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
and that all participants are in a listen only mode.
At the request of the company, we will open up the call for a brief question and answer period at the end of the presentation. I would like to introduce Susan Kim, CRISPR Therapeutics' Vice President of Investor Relations, Incorporate Communications. Please go ahead.
Good afternoon and thank you for joining us as we report Updated results from the CARBON trial. An ongoing Phase 1 study of CTX-one hundred and ten, a healthy donor derived gene edited allogeneic CAR T therapy the treatment of CD19 positive 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 Joining me this afternoon are Sam Pokarni, our Chief Executive Officer Evelina Moraba, 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 1 PARPID study of CTX-one hundred and ten 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 $2,500,000,000 We were the 1st to demonstrate the power of critical gene editing in patients with genetically defined diseases with our lead program CTX-one. 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 CTX-one in the next 18 to 24 months. Building beyond CTX-one, we have advanced 3 gene editing allogeneic CAR T programs into the clinic. With today's release, we show clinical proof of concept for CTX-one hundred and ten, 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 Christopher 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 CTX-one hundred and ten 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 a new frontier in the fight against cancer.
We believe that our CRISPR platform is uniquely capable A 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 1st generation of approved CAR T therapies. The advantages of allogeneic CAR T include 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 CTX-one hundred and ten, we made 3 simultaneous edits that are designed to avoid graft versus host disease, Target the CAR T cells of the tumor and resist immune rejection sufficiently to enable durable responses without the need for more toxic Lymphodepletion regimen. In today's data release, we believe that CTX-one hundred and ten has shown a safety and efficacy profile that can compete with autologous CAR T in relapsedrefractory large cell lymphoma. A single dose of CTX-one hundred and ten 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 demonstrate the potential for CTX-one hundred and ten to produce durable remissions as evidenced by a 21% 6 month CRA, also similar to autologous CAR T therapies. Importantly, CTS-one hundred and ten achieved this efficacy with a positively differentiated safety profile. We have not observed any Grade 3 or higher CRS And eye cancer 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 Q1 of next year. This trial will incorporate consolidation dosing, which is supported by the safety, pharmacokinetic profile and clear dose response to CTX-one hundred and ten.
We believe that a consolidation working strategy will increase the rate of durable complete remissions already observed at CTS-one hundred and ten. I will now turn the call over to Doctor. Evelina Muraova, our Vice President of Clinical Development, who will present updated data from the CARBON trial.
Thank you, Sam. The primary objective of the Phase 1 CARBON trial is to evaluate the safety and efficacy of escalating doses of CTX-one hundred and ten. Dose escalation of CTX-one hundred and ten was performed in adult patients With relapsed or refractory large T cell non Hodgkin's lymphoma, we're failed at least 2 lines of therapy. Patients who received prior autologous CAR T cell therapies are not eligible. Patients received 2 days of menthol depleting chemotherapy consisting of cluverabine at 30 milligrams per meter squared And cyclophosphamide is 500 milligrams per meter squared followed by a single CTX one time infusion.
Some patients have completed screening in the It was 3 days and the median time from enrollment to start of lymphodepleting chemotherapy was only 2 days. This timeline was possible because there is no need for leukapheresis, breathing chemotherapy and CTX-one time is available at the site before a patient is enrolled. Finally, patients who showed a response to the first PCX-one infusion could be re dosed 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 CTX-one hundred and ten and had at least 20 days of follow-up.
Only one patient who was enrolled in CARBON did not receive CTX-one hundred and ten. Historically, autologous CAR T studies have reported primary efficacy results using a modified intent to treat or MICT approach. This methodology excluded up to 1 third of enrolled patients from the analysis. The excluded patients are primarily those who experience 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 PTX-one hundred and ten are essentially unchanged when we applied an intent to truth or ICT analysis, which includes all enrolled and evaluable patients.
It is important to emphasize that Carbon has exclusively enrolled patients with large D cell lymphoma, including CoDCL MOS, High grade double or triple hip lymphomas were 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 and off the shelf CAR T cell therapy. Notably, nearly a third of patients enrolled in CARBON have received CTX-one hundred and ten with the 9 months of their first treatment for large cell lymphoma, which speaks to the very rapid disease tempo and lack of responsiveness the prior therapies for patients treated on this trial. This table summarizes the baseline characteristics for patients who have received CTX-one timing 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 central transplant and the majority of patients had stage 4 lymphoma and they'll refractory to their last line of therapy before entering the trial. Responders to CTX-one hundred and ten were assessed by trial investigators using the 2014 Lugano criteria. This table summarizes response rate to the first BTX quantime 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 CX-one hundred and ten. Complete responses were seen in dose levels 2 to 4.
Responses were seen in a variety of patients, including patients with refractory disease, Volcan disease or who had progressed at the prior tolerability transplant. When you look at the 23 patients who received CTX-one hundred and ten 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 frontline talk shows that CTX-one hundred and ten 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 CTX-one time 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 11 months after a single CTX-one time infusion. In addition, the 4 bars show the patients treated at dose level 3 for the complete response at the day 28 month 3 visits. The LIFONTRA have a single small STG added 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 anti cancer therapies. Finally, the 5th bar comes from a patient who is initially treated at dose level 3.5 An acute day CR at the day 28 assessment will progress at month 3.
This patient received a second CCX-one hundred and ten infusion and we recently learned it's now back in CR. Together, we believe these efficacy data tell us that a single CTX-one hundred and ten infusion Symprobe's 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. Evergood safety data For the 23 patients treated at dose level 2 and above are summarized in the far right column. CTX-one hundred and ten was well tolerated across all dose levels.
There are several specific aspects to PTX-one hundred and ten safety profile that are important to highlight. First, there have been no cases of records with host disease. 2nd, there have been no infusion reaction to either lymphodepleting chemotherapy or CTX-1x. 3rd, looking at the established class effects of CAR T cell therapy, there have been no cases of Grade 3 or higher CRS with CTX-one hundred and ten. Importantly, all cases of CRS was Grade 1 or 2 Per the ASCCC criteria, Enidra requires no specific intervention or results following standard CRS management.
Neither the frequency nor the severity of CRS has increased in patients who are read based with PTX-one time. The only case of Grade 3 or higher ICANN was in a patient with concurrent HHV-six encephalitis, who was discussed in-depth during our last data release. There have been no new cases of iCAMS 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 HE36 encephalitis and one patient who develops psudomonal factors that results in full days.
Overall, CTX-onex has an emerging safety profile that is positively differentiated from autologous CAR T therapies based on the lower frequency of severe CRS or ICAM and from allogeneic CAR T therapies that require more toxic lymphodepletion regimens, which can result in prolonged immune suppression and increased Risk of serious infection. CPF-one hundred and ten'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 The patient relapsed after transplant and enrolled in carbon with a baseline 6 centimeter macinearis mass that was dose 5 on PET scans. She received a single CCS one time infusion at dose level 3 and had an uncomplicated clinical course without any CRS, eye cancer infection. At her 1 year assessment, There was no evidence of lymphoma by toxicity.
The patient remains clinically well with no ongoing toxicity from treatment. A second patient speaks to the safety and clinical benefit of multiple CCS-one time 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 MOS, the patient received 2 prior lines of therapy with a best response of partial response Endicom trial entry has multimodal involvement in several areas as well as 30% lymphoma cells in bone marrow. He was initially treated at dose level 2 and achieved a CR day 28 post PTX onetime infusion. However, approximately 7 months after the first infusion, he experienced disease recurrence.
The patient received a second CTX-one hundred and ten fusion 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 does not experience CRS, ICANN or infection after receiving either CTX-one hundred and ten infusion. We have observed these responses with CCX-one time. The waterfall plot on the left shows the best percent change in target lesion diameter for the 23 patients treated at dose level 2 above. The color of the bars reflects the best overall response inclusive of redoxant.
On Arrive is a similar product data from 95 patients treated with Axicell and the ZUMA-one 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 the coloDx CAR T therapies, I believe we are seeing efficacy with PTX-one hundred and ten that shares many key similarities, importantly, without the requirement for patient specific And now I'm going to hand it over to Doctor. Tony Ho, our Head of R and D to contextualize the CCX-one hundred and ten clinical data and share our plans for CTX-one hundred and ten moving forward.
Thank you, Evelina. Looking at the CTX-one hundred and ten data we've shown today and the results of trial that led to the approval of the OTOZ CAR T product, Yes, Carta, Timaya and Brianca, it's important to keep 2 things in mind. First, The publications and improved 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 on to when zucophoresis in these trials did not receive a powered CAR T cell infusion and are excluded from these MITP analyses. This update includes patients with the most aggressive forms of disease who experience progression, toxicity or death All for whom a TALUS CAR T manufacturing was unsuccessful.
In contrast, because PTX-one hundred and ten is off the shelf and does not require patient specific manufacturing. Only one patient enrolled in CARBON did not receive CTX-one hundred and ten infusion. Using an ICT approach, the overall response and complete response rate in carbon are similar to previous Aptalis CAR T studies. 2nd, because our polycarbonate CAR T can cause severe or life threatening CRS WiCan, in a significant fractional patient, their use is primarily limited to academic centers and requires periods of mandatory inpatient admission. In contrast, CTX-one hundred and ten 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 already competitive profile for TCX-one hundred and ten based on its pharmacokinetic profile and clear dose response. The PK profile for CTX-one hundred and ten shows significant and consistent expansion. CDX-one hundred and ten cells routinely extend over several lost orders of magnitude, with peak expansion typically occurring 8 to 10 days following infusion. In most patients, CPX-one hundred and ten levels decreased over the following 2 to 3 weeks And Proteus der Lindel's detection in Phase 28. Expansion profiles are similar for second infusion With no evidence that anti HOA or anti drug antibodies accelerate the clearance of CAR T cells.
These data indicate that a standard dose of 3 sites creates a window for CTX-one hundred and ten activity and support consolidation dosing of 1 month. TPX-one hundred and ten has a clear dose response, which we believe is driven by the factor to target ratio. The plot on the right shows a correlation between clinical response and ETP ratio. There is a parent 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 of the 12 or 70% have achieved CR. Simply put, if the CTX-one hundred and ten cells are administered when tumor volume is low, complete responses are likely.
These data strongly support a consolidation dosing strategy, where a second dose of PTX-one hundred and ten 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 choose complete elimination from a single dose. Let me turn back to Sam to conclude our presentation.
Thank you, Tony. We've shown today that CTS-one hundred and ten Has the potential to be a best in class allogeneic cell therapy in patients with relapsed and refractory large cell lymphoma. CTS-one hundred and ten 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 Infection. Furthermore, we have the potential to improve on the efficacy profile with a 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 views 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're 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 potent GIV 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 We've participated in this groundbreaking clinical research.
We thank them for their efforts and bravery. We're now happy to take questions. Operator?
I'll move first to Joon Lee with Truist Securities. Please go ahead.
Hi. Congrats on the data and thanks for taking our questions. 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 endogenous NK Mediated injection of CTX-one hundred and ten. And would you consider using Enhanced clinical depletion method or adding some other dozen vessels like HLA E?
And I have a follow-up. Thank you, Joon, for your question. We're very pleased to see that our allogeneic CTS-one hundred and ten can produce durable responses and do it In a 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 and D, To answer the specifics to your questions around the PK curve.
Yes. So from today's data, you can see that on patient to patient basis, We do see a consistent expansion profile with CTX-one hundred and ten, and this is As you can see from today's presentation, And we believe that with consolidation does, then we can actually improve this 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, any genetic anomalies, just out of curiosity. Thank you so much.
Yes. Thank you, Jun. 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 it's something we discuss with regulators.
I think to finish off on your previous question, I think that the PK curve here is actually a feature, not a bug Optic 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 read the limited detection, yields this beautiful balance between Having the efficacy we're seeing, producing 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 the month, we can have a second dose, which could completely eliminate the cancer and increase the
We'll move next to Maury Raycroft with Jefferies. Please go ahead.
Hi, everyone. Congrats on the updates, and thanks for taking my question. First one is just if you can talk about what a registrational study could look like. And in order to start in 1Q 'twenty two, Can you say if you have had any preliminary FDA buy in on this and what next steps are? Thank you, Maury.
I think for our the data today are quite remarkable. If 2 years ago when people were talking about allogeneic CAR Steve, if you said, are you going to get durable responses with a single dose of alginate CAR T? People were not very confident of that. And here, we've seen That with one single dose of alginate CAR T, we can get these durable responses. Not only that, but you get that in a safe with a very differentiated safety profile And we can only improve upon these responses of consolidation dosing.
All those factors point us towards and give us great confidence that we can start our pivotal trials. In fact, it's not start up early 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
We'll We'll take our next question from Geoff Meacham with Bank of America. Please go ahead.
Hey, guys. Thanks for the question. And also want to offer up some congrats on the data. I have 2 related Questions and Sam, they're mostly related to the 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 having safety and AE guardrails just in Yes. Thank you, Jeff. I'll start with the first part of your question and then have Laurence Klein, our CEO, 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, but 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 DTI-one hundred and ten here.
In our case, 20 out of the 24 patients enrolled receive 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 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 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 commentary on the REIT in light of the recent events, I'll turn it over to Laurence Cline, our COO.
Hi, Jeff. Thanks for the question. I think the first thing I'd say with respect to the recent new treatment, We have very little data at this point to say anything definitive or specific about that and the read through to CTX-one hundred and ten. 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 that there are a number of differences Between what we're doing with CTX-one hundred and ten and what Allogene does is ALLO-five zero one and ALLO-five zero one A. The first being that we use CRISPR versus allergy using tailings to edit the cells. And those 2 editing technologies Have different profiles in terms of their efficiency of editing, 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 construct, 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 3rd difference key difference is that, Algen uses a CD52 or anti CD52 depleting Agent or as we use standard lymphodepletion. And those types of agents can lead to very deep Cytopenias that don't result as significantly from the type of lymphopletion 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 We'll be watching for as we go forward. At the moment, we're not changing anything we're doing with CTX-one hundred and ten 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. Please go ahead.
Good afternoon. Thanks for taking my questions. Could you Speak to the baseline characteristics well, actually, the prior treatments for your patients in the context of 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, Charlie, for the question. I'm going to have Evelina, 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 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 We have enrolled similarly as the HUMIUSCARTA Embry, MD trials, aggressive lymphoma patients such as DLBCL, NOS, triple or Double hip lymphomas and transformed follicular lymphoma. We haven't enrolled any patients with low grade lymphomas like So just follicular lymphoma, because we knew there was a higher unmet need in these large cell aggressive lymphoma.
Regarding the median number of prior treatment, 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 asologous transplantation. So Well, we look holistically as a patient population, it's quite consistent in terms of medium 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, It's here for DTX-one ten infusion. In terms of what we hope to take into our cohort expansion, We are planning to proceed with dose level 4 at 600,000,000 CAR T cells with standard fluid size lymphodepletion In addition to an early consolidation dose, similarly with Flucai and dose level 4 of 600,000,000 CAR T cells, And we believe that this consolidation will further even increase the CR rates and produce durable permission.
And Salveen, I'll just add
to that, which is if you
look at our data where we show the dose response, you see a very close dose clear dose response. Navin, this important notion of effector to target ratio. What we've shown is the correlation of responses To the effector to target ratio and you see a very clear delineation where when you're above a certain effector to target ratio, Your chances of getting a complete response are much higher. And that's why we have very good confidence that going at the DL 4, dose level 4, with the consolidation dosing where the second dose is coming in with a tumor volume is already reduced And you have an even higher ETA 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. Please go ahead.
Thank you for taking my questions. 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, can CR 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 patients?
And that was my first question. And also regarding the Just want to make sure like I understand correctly. So for Bose, would that be mandatory for pivotal study, Then we'll be adding additional dose, consolidation dose for dose level 4 for the pivotal study. And then related the other set of the question is regarding the safety that related to allogene events. And thank you for all the Additional thoughts you have and one question we got to ask a lot is the translocation, the potential risk.
So wondering, does your drug product QC Release SC 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. Gina and I'll have Laurence 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 DL3.5 first and then got the DL4. I think what we've included is the full out of the 23 patients shown on the swim lane chart, the first four patients. And obviously, the first patient The patent redose and is in response at 18 months, then we have 2 patients with single dose that are well beyond 10 months in terms of response. The 4th patient in swim lane got a DL3 at dose of CTX-one hundred and ten. Now while we show a Progression there, it was really, as Elena explained, a very small lesion that was excised out and the patient has not received any of the therapy.
This is a relatively sick patient that came into the trial and 14 months out continues to do well without any systemic anti cancer therapy since 1 100 and 10. 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's DL3.5 With subsequent receipt of DL4, that number will 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 of 1 dose to get the 2nd dose because that's the notion of consolidation. You're trying to eliminate every single cancer cell that 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 PR or 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, Gina.
So we do As a our drug product for translocations, and we do see the translocation between the traglobe is mutated It's as it would be expected. Typically, it's at a rate around 1% in the drug product, And that's something we asked before in the release. So that's not expected to cause any issue and we've done a number of assays 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 That's how we handle that, definitely. We'll
Hi. Thank you for taking the question and congrats on the update. Was there any difference in safety as you administer the 2nd dose, I'm just wondering how many of these safety kind of Grade 3 plus We've indicated here came up with the redose for the second dose versus the first dose.
Thank you, Luisa. Carolina?
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 And I think this is why it's so incredibly exciting that we are able to think about this consolidation And so even in the patients with the redosing, the rates that you are seeing, No Grade 3 for CRS, no ICANS except those 2 patients we have mentioned before, no GVHD, no infusion reaction. This is all consistent with the first infusion and the second infusion and hopefully will allow significant amount of patients to be re dosed
Moving next to Ted Tenthoff with Piper Sandler. Please go ahead.
Great. Thank you, everyone, and congrats. Impressive. So two quick questions
for me. Firstly, did you mention how many
And
then, today's focus is on ON-ten. When do you think we could get data from the 120 and 130? And I guess I have my 2 questions. What would you envision as maybe future potential edX that might enhance the lifetime profile? Thanks guys.
Yes. Thank you, Ted. It's a little hard to hear you, but I think let me just repeat the question 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 then next in 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 I've enrolled anywhere between 75 100 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 Yes. So we're quite confident that I think with this consolidation dose, even without the consolidation dose, we have something that could be a product here. So we're all hands on deck in terms of execution to move it into the expansion expanded into pivotal trials.
In terms of next gen, obviously, we have a very robust R and D organization. We're working on Future generation versions of all our CAR Ts. And as we identify new edits for improving The persistence added to improve the potency of the initial response, I think we'll incorporate those into our CAR Ts. At this point, though, I think on CD19, we think we have a not just the 1st 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, 130, but Generally, I think, more it's hard sometimes with stuff like the forest and 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 IO 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 other CAR Ts and the rest of our franchise as well.
We'll move next to Raju Prasad with William Blair. Please go ahead.
Thanks for taking the question. The data has a couple of interesting points From a platform perspective, 1, I think about the consolidation regimen 2, potential dose selection and 3, this affected the 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 establishing a similar Regimen for multiple myeloma for solid tumors, the consolidation with this dose level and with this effective target ratio cutoff, is Something that we might see extrapolated from here on out. Do you think you need to get some color on that? Thanks.
Certainly, there are a lot of learnings here. Thank you for your question, Juanjo. I think one of the things we've done is always say that we want to do 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 lymph depletion 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 timelines are very important and we want to move fast given the space Competitive, we want to do a proper experiment. And I think that's
what we would do with
our other CAR team as well. I think we want to understand what's the activity of the single dose, What is the right dose level? Take our CTKS-one hundred and thirty, for instance. That has an additional edit beyond what CTKS-one hundred and ten 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 effect to the target ratio phenomenon with CTX-one hundred and thirty. So we'll have more updates for you in the near future. But I think overall, I think we want Take a solid, a scientific approach in terms of how we develop these programs with the view of making them best in class.
We'll move next to Yigal Nochselovitz with Citigroup. Please go ahead.
Hi, great. Thank you very much for taking my questions and 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 month 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 Evelina for the second part of your question. Just to be clear on the numbers, if you look at Remelane chart, you have Page 23 patients that were dosed with CTX-one hundred and ten above dose level 2.
Of those patients, 5 patients are not evaluable for their 6 month visit. They're still in response or in stable disease, but have not reached their 6 month evaluation point. So the denominator It's actually less 5 less than the 23, but then we add the 1 patient to have a From an ITT perspective, the one patient that never received CTX-one hundred and ten 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 CTS-one hundred and ten infusion. That's how we arrive at the efficacy number.
To your second part of the question, Evelina?
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 relapse. And one of the conditions for patients Entering on our trials that they have to have failed two lines of therapy.
So for patients who are relapsed, those typically come after a 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.
And we'll move next to Jay Olson with Oppenheimer. Please go ahead.
Thank you for the update and thanks for taking my questions. 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 CTX-one hundred and ten? Yes. So I'll answer the first part of your question, Jay, and then turn over to have Helena for the second part of your question.
So I think on the dose a good question, why not dose level 5, right? I think what we've seen again, you look at the effective target ratio plot, When you're above a certain threshold, you're very likely to get a response. I think there's a clear correlation and relationship there. So I think based on best judgment, we believe that doing dose levels forward 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 DL4 dose level twice and seems like the best path to go. Elena?
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 sorry, who responded or didn't respond both had expansion Of their CAR T cells. And the difference isn't very significant in most of the analyses. And for our product, what we're seeing with PTX-one hundred and ten is a consistent expansion around day 8.
The cells disappear from most probably from the level of detection by day 28, and this is one of the reasons we're able to redose the 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, 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 that single dose of CTX-one hundred and ten can give you dual response and we can further enhance this based on our E to T ratio analysis. When you have greater factors to tumor size, we can sort of further enhance this with consolidation dosing.
We'll take our last question from Silvan Toukren with JMP P Securities, please go ahead.
Hey, good afternoon. Thanks for taking my question and congrats on this great data. I have two questions. Just a follow-up on Jay's question here. In the patients that don't respond in the durable responses, it seems like that's around month 1 when they will progress.
What would consolidation do To these kind of patients here, any chance that would delay progression? Or are these cases more or less are lost cause with past Progression? And then the second question around your the CR rate in dose level 4 versus Those levels are 3.5%. It seems like overall, you have a high response rates, but CR rate may be going down. Obviously, this may just be numerical in here.
Is there any way that you could comment on that? Could that be boosted as well? Thank you very much for taking my questions. 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 one of It's a notion of 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 the 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 as well you have for the 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 you can see CR, but there are still Some low level tumor, this is when you give them a second dose that can actually now the second dose So it's actually packed on a much smaller tumor volume, so much higher effector to tumor ratio.
And in this case, You are actually able to completely eradicate that, the small molecule enough, 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 catheter, you go by waves, second wave, Fresh group, it's royalty, tremendous health.
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 that 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's this open window when you dose these patients with standard of liquid depletion Where they do the cancer killing. Now if you have enough cells, they completely eliminate the tumor.
If not, you 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 the cells go away, either they're eliminated by the host immune system Or they may be getting exhausted. 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?
Is the retoxin combination cause a 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, 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 a very high level, we're very happy to provide this update.
We're incredibly excited. I think In the 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 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 MK and T cells coming together, By this point, T cells have shown to be the best effector cells. And the CTX-one hundred and ten, we have What's not what could be best in class, not just 1st 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 the 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.