses or retroviruses can cause clonal expansion or different types of expansion of T cells. So that could be contributing. And then the third difference -- key difference is that Allogene uses a CD52, anti-CD52-depleting agent, whereas we use standard lymphodepletion. And those types of agents can lead to very deep cytopenias that don't resolve as significantly from the type of lymphodepletion that we're using. So any of those factors could be contributing. They could be contributing in some combination. It's too early to say. But those are the types of things we'll be watching for as we go forward. At the moment, we're not changing anything we're doing with CTX110 because we don't expect to see something like that with our trials.

We'll take our next question from Salveen Richter with Goldman Sachs.

Could you speak to the baseline characteristics -- well, actually, the prior treatments for your patients in the context of a median number of prior treatments and refractory versus the autologous therapies out there on the comparative tables? And then also, any sense at this point of the dose that you're going to take forward in the pivotal program as well as on consolidation therapy?

Yes. Thank you, Salveen, for the question. I'm going to have Ewelina, our VP of Clinical Development, answer that question.

Yes. Thank you so much for the question. If you look at the inclusion/exclusion criteria for our CARBON trial, it is very similar to the autologous CAR-T trials. And we tried to stay consistent so we could be -- we could have a comparative product. If you look at the median age, the types of lymphomas we have enrolled, we have enrolled similarly at the KYMRIAH, YESCARTA and BREYANZI trials, aggressive lymphoma patients such as DLBCL NOS, triple- or double-hit lymphomas and transformed follicular lymphomas. We haven't enrolled any patients with low-grade lymphomas like -- such as follicular lymphoma because we knew there was a higher unmet need in these large cell aggressive lymphoma. Regarding median number of prior treatments, these are consistent with what we see with autologous trials. It's usually 2 to 3 type -- 2 to 3 lines of prior therapy, including patients who have failed autologous transplantation. So when you look at holistically at the patient population, it's quite consistent in terms of median lines of prior therapy, patients who are refractory and also patients who have had aggressive lymphomas. And that's why we're incredibly excited by the data we see with the first dose -- first CTX110 infusion. In terms of what we hope to take into our corporate expansion, we are planning to proceed with dose level 4 at 600 million CAR-T cells with standard flu/cy lymphodepletion in addition to an early consolidation dose, similarly with flu/cy and dose level 4 of 600 million CAR-T cells. And we believe that this consolidation will further even increase the CR rates and produce durable remissions.

And Salveen, I'll just add to that, which is, if you look at our data that -- where we show the dose response, you see a very clear dose response, but then this important notion of effector:target ratio. What we've shown is the correlation of responses to the effector:target ratio, and you see a very clear delineation. Where -- when you're above a certain effector:target ratio, your chances of getting a complete response are much higher. And that's why we have very confidence that going at the DL 4, dose level 4, with the consolidation dosing, where the second dose is coming in, where the tumor volume is already reduced, and you have an even higher E:T ratio, should yield much deeper responses, and hopefully, many more durable responses of the patients we treat.

We'll take our next question from Gena Wang with Barclays.

I have a few. First, just wanted to -- first, wanted to -- congrats on the data. The -- also regarding the 4 out of 9, the CR, continuing to maintain CR, I just want to confirm. Was 1 CR included the patient that received 2 doses, like dose level 3.5 and dose level 4? Was that one of the patient? And that was my first question. And also regarding the -- I just want to make sure like I understand correctly. So for both, would that be mandatory for a pivotal study that it will be adding additional dose -- consolidation dose for dose level 4 for the pivotal study? And then related -- the other set of question is regarding the safety that related to Allogene events. And the one question we got ask a lot is the translocation, the potential risk. So wondering, does your drug product QC release assay involve high-throughput sequencing? And also what is your translocation rate? And what will be your cutoff for drug release?

Okay. Let me take those questions in order, Gena, and I'll have Lawrence comment on the last question -- last part of your question. We've gone from 2-part questions to 3-part questions now. That always makes it fun. No, we have not included the patient, which -- who received the DL 3.5 first and then got the DL 4. I think what we've included is the -- out of the 23 patients shown on the swim lane chart, the first 4 patients. And obviously, the first patient had a redose and is in-response at 18 months. Then you have 2 patients with single dose that are well beyond 10 months in terms of response. The fourth patient swim lane got a DL 3 dose of CTX110. Now while we show a progression there, it was really, as Ewelina explained, a very small lesion that was excised out. And the patient has not received any other therapy. This is a relatively sick patient that came into the trial and 14 months out continues to do well without any systemic anticancer therapy since 110. So those are the 4 patients included. There are other patients that continued on the trial that have not progressed and they're not in the denominator, but that's how we came to our 21%. So if we include that patient, that DL 3.5 that will subsequently receive DL4, that number would be higher than 21%, of course. To your question on whether the redose is mandatory in the pivotal trial, I think we believe that you get the greatest benefit even if you have a complete response at one dose to get the second dose because that's the notion of consolidation. You're trying to eliminate every single cancer cell that the patients may have in their body, and that's what leads to durable responses. So I think that's how we're writing the trial, is to get that consolidation dose, regardless of whether they have a PR or a CR. To your last question on the data from Allogene, again, it's not our practice to comment on other companies' trials. But to your specific question around our release criteria, Lawrence, do you want to add to that?

Sure, Gena. So we do assay our drug product for translocations, and we do see the translocation between the TRAC locus and the beta2m locus, as would be expected. Typically, it's at a rate of around 1% in the drug product, and that's something we assay for in the release. So that's not expected to cause any issue, and we've done a number of assays to show that, that doesn't cause any issue with the cells. That's something that's always been part of the process and has been a component of all of our discussions with the FDA around initiating these clinical trials. And so if we were to assay the cells in a patient after treatment and we saw percentages are consistent with what we saw on the drug product, we don't expect there would be any issue there. That's how we handle that topic.

We'll take our next question from Liisa Bayko with Evercore ISI.

Congrats on the update. Was there any difference in safety as you administer the second dose? I'm just wondering how many of these safety kind of Grade 3 plus that you've indicated here came up with the redose or the second dose versus the first dose?

Thank you, Liisa. Ewelina?

Yes. Thank you for the question. I think what you -- what's really exciting is that what you saw during the presentation and the safety table is actually inclusive of the 8 patients that were redosed. And I think this is why it's so incredibly exciting that we are able to think about this consolidation dose to further improve CRs, and hopefully, durable CRs. And so even in the patients with the redosing, the rates that you are seeing, no Grade 3/4 CRS, no ICANS except those 2 patients we have mentioned before, no GvHD, no infusion reactions. This is all consistent with the first infusion and the second infusion, and hopefully will allow a significant amount of patients to be redosed with the consolidation dose in the pivotal trial.

We'll move next to Ted Tenthoff with Piper Sandler.

Congrats. Impressive. So 2 quick questions for me. Firstly, did you mention how many patients do you think might be needed in the pivotal trial? And then a question. Today's focus is on 110. When do you think we could get data from 120 and 130? And I guess -- actually, I have 3 questions. What would you envision as maybe future potential edits that might enhance the 110 profile?

Yes. Thank you, Ted. It was a little hard to hear you, but I think -- let me just repeat the questions to make sure it's how many patients do we envision in the pivotal trial and what is -- how do we think about 120 and 130 and the next-gen edits. In terms of the size of the trial, we'll give you further details as we go forward. But generally, these single-arm trials have been -- have enrolled anywhere between 75 and 100 patients. And that's about the size of the trial we anticipate we'll need to do to get to approval with this product. I think -- so we're quite confident that I think with this consolidation dose -- even without the consolidation dose, we have something that will be a product here. So we're all hands on deck in terms of execution to move it into the expansion -- expand it into pivotal trials. In terms of next-gen, obviously, we have a very robust R&D organization. We're working on future generation versions of all our CAR-Ts. And as we identify new edits for improving the persistence, edits to improve the potency of the initial response, I think we will incorporate those into our CAR-Ts. At this point, though, I think on CD19, we think we have a -- not just a first-in-class, but a best-in-class allogeneic therapy. So we want to focus on execution to get this into the pivotal settings. We'll provide further updates on 120 and 130. But generally, I think where we -- it's hard sometimes to separate the forest from the trees. But at 20,000-foot level, this data update is really important because it signals that allogeneic cell therapies are going to be the -- are going to eventually leapfrog autologous and be the frontline of our fight against cancer. And for our entire I/O franchise where we've invested quite a bit, whether it's on next-gen edits, on our next-gen manufacturing, I think, this bodes really well for not just 110, but our other CAR-Ts in the rest of our franchise as well.

We'll move next to Raju Prasad with William Blair.

The data has a couple of interesting points for -- from a platform perspective. One, I think about the consolidation regimen; two, potential dose selection; and three, this effector:target ratio you mentioned, Sam. So as we think about kind of 120 and 130 and kind of the platform potential that you have here, I mean, are we thinking this kind of as establishing a similar regimen for multiple myeloma, for solid tumors, the consolidation with this dose level? And with this effector:target ratio cutoff, is that something that we might see extrapolated from here on out? The -- interesting to get some color on that.

Yes. Certainly, there are a lot of learnings here. Thank you for your question, Raju. I think one of the things we've done is always to say that we want to do a systematic experiment. I think that's why we didn't start our trials in a combination setting or with something that's a very different conditioning regimen. We want to see how does a single dose of our CAR-T work with standard lymphodepletion regimen. Let's get a good handle on that, not in like 4 or 5 patients, but a good set of 25, 30 patients. Then we know how to improve upon that, and then we want to take that into pivotal. While it's timing -- time lines are very important and we want to move fast given the space is competitive, we want to do a proper experiment. And I think that's what we would do with our other CAR-Ts as well. I think we want to understand what's the activity of the single dose, what is the right dose level. Take our CTX130, for instance. That has an additional edit beyond what CTX110 has. So I think we do need to fully figure out how that works as a single dose at different dose levels. Do we see the same effector:target ratio phenomenon with CTX130? So we'll have more updates for you in the near future. But I think -- overall, I think we want to take a solid scientific approach in terms of how we develop these programs with the view of making them best in class.

We move next to Yigal Nochomovitz with Citigroup.

Let me add my congrats on the data. I have 2 quick questions. First of all, just a technical one. It's a bit unclear how you're calculating the 21% 6-months CR rate. I wasn't able to ascertain what the denominator is for that metric. And then, secondly, could you just explain how patients that were not refractory to their last prior therapy were able to enter the study?

Thank you, Yigal. I'll start with the first part of your question and turn it over to Ewelina for the second part of your question. Just to be clear on the numbers, if you look at the swim lane chart, you have 23 patients that were dosed with CTX110 above dose level 2. Of those patients, 5 patients are not evaluable for their 6-month visit. They're still in response or in a stable disease that have -- but they have not reached their 6-month evaluation point. So the denominator is actually less -- 5 less than the 23, but then we add the 1 patient to have a -- from an ITT perspective, the 1 patient that never received CTX110 that was enrolled in the trial because we want to keep everything apples-to-apples. So from an ITT standpoint, the denominator is 19. And we have 4 patients, the top 4 shown in the swim lane, that have had the 6 months of clinical benefit and continue to do well, well after their initial CTX110 infusion. That's how we arrive at the efficacy number. To your second part of the question, Ewelina?

Yes. Thank you. It's a great question. So similarly, like other autologous CAR-T cell trials, we've included patients who are refractory or relapsed. And one of the conditions for patients entering on our trials that they have to have failed 2 lines of therapy. So for patients who are relapsed, those typically come after autologous stem cell transplant or for whatever reason the patient didn't receive a transplant and relapsed after their second line of therapy. So very similar to what autologous CAR-T cells have done.

We'll move next to Jay Olson with Oppenheimer.

Do you think that you've optimized the dose response? Or could you push the dose higher than dose level 4 to achieve higher efficacy? And then, separately, can you talk about the degree of CAR-T expansion in patients who do not respond to CTX110?

Yes. So I'll answer the first part of your question, Jay, and then turn over to Ewelina for the second part of your question. So I think on the dose, it's a good question. Why not dose level 5, right? I think -- what we've seen -- again, if you look at the effector:target ratio plot, when you're above a certain threshold, you're very likely to get a response. I think there is a clear correlation and relationship there. So I think based on that judgment, we believe that doing dose level 4 twice, the initial dose and the consolidation dose, is the best approach. We can certainly push the dose levels higher given that we do manufacturing based on healthy donors and we have no limitations. But I think the DL 4 dose level twice seems like the best path to go. Ewelina?

Yes. It's a great question and one that we've been looking at very closely. If you look at some of the published data for autologous CAR-T cells, what you're going to see is that patients who have expanded or didn't expand -- or I'm sorry, who have responded or didn't respond both had expansion of their CAR-T cells. And the difference isn't very significant in most of the analysis. And for our product, what we're seeing with CTX110 is a consistent expansion around day 8. The cells disappear for most part, at least from the level of detection by day 28, and this is one of the reasons we're able to redose the patient. We haven't seen significant differences from a level of expansion for patients that have responded or didn't respond, which is similar to what we've seen with autologous.

Tony, is there anything you'd like to add on that -- on the PK front?

Yes. Like Sam was saying that we probably have found a single dose of CTX110 can give you durable response, and we can further enhance this based on our E:T ratio analysis. When you have greater effectors to tumor size, we can sort of further enhance this with consolidation dosing.

We'll take our last question from Silvan Tuerkcan with JMP Securities.

Congrats on this great data. I have 2 questions, just to follow up on Jay's question here. In the patients that don't respond in the durable responses, it seems like that it's around month 1 when they would progress. What would consolidation do to these kind of patients here? Any chance that would delay progression? Or are these cases more or less a lost cause with fast progression? And then a second question around your -- the CR rate in dose level 4 versus dose level 3 or 3.5. It seems like overall you have a high response rate, but the CR rate may be going down. Obviously, this may just be numerical here. Is there any way that you can comment on that? Could that be boosted as well?

Yes. I think it's small numbers here when you look at the CR rates, but the response rate obviously has a very clear correlation. But this -- your question gets to the heart of what's one of the [Technical Difficulty] is the notion of the consolidation dose and why we believe the second dose not just delays progression but could yield a durable to complete response.

Yes. So there's quite a bit of variability between patient to patient, the size of the tumor, refraction of tumor. But as you can see in our analysis, what comes out is not really cell expansion relationship to clinical response, but it's really how much killing capacity, if you will, you have for these CAR-T relative to the tumor. And when you give the first dose, you can see on some patients with smaller tumor size, we can completely eradicate the tumor and get a very durable response, as you have seen in some of our patients here. For those patients who sometimes even see CR, but there are still some low-level tumors, this is when you give them a second dose, that can actually now -- the second dose is actually tackling much smaller tumor volume, so much higher effector:tumor ratio. Then in this case, you were actually able to completely eradicate that -- this small amount of tumor now that's what's left. And that's why we believe a consolidation dosing is the way to go, in this case, very much how you attack a cancer. You go by waves, second wave, fresh coop and kill all these tumor cells.

Yes. That's the important concept. I think what we have here with an allogeneic therapy is a way to develop it in the proper fashion to accrue the most benefit to patients in a systematic fashion, right? With autologous therapies, as you saw with the initial data, it wasn't clear why are some patients relapsing, why are some patients progressing. There's a lot of patient-to-patient variability because every patient's drug manufacturer is different. Here, we have a very consistent drug. We have a very strong relationship with dose response. We can see what's happening in every patient from a PK standpoint. And what it's telling us is there is this open window when you dose these patients with standard lymphodepletion where they do the cancer killing. Now if you have enough cells, they completely eliminate the tumor. If not, you would have a second consolidation dose where the remaining tumor is cleared, and that should yield better data. But even in the first instance, you're seeing that there is very strong expansion as you get to day 10, and then some of cells go away. Either they're eliminated by the host immune system or they may be getting exhausted. And -- but I think understanding all these mechanistics of how these CAR-Ts work, having a very clear dose response, we don't have questions of, oh, the conditioning agent caused the response. Is there any combination? Does the rituxan combination cause the response? We don't have any of that. We have a single-agent drug here that's showing you very clear activity in a very safe manner, and I think it's going to push the field forward. I know we're at the end of our time here, and I'm sure there are more questions. But I'll just tell you, at the very high level, we're very happy to provide this update. We're incredibly excited. I think in a moment, there are a lot of questions about how these drugs are working. But at a very high level, what we've entered is this era of smart engineered cells versus cancer. We've had a 60-year modern war on cancer, and we've thrown the kitchen sink of toxic chemicals at cancer and a number of antibodies against targets. And we made some progress but not a lot. And now we're entering an era of smart engineered cells where we have -- we can direct them to go kill the cancer in a relatively benign fashion, and that's only going to get better over time. And the way to do it is allogeneic cell therapies. You can argue all you want about healthy donor versus iPS cells, CAR-T versus NK cells. I think as long as they're allogeneic, and at some point, you may have a notion of NK and T cells coming together, but at this point, T cells are shown to be the best effector cells. And with CTX110, we have what's not -- what could be best-in-class, not just first-in-class, among the allogeneic cell therapies. And we look forward to providing you more updates, but most importantly, we look forward to providing great clinical benefit to a large number of patients, not just in specialized academic centers, but in community settings and outpatient settings all around the world and help them fight the cancer. So thank you all for your questions. Thank you for listening in. I want to thank the team for a wonderful job here at CRISPR Therapeutics, but I also want to thank the brave patients and their families and the investigators who have been part of our trials in getting us to this point and look forward to working with everyone. It does take a village to bring a new platform to patients in a safe and effective manner. And we are fully motivated and excited here to keep everything -- keep it going as fast as we can with a great deal of urgency. Thank you, everyone.

This does conclude today's program. Thank you for your participation. You may disconnect at any time.