FATE - NASDAQ

Welcome to the Fate Therapeutics First Quarter 2022 Financial Results Conference Call. At this time, all participants are in listen-only mode. This call is being webcasted live on Investors Section of Fate’s website at fatetherapeutics.com. After the speakers presentation, there will be a question-and-answer session. [Operator Instructions] As a reminder, today’s call is being recorded. I would now like to introduce Scott Wolchko, President and CEO of Fate Therapeutics.

Thank you. Good afternoon and thanks everyone for joining us for the Fate Therapeutics first quarter 2022 financial results call. Shortly after 4:00 PM Eastern Time today, we issued a press release with these results which can be found on the Investors section of our website under Press Releases. In addition, our Form 10-Q for the quarter ended March 31, '22 was filed shortly thereafter and can be found on the Investors section of our website under Financial Information. Before we begin, I would like to remind everyone that except for statements of historical facts, the statements made by management and responses to questions on this conference call are forward-looking statements under the Safe Harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements involve risks and uncertainties that can cause actual results to differ materially from those in such forward-looking statements. Please see the forward-looking statement disclaimer on the company's earnings press release issued after the close of the market today as well as the risk factors included in our Form 10-Q for the quarter ended March 31, 2022 that was filed with the SEC today. Undue reliance should not be placed on forward-looking statements which speak only as of the date they are made as the facts and circumstances underlying these forward-looking statements may change. Except as required by law, Fate Therapeutics disclaims any obligation to update these forward-looking statements to reflect future information, events or circumstances. Joining me on today's call are Dr. Wayne Chu, our Chief Medical Officer; Ed Dulac, our Chief Financial Officer; and Dr. Bob Valamehr, our Chief Research and Development Officer. Today, we will highlight the clinical progress we have made during the first few months of 2022 with our off-the-shelf, iPSC-derived NK and T cell programs for the treatment of cancer as well as note several key milestones that we are striving to achieve over the next several months across our four disease franchises. In addition, we continue to advance our collaborations with Janssen and Ono with strong momentum and we will discuss the upcoming milestones that we have the potential to achieve during 2022 under these collaborations. And finally, we will touch on our continued leadership in innovation and highlight certain preclinical programs and data that we featured at the American Association for Cancer Research in April and that we plan to unveil at the American Society of Gene and Cell Therapy in May. I would like to begin today by highlighting our recent progress in advancing our off-the-shelf, iPSC-derived NK and T cell programs for patients with hematologic malignancies and solid tumors. In the setting of B-cell lymphoma, we continue to enroll patients with relapsed/refractory disease in our FT516 and FT596 Phase 1 studies. With respect to our FT516 program in combination with rituximab, multiple disease-specific expansion cohorts are currently ongoing as we continue to assess a multi-dose, multi-cycle treatment schedule of three once weekly doses at 900 million cells per dose. With respect to our FT596 program in combination with rituximab, based on the favorable safety profile we have observed in the single-dose multi-cycle cohort, I am pleased to announce that we have now dose escalated this single-dose multi-cycle cohort to 1.8 billion cells. In addition, we continue to enroll a two dose multi-cycle cohort at 900 million cells per dose with FT596 administered on days one and 15 and intend to dose escalate this two dose multi-cycle cohort to 1.8 billion cells per dose. In addition, we are seeing investigator enthusiasm for our FT819 program, the first ever T cell therapy manufactured from a clonal iPSC line to undergo clinical investigation. The clonal master iPSC line for FT819 is created from a single iPSC that has a novel CD19-targeted 1XX CAR construct, integrated into the T cell receptor alpha constant locus, ensuring complete biolelic disruption of T cell receptor expression and promoting uniform CAR expression. We are pleased to announce that we have now dose escalated the single-dose cohort to 180 million cells from 90 million cells. We are continuing to backfill the single-dose cohort at 90 million cells which cleared with no dose-limiting toxicities and no FT819-related Grade 3 or greater adverse events. In addition to the single-dose cohort, we are also enrolling a multi-dose cohort with FT819 administered on days one, three and five. And the first patients have been treated in this multi-dose cohort at 30 million cells per dose. As we consider registrational pathways in relapsed/refractory B-cell lymphoma, we continue to believe a critical unmet need exists for patients who have progressed on multiple lines of therapy, especially CD19-targeted CAR T cell therapy. While autologous CD19-targeted CAR T cell therapy has led to remarkable improvements in outcomes for relapsed/refractory patients, it is important to remember that about 30% of patients are primary refractory to CAR T cell therapy and the majority of responding patients will ultimately experience disease progression. Under our FT516 RMAT designation, we plan to engage the FDA in the coming weeks and hold a multi-disciplinary meeting to discuss our proposed pivotal study design in patients who have progressed or relapsed following prior treatment with FDA-approved CD19-targeted CAR T cell therapy. Importantly, no standard therapies are available for these patients. And recent retrospective analysis of real-world data presented at the 2021 Annual Meeting of the American Society of Hematology demonstrates extremely poor treatment outcomes with complete response rates of administered therapies ranging from 5% to 25% and overall survival ranging from five to seven months. Under our FT516 RMAT designation, we also plan to discuss with the FDA key CMC topics applicable to our first-of-kind iPSC product platform. With the operational launch of our second GMP manufacturing facility scheduled for mid-2022, we believe we are well equipped with the in-house expertise and capabilities to fulfill CMC requirements that are necessary for pivotal trial conduct, BLA submission and initial commercial launch. We continue to believe that the post-CAR T cell setting represents a potential fast-to-market development pathway based on the critical unmet need and we are working to launch a pivotal study, whether that be with FT516 or FT596 by the end of 2022 for patients with aggressive lymphomas previously treated with autologous CD19-targeted CAR T cell therapy. In addition to delivering transformative outcomes to heavily pretreated patients with relapsed/refractory B-cell lymphoma, we are also seeking to reach patients in the community setting, who might benefit from earlier treatment with cell-based cancer immunotherapy. We believe the delivery of off-the-shelf cell therapies in the community setting without Cy/FLu chemotherapy conditioning as an add-on to frontline immunochemotherapy regimens has the potential to transform outcomes for many patients with cancer. To that end, over the past several months, we have worked with investigators and key opinion leaders on a clinical protocol that brings FT596 into the community setting as an add-on to R-CHOP, the standard first-line immunochemotherapy for patients with aggressive lymphomas. The proposed treatment schema in patients with newly diagnosed aggressive lymphomas includes administering up to six doses of FT596 without Cy/Flu chemotherapy conditioning with one dose of FT596 administered with each of six standard cycles of R-CHOP. In the second quarter of 2022, we plan to submit the FT596 plus R-CHOP protocol to the FT596 IND and expect to begin treating patients in the second half of 2022, subject to its allowance by the FDA. In the setting of multiple myeloma, we continue to enroll patients with relapsed/refractory disease in the dose escalation stage of our FT538 and FT576 Phase 1 studies. With respect to our FT538 program in combination with daratumumab, the multi-dose treatment schedule of three once weekly doses at 100 million cells per dose, cleared with no dose-limiting toxicities and enrollment is now ongoing at 300 million cells per dose. In addition, with respect to our FT576 program, the single-dose cohort as monotherapy at 100 million cells cleared with no dose-limiting toxicities [Technical Difficulty] and we have now treated the first patients in the single-dose cohort in combination with daratumumab at 100 million cells. We are preparing to initiate multi-dose escalation cohorts with FT576 administered on days one and 15 as monotherapy and in combination with daratumumab. In the setting of AML, the company's Phase 1 study of FT538 which is designed to assess three once-weekly doses of FT538 as monotherapy in relapsed/refractory patients is currently enrolling patients at 1 billion cells per dose. In addition, an investigator-initiated study of FT538 in combination with the CD38-targeted monoclonal antibody daratumumab which is designed to assess the therapeutic potential of targeting CD38 positive leukemic blasts is also enrolling patients at 1 billion cells per dose. Both studies include the potential for further dose escalation. In the setting of solid tumors, I'm pleased to announce that we are poised to initiate a multi-center Phase 1 clinical trial of FT536, the company's first iPSC-derived CAR NK cell program for solid tumors. FT536 incorporates the company's high-affinity, non-cleavable CD16 Fc receptor to maximize antibody-dependent cellular cytotoxicity as well as a CAR targeting the major histocompatibility complex Class 1-related proteins MICA and MICB. High expression of MICA and MICB proteins which is induced by cellular stress, damage or transformation, has been reported on many solid tumors, although the proteolytic shedding of the alpha-1 and alpha-2 domains of these proteins is recognized as a common tumor escape mechanism. The clonal master iPSC bank for FT536 was created from a single iPSC-engineered with four functional elements, including the novel CAR which uniquely targets the alpha-3 domain of MICA MICB and is designed to overcome tumor escape mechanisms mediated by loss of MHC Class 1 expression and proteolytic shedding. We believe the product tenants novel mechanisms of attack and ability to synergize with monoclonal antibody therapy can drive significantly improved outcomes for patients with solid tumors. We have successfully completed manufacture and are conducting final release testing of FT536 and we are working with the study's first clinical sites to initiate first patient enrollment by the end of May. The six arm clinical study is designed to assess a multi-dose, multi-cycle treatment schedule of FT536 as monotherapy and in combination with monoclonal antibody therapy for advanced solid tumors. We look forward to providing clinical updates for our multiplexed-engineered iPSC-derived NK and T cell product candidates across our disease franchises in the second half of 2022. Turning to our collaborations with Janssen and Ono. We continue to show strong momentum in bringing multiplexed-engineered iPS-derived CAR NK and CAR T cell product candidates to patients for the treatment of hematologic malignancies and solid tumors. Under our collaboration with Janssen, we have now initiated IND-enabling activities for two iPS-derived CAR NK cell collaboration candidates. And we are actively working together with Janssen to prepare and submit IND applications for both of these candidates. For each of these collaboration candidates, Janssen maintains the option subject to its payment of an option fee prior to IND submission to initiate worldwide clinical development. We maintain the right in the U.S. alongside Janssen to co-commercialize and share equally in profits and losses of each collaboration candidate. As a reminder, under our collaboration, Janssen has the right to designate and contribute novel binding domains targeting up to four tumor-associated antigens. Janssen has now designated and contributed novel binding domains targeting three antigens. And we have now successfully achieved preclinical milestones for collaboration candidates targeting all three antigens. Under our collaboration with Ono, Ono has contributed a novel binding domain targeting a solid tumor-associated antigen and we have now initiated the generation of the master cell bank for a multiplexed-engineered iPS-derived CAR T cell collaboration candidate targeting the solid tumor-associated antigen. We are poised to initiate IND-enabling activities for the solid tumor CAR T cell collaboration candidate during the third quarter of 2022, at which time, Ono has the option, subject to its payment of an option fee, to exercise its rights for worldwide clinical development and commercialization, while we maintain the right to co-develop and co-commercialize the CAR T cell collaboration candidate in the U.S. and Europe alongside Ono. We are very pleased with the success we have achieved with Janssen and Ono in developing multiplexed-engineered iPS-derived CAR NK and CAR T cell product candidates for both liquid and solid tumors. And we are now poised to achieve significant milestones in connection with option exercised by Janssen and Ono over the course of the next three to six months. Turning to our continued leadership and innovation. We continue to invest in building a first-in-class pipeline of multiplexed-engineered product candidates for solid tumors, including through the development and incorporation of new functional elements designed to overcome critical barriers that limit cell therapy such as the requirement for patient lymphoconditioning, tumor antigen escape and the immunosuppressive tumor microenvironment. At the American Association for Cancer Research in April, we presented our synthetic alloimmune defense receptor or ADR which targets 4-1BB upregulated on host allo-reactive immune cells and is designed to eliminate the need for patient conditioning at administering off-the-shelf cell-based cancer immunotherapy. In preclinical models, we show that ADR-armed iPS-derived NK cells demonstrate enhanced functional persistence in vitro in the presence of allo-reactive NK and T cells and exhibit durable antitumor activity in vivo in the presence of allo-reactive T cells. These preclinical data provide proof of concept that ADR-armed cell therapies have the potential to persist and induce potent antitumor activity without requiring a patient to undergo chemotherapy conditioning to deplete the host immune system. In addition, we showcased our novel chimeric CD3 fusion receptor or CD3FR which is designed to enable off-the-shelf cell-based cancer immunotherapies to combine and synergize with CD3 bispecific engagers. In developing off-the-shelf CAR T cell therapies, TCR expression must be eliminated to prevent graft-versus-host disease. However, the absence of TCR expression leads to loss of surface CD3 expression. Similarly, NK cells naturally lack TCR expression and have no surface CD3 expression. In preclinical models, we showed that CD3FR-armed, iPS-derived CAR T cells in combination with a bispecific engager, demonstrate target-specific cytotoxicity in vitro through CD3FR engagement and enabled dual-antigen targeting. These preclinical data provide proof of concept that much like our hnCD16 Fc receptor that enables synergy with monoclonal antibody therapy, our CD3FR enables armed iPS-derived CAR NK and CAR T cells to effectively combine and synergize with CD3 bispecific engagers for a multi-pronged attack on heterogeneous solid tumors. Later this month, at the American Society of Gene & Cell Therapy, we plan to present nine abstracts covering our proprietary iPSC product platform, including the unveiling of our most sophisticated multiplexed-engineered iPS-derived cell product to date. We are currently developing an off-the-shelf iPS-derived CAR T cell product candidate for solid tumors. That incorporates seven functional modalities, including three modes of tumor targeting to overcome tumor heterogeneity as well as a novel synthetic CXCR2 homing receptor to promote traffic into solid tumors and a novel synthetic TGF beta redirector receptor to promote activation in response to repressive signaling in the tumor microenvironment. While we will not yet disclose the CAR construct solid tumor target, preclinical data will show that the novel binding domain exhibits unique antigen recognition and tumor selectivity with the ability to discriminate between antigen expressed on tumor cells versus normal tissue. We look forward to advancing our first off-the-shelf iPS-derived CAR T cell product candidate for solid tumors into IND-enabling activities later this year. I would now like to turn the call over to Ed to highlight our first quarter financial results.

Thank you, Scott and good afternoon. Fate Therapeutics is in a strong financial position to advance our platform and pipeline. Our cash, cash equivalents and investments at the end of the first quarter of 2022 were approximately $642 million. In the first quarter of this year, our collaboration revenue derived from our partnerships with Janssen and Ono Pharmaceutical increased by $7.3 million to $18.4 million compared to $11.1 million for the same period last year. Research and development expenses for the first quarter increased by $27.3 million to $72.1 million compared to $44.9 million for the same period last year. The increase in our R&D expenses was attributable primarily to increases in employee headcount and compensation, including share-based compensation. The increase in our G&A expenses was attributable primarily to an increase in employee headcount and compensation, including share-based compensation and talent acquisition and facility-related fees. Total operating expenses for the first quarter were $92.9 million which includes $19.2 million of non-cash share-based compensation expense. Note that in connection with the development of our off-the-shelf iPSC-derived CAR T cell product candidate FT819, we previously achieved the clinical milestone set forth in our amended license agreement with Memorial Sloan Kettering Cancer Center which triggered a first milestone payment to MSK in 2021. Up to two additional milestone payments may be owed to MSK based on subsequent trading values of the company's common stock ranging from $100 to $150 per share. We assess the fair value of these contingent milestone payments currently valued at $15.8 million on a quarterly basis. In the first quarter, we recorded a non-cash $8.4 million non-operating benefit associated with the change in fair value. Our net loss for the first quarter of the year was $65.7 million or $0.68 per share. Finally, our year-end cash guidance remains unchanged and we expect to end this year with at least $400 million in cash, cash equivalents and investments. This does not include potential success-based milestone payments from our collaborations with Janssen and Ono Pharmaceutical. I would now like to open the call up to questions.

[Operator Instructions] Our first question comes from Tyler Van Buren with Cowen.

This is Tara [ph] on for Tyler. I was just wondering if we can get an update on when we might expect initial data from the AML, multiple myeloma and potentially from the solid tumor clinical programs this year?

I think in our prepared remarks we made a statement that we plan on providing clinical updates across our four disease franchises in the second half of 2022.

Well, can I actually ask one more. So one thing that you mentioned last quarter was that you -- for FT516, you were doing this R-Benda combination and I didn't hear you mention it here. So I was wondering if that was still in the plan? And for the FT596 plus R-CHOP will those patients that are now being treated, will they be included potentially in August update or at ASH?

So I mentioned with respect to the FT516 study, there are multiple dose expansion cohorts ongoing in the FT516 study which would include R-Benda. With the FT596 study, we are preparing the clinical protocol for FT596 plus R-CHOP to submit to the FDA. And I mentioned, I believe, that we plan on beginning -- subject to its clearance, we plan on beginning treating patients in the second half of 2022 with respect to FT596 plus R-CHOP.

Our next question comes from Michael Yee of Jefferies.

Two questions for us. I thought your comments around 819, iPSC CAR T were pretty interesting and I guess, you started dosing patients. So maybe you could talk a little bit about how we should expect the bar for you, given other peers out there, I know you have -- maybe have some data at the end of this year. So how should we think about that data in comparison to others and the bar set there considering you're probably at low doses? And then second question is similar. In myeloma as well, there's obviously a bar out there for some pretty compelling drugs, particularly CAR T. You have a drug I think obviously with CD30 and BCMA. So maybe just talk a little bit about how we would expect that efficacy bar and whether patients would or would not have lost BCMA and would that still work, et cetera, et cetera?

So let me start with the myeloma and then I can move to 819. So with myeloma, I think again, it's early but I'm not going to be -- I think I've said this before, I'm not going to be surprised if the strategy plays out similarly to how we're pursuing lymphoma. Meaning that, with FT576, we think obviously with its dual antigen targeting potential, it could potentially be used down line of patients who have received, for instance, CAR T-targeted BCMA therapy. And in fact, in our studies, both with respect to 538 as well as 576, I believe we are -- we have treated patients that are in fact have previous experience with the approved CAR BCMA cell therapies. So obviously, I have to look at the data. We're earlier on in myeloma compared to lymphoma. But I do think there are potentially in myeloma will be a similar fast-to-market strategy that may emerge initially down line of the FDA-approved CAR BCMA therapies. Does not mean that the totality of our development path. Obviously, we've developed product candidates that we believe can synergize with daratumumab and daratumumab is used early and often throughout multiple lines of therapy but I do think there will potentially be a fast-to-market strategy that evolves in myeloma much like lymphoma. And we're excited about those opportunities as a first opportunity, as a first chance to put a stake in the ground for our product candidates and begin to develop around that. With respect to 819, look, this is our first experience with an iPS-derived CAR T cell therapy. I mean, this has been long in development over the past. I think we entered into the collaboration with Memorial Sloan Kettering back in 2016 to develop the first ever iPS-derived CAR T cell therapy. We're here, we're treating patients. Interestingly enough, we started at 90 million cells per dose. And I think if you look at the approved CAR T cell therapies in DLBCL patients, aggressive lymphomas, the dose that is often given to those patients is probably in the 100 million to 200 million cell range. So in starting at 90 million cells per dose, I'm not suggesting by any means it's the most efficacious dose but we are starting at a dose that if we truly do make essentially alpha-beta T cells, we may be starting at dose levels that have the potential to show activity.

Our next question is from Yigal Nochomovitz with Citigroup.

I'm just wondering with regard to the RMAT meeting that's coming up, could you just clarify as to why FT596 does not appear to be part of that discussion? I would have thought that FT596 would also be a useful option in the post-CD19 CAR T setting for B-cell lymphoma.

So to be clear and clear up any confusion, I absolutely believe FT596 is applicable down line of CAR T cell therapy without a doubt. The RMAT designation is very specific for FT516. So the meeting that we're planning is specific to FT516. It was grant -- the RMAT designation was granted to FT516. That said, many of the topics we will be covering, whether it relates to clinical study design, endpoints, CMC are applicable to FT596. And so what we plan on discussing with respect to the RMAT discussion -- with the upcoming RMAT discussion really is more agnostic to product candidate. What is the clinical study design, what are end points. We have a proposed study design that we would like to review with the FDA. There are CMC issues that are unique to iPS-derived cell therapies that we also plan on discussing with the FDA. So while this meeting is specific for 516, we do believe the output of that meeting will be highly applicable to FT596. And ultimately, as we progress into the second half of 2022, we will make a decision with respect to FT516 or FT596 for conduct of the pivotal study.

And then I just had a question on FT596 plus rituximab and the new dosing regimens that you're rolling out. So just curious, based on everything you know about 596 NK cell biology and NK cell persistence, just wondering and asking you to speculate which do you think would be more effective, the single-dose 1.8 billion or the multi-dose 900 million given twice which you believe is likely to be superior or do you think they could just end up being very similar?

So I think I've always been on record saying that I think the right schedule for treating patients with NK cells very likely includes multiple doses and I still believe that today. So I do believe when delivering an NK cell, given their relatively short persistence compared to a T cell and given they are significantly less prone to expand and proliferate as compared to a T cell, I fundamentally believe a multi-dose schedule for an NK cell is going to be the most efficacious path. And to be clear, we are delivering multiple doses at 900 million cells per dose. We're also delivering a single dose at 1.8 million -- sorry, 1.8 billion. Both pathways provide -- enable us -- the clearance of those pathways enable us to get to 1.8 billion times two, day one and day 15 and that's where we're headed.

And then, if I could just throw in one more on myeloma. So obviously, you've done a lot of great work building a cell therapy that can function in combination with DAR

We've done some preclinical work in assessing other combinations but you are correct. I mean the driver with respect to the therapeutic design of both FT538 or FT576 was really about creating a cell type that could uniquely synergize with daratumumab given the concern with respect to fracture side. Obviously, activated NK cells, activated T cells express CD38. And so there was the potential for fracture side. We always thought there would be significant opportunity to synergize with DAR

Our next question is from Daina Graybosch of SVB Securities.

I think a couple for me. One, we're talking so much about dose, 900 million, 1.8 billion cells, I wonder whether you could help put that into context. How many NK cells are circulating in an average patient or healthy human? And how does that compare to, let's say, 900 or 1.8 billion cells?

Bob or Wayne, do you want to address that question, if you're -- we're not in the same room but either one of you?

Sure, I can start. We typically have somewhere between 1 billion to 2 billion. So we're here with each dose at those high doses already constituting the NK compartment of a normal patient.

That's an easy answer. The second one for multiple myeloma. I wonder if you could talk a bit more about your binder for BCMA. I think you've called it avidity like? And I wonder if you could talk about what gives you confidence that your binder will give the same effect as avidity that's been used successfully in the -- from BCMA CAR T?

I think, again, either Bob or Wayne, Bob, do you want to address that question as I think you're most familiar with the unique characteristics of our particular binder.

So the binder was well characterized in a molecular therapy article back in 2018 by [Indiscernible]. And so there he showed that the affinity of the binder allows the preclinical studies to target cells that had less than 1,000 BCMA per cell. So he was able to target BCMA per cell in the 100 range. So that gave us confidence that this binder is going to be unique. We've compared it to the competitors where we have access to the sequence and it does outperform. So [Indiscernible] initial work and some of our preclinical work suggest that this binder is going to be of higher quality, higher avidity and hopefully it gives us better results and outcome.

Our next question is from Nick Abbott with Wells Fargo.

I do like to apologize if maybe you addressed that. But maybe starting off with 516 and RMAT. That IND was approved several years ago notwithstanding the fact you've had several INDs approved since, seems like FDA is getting more focus on safety. So do you think there could be any weaknesses in the manufacture of 516 and any weaknesses you think might be there to maybe address without affecting the timeline?

So it's a great question and your point is well taken. Yes, we did make the -- FT516 IND was cleared, I think back in 2019, if I'm remembering correctly. Look, I think certainly while it is an early generation product candidate, I think as you probably will appreciate, our manufacturing process is agnostic to the master cell line. So the methods we're using, for instance, to create FT596 or FT576 are really the same exact methods that we used to create FT516. So the manufacturing processes that we use today in taking a master cell bank and creating large quantities of NK cells really transcends the product candidate. And that's back to Yigal's question, this is why I think certainly while we're having a discussion around FT516 with respect to RMAT, I think many of the questions that we are intending to ask speak to the platform.

And then on 516, I'm looking at the press release. I'm trying to pass the terms progressed or relapsed following prior FDA approved CAR T. They're almost seems same to me but I'm sure you pulled over this press release. What is the difference between some of those progressed or relapsed following prior CAR T?

I don't have the press release in front of me. I can go back and look at it. But the idea in patients -- these are in patients that have been previously treated that have progressed and they may not have had a response or have relapsed following a response. That's the patient population we're targeting down line of CAR T.

So does that include patients then who are primary refractory?

It could include patients that are primary refractory, that is correct.

And then just in terms of the R-CHOP combo, these patients are going to be treated in the community. That's where they've been treated today. So is this a study that you can do in a sort of true community setting as opposed to in kind of outpatient setting of MGH, for example?

Yes, I think we're pretty confident in that. I mean, I'll turn it over to Wayne and he could talk about this a little bit more because he's done a lot of work here, working with the investigators and the KOLs that helped us develop the protocol.

So yes, we've spoken quite a lot to investigators and key opinion leaders around the concept of this which at its most basic form, it's essentially standard dose and schedule of R-CHOP and then administration of FT596, a certain period of time after each cycle of R-CHOP. And we've demonstrated with our Phase 1 data of FT596 that from a safety perspective, FT596 at the doses we treated to date is quite safe in the sense that very little in the way of cytokine release syndrome, no ICANS, no GvHD. And so when we developed the protocol with -- in partnership with investigators, they were quite comfortable with the idea that, one, from a safety perspective, there doesn't seem to be anything that would be disqualifying in terms of starting the study. And then secondly, there is quite a degree of comfort that not only would they be able to get patients to be treated with this but also treat these patients in a way that's reasonably convenient, i.e., giving -- administering FT596 in an outpatient study. So we're very confident that we will be able to have quite robust enrollment into this trial.

So if I can just follow-up on that. I mean, I can envisage a situation where the patient gets a R-CHOP in the oncology office. It sounds like then you might be sending the patients to the local CAR T treatment center?

No, that's not what's contemplated here. That's not what's contemplated. This is community setting outpatient treatment.

Our next question is from Michael Schmidt with Guggenheim.

This is Kelsey on for Michael. For 596 plus rituximab, I guess, up to how many dose cycles can be administered? And can you just remind us what patients are eligible to receive additional cycles now that the protocol amendment I think is in place? And then just a quick follow-up on that. I guess, there was some competitor CAR NK cell data last week. And I think for them, at least, the data suggested that three doses per cycle was better than two doses. I guess, is this something that you guys would consider looking at your treatment schedules or are you pretty set on two doses per cycle for 596 at this time?

I guess, I'll address the last question first. Yes, I mean, we are giving two doses of FT596 on day one and day 15. In addition, 576 being delivered on day one and 15. The reality is we've seen responses from single doses. So I think -- and we've looked at a lot of translational data and feel very comfortable with the functional persistence profile extending for about two weeks. So we feel pretty comfortable with the two dose schedule given what we've seen on the translational side and given the fact that we've seen responses at with a single-dose. That said, our protocols have a tremendous amount of flexibility in them. And we certainly have the opportunity to backfill patients into a three dose cohort if we chose to do that. So we have a lot of flexibility under the existing protocols. I would say, similarly with respect to cycles, the protocols are set-up essentially as a first cycle, a second cycle. And then I think under the existing protocols and Wayne you can correct me if I'm wrong, I believe under the existing protocols, patients do have the ability to go on to additional cycles. I don't know, Wayne, do you want to comment on the cycles?

Yes, that's absolutely correct. Right now because of the FDA allowing us to proceed directly to a second cycle, we consider an initial treatment course with FT596 is consisting up to two cycles. And then in addition to that, specifically in patients who have an initial response and then subsequently progress, we have the option for retreatment of those patients as well.

Our next question is from Mara Goldstein with Mizuho.

Scott, I want to be respectful obviously of trade secrets and the like but maybe you can talk a little bit about the CMC and what would be considered from your viewpoint a positive outcome from FDA with respect to the upcoming meeting? And really, maybe if you could just give us something to think about in terms of what are the types of questions that you might be asking? And then I just had a question on the 516 trial. I'm curious if the protocol allows for the individual set of relapsed patients versus refractory patients?

So can you just clarify the second question first? Do we treat refractory patients with relapsed -- refractory/relapsed therapy as opposed to relapsed/relapsed therapy? Is that the question, relapsed therapy?

Right. And if you are able to look at the outcomes within those buckets of -- within those different subgroups or it's just a global subgroup relapsed/refractory?

Currently, the cohorts are relapsed/refractory in the same cohort but that doesn't mean we can't segregate that on a go-forward basis if we chose to do so and treated them as unique populations. We would certainly be able to do that on a go-forward basis. But currently, the cohorts are relapsed/relapsed therapy as well as refractory/relapsed therapy. CMC, I guess -- and thank you for making a comment about respectful of trade secrets. I think one of the elements that has hung up cell therapy companies in the past, as I think you're well aware, is there are oftentimes potency assays. So you may suspect that one of the things that we certainly want to get ahead of in conversation with the FDA are for instance some of the potency assays that we've developed. And now you could say, for instance, whether it be CAR19 or CAR BCMA, there may not be a lot of trade secrets or a lot of innovation with respect to those potency assays but CD16 is a powerful mechanism here. And so we are suspecting, don't know but suspecting that we will require a potency assay for CD16. And so that's certainly something as an example that we would want to discuss with the FDA given the prevalence of CD16. That feature a high affinity non-cleavable CD16 receptor that we're using throughout our product candidates. Again, sort of harkening back to the comments that I made that many of the questions we're going to ask here are not just relevant for 516 but are relevant for 596 as well as our platform. I think the other thing that we want to have a conversation with FDA about is obviously not necessarily potency assay but there are a whole host of other release specifications that are relevant for cell therapies and beginning to reach agreement on release specifications for the conduct of a pivotal study I think again can apply universally to our product candidates.

And if I could just ask a question. I mean, clearly, you have a lot of resources. You end this year with $400 million. I understand not including any types of milestones or whatnot. But given the pipeline that you have and the plans to go into additional bigger and potentially more complex studies, I mean, how do you think about financing post-2022?

Look, I think we have two terrific collaborations with Ono and J&J that can provide meaningful streams. Do I think they're going to offset the entire burn of the company? No, I don't. But I do think the Ono and Janssen collaborations, we have strong momentum. We're seeing success. It's publicly out there, maybe not exactly with respect to timelines and milestones at each stage but it's publicly out there what the milestones can represent with respect to each and every product candidate. And currently, I alluded to the fact that we think we have three product candidates emerging from the two collaborations. And I do think there's the room for the company to do more collaborations. And I think we are actively in discussions to engage in more collaborations.

Our next question is from Robyn Karnauskas from Truist Securities.

I could spend the whole day on your new technology but let me just ask a few. So on the dose, there's another question on the competitor data. That data used very high doses of 1 billion to 1.5 billion cells multiple times in AML and DLBCL. I was just curious your thoughts on the read here despite to your whole program in dosing that high. Like does the cell type matter, like ITC versus just either donor-derived or another form of an NK cell or does this tell you that high doses really might work the best? I mean, you may have to get up to that 1 billion to 1.5 billion dose. The second question is just how high for dose will you go? And then I had a follow-up on the RMAT trial.

So I guess a couple of things. And I will say with respect to dose, again, there's a lot of literature and obviously clinical experience with NK cells versus T cells. And let's just stick in the lymphoma space because it's the easiest to compare and contrast. In the lymphoma space, obviously, with CAR T cells, in the approved CAR T cells, we've seen doses that are fairly modest compared to an NK cell. I mean, we've seen doses in the 100 million to 200 million range. Single-dose 100 million to 200 million cells with YESCARTA is the recommended dose, is the dose that's used today. I mean, that's exceptionally low compared to NK cell and the history of donor-derived NK cell. If you look at the history of donor-derived NK cell therapy and you go back and you look at the history, my gosh, people are giving not 900 million cells, they're giving like 5 billion, 6 billion, 7 billion, 8 billion cells. So back to Daina's question, I mean, the history of donor-derived NK cell therapy in order to try and drive even modest efficacy, folks have been delivering a multiple of the NK cell compartment that actually just exists within your body which obviously, now when we've always said and others in the industry will say the same thing, if you really want to make an NK cell efficacious, you're going to have to engineer in functional elements. And I think with those engineering in functional elements, whether it be a CAR or CD16 receptor or what have you, I do think you'll see dose levels of NK cells, lower dose levels of NK cells be more efficacious but clearly, they are going to be at dose levels I think that are higher than T cells. And I think that gets back to a little bit of the nature of a T versus an NK. When a T cell gets activated, it is quite capable of undergoing significant expansion and proliferation and they do persist longer compared to an NK cell which is not going to significantly expand as a T cell would and it's nowhere it is not going to functionally persist as long as a T cell. So I think we've always believed and I think it's playing out that the NK cell doses and schedules will be different than what you have typically seen with T cells. The good news, I would say, from -- with respect to the NK cell community, while it may require higher doses, while it may require multiple doses, safety profile I still think is significantly differentiated compared to a T cell.

And since you don't know how durable the chances are yet, would you dose higher than where your...

Yes, I mean, I think that's the feedback that we got at ASH at some basic level from our investigators. We don't know what the durability is of an NK cell versus a T cell. No one knows, I mean really. That question has not been answered in the community yet, what's the durability of an NK cell. And so given the safety profile, yes, we absolutely -- and we're at 1.8 billion cells. So we will continue to dose escalate. We think we certainly have a platform that allows for the delivery of high doses if that's necessary and multiple doses.

And then a follow-up question on the RMAT 516 meeting. Do you have a sense of for your clinical trial how far out you might have to follow patients? There's been a lot of discussion versus the early CAR T studies that you kind of knew like within six months that there was durability or deep response. Can you give any sense of that? And then I'm sorry, squeeze this one in for your ADR, how close to the market are you? And no more questions.

So let me discuss the clinical trial design obviously with the FDA and discuss potential endpoints. I think, again -- I think the one thing I would point out is at least in the post-CAR T cell patient population, I had some remarks with respect to the benchmarks that are out there with respect to therapies that are being at least trying to be deployed by physicians today. And I think we made a remark that the complete response rates are somewhere between 5% to 25% and overall survival is around six months. So I think you're potentially looking at a very difficult to treat patient populations where outcomes for better or for worse are determined very quickly. With respect to ADR, we have a lot of preclinical data with ADRs. We have not necessarily decided yet what product candidate to incorporate ADR technology into. That said, we think ADR technology and the idea of chemotherapy-free conditioning and delivery of cell therapy is the direction the field must go. We absolutely believe that Cy/Flu long-term is a barrier to cell therapy's ultimate potential and technologies will need to be developed and utilized to reduce the dependency and requirement on Cy/Flu. And I do think we are targeting a 2023 time period for the integration of ADR technology.

And at this time, I would now like to turn the conference back to Scott Wolchko.

Thank you very much. I appreciate everyone's time this afternoon. Thank you all for participating. Be well and we look forward to catching up soon.