Welcome to the Fate Therapeutics Fourth Quarter 2021 Financial Results Conference Call. At this time, all participants are in a listen-only mode. This call is being webcast live on the investor section of Fate's website at fatetherapeutics.com. 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 Fourth Quarter 2021 Financial Results Call. Shortly after 4:00 P.M. Eastern Time today, we issued a press release with these results, which can be found on the investor section of our website under Press Releases. In addition, our Form 10-K for the year ended December 31, 2021 was filed shortly thereafter and can be found on the investor section of our website under Financial Information.
Before we begin, I'd like to remind everyone that except for statements of historical facts, the statements made by management in 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 market today, as well as the risk factors included in our Form 10-K for the year ended December 31, 2021 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 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 Bob Valamehr, our Chief Research and Development Officer.
Today, we will highlight key clinical development initiatives that we are pursuing for our four disease franchises and certain milestones that we are seeking to achieve in 2022 with our off-the-shelf iPSC-derived NK and T-cell programs for the treatment of cancer. I would like to begin today by highlighting several development opportunities that we are aggressively pursuing with our off-the-shelf iPSC-derived NK cell programs for patients with B-cell lymphoma. We are seeking to reach patients across the continuum of care and deliver transformative outcomes to heavily pre-treated patients being treated at specialized centers who have progressed on multiple lines of therapy, as well as to patients in the community who might benefit from earlier treatment with cell-based cancer immunotherapy.
In particular, for those patients who have progressed on multiple lines of therapy, including autologous CD19-targeted CAR T-cell therapy, we believe our off-the-shelf iPSC-derived NK cell programs have shown unique potential in addressing this area of critical unmet medical need. While autologous CD19-targeted CAR T-cell therapy has led to remarkable improvements in patient outcomes, 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. There is no established standard of care for these patients, and unfortunately, outcomes with currently available therapies are dismal. For example, to
According to a publication from the US Lymphoma CAR T Consortium, published in Blood in April 2021, an analysis of physicians' choice of first salvaged therapy following CD19-targeted CAR T-cell therapy showed complete response rates ranging from only 12%-20%, median progression-free survival ranging from 48-88 days, and median overall survival ranging from 3.5-11 months. Similar outcomes from additional retrospective studies were reported at the 2021 ASH Annual Meeting in December. At ASH, we reported clinical responses from our FT516 and FT596 programs in patients previously treated with autologous CD19-targeted CAR T-cell therapy. Three of eight patients treated with FT516 and five of eight patients treated with FT596 achieved a complete response at a minimum dose level of 90 million cells in combination with rituximab.
In addition, we announced that our FT516 program was granted Regenerative Medicine Advanced Therapy or RMAT designation by the FDA for relapsed refractory diffuse large B-cell lymphoma. RMAT designation is an FDA program designed to expedite the development and review of therapies that have demonstrated the potential to address an unmet medical need based on preliminary clinical evidence. We believe we are well positioned 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, and that this development pathway represents a potential fast-to-market strategy. During the first half of 2022, we plan to engage the FDA to discuss CMC, manufacturing, and pivotal study design in pursuit of this significant unmet medical need.
This timeline also coincides with the operational launch of our second GMP manufacturing facility, which is designed for pivotal and commercial production. Recall that about 18 months ago, we began investment in the building of our second GMP manufacturing facility, as we believe in-house manufacturing expertise and capabilities are critical to the successful development and commercialization of complex cell therapies. This 50,000 sq ft facility remains on schedule to be operational by mid-2022. We believe production of pivotal and commercial drug product from this facility will allow us to most effectively fulfill CMC requirements that are necessary for pivotal trial conduct and BLA submission and to reduce the possibility of delays that other cell therapy companies have confronted in preparation for commercial launch.
In addition to improving outcomes for heavily pretreated patients who have progressed on multiple lines of therapy, we are also seeking to reach patients in the community setting who might benefit from earlier treatment with cell-based cancer immunotherapy. To this end, we are actively working to bring FT596 without Cy/Flu conditioning chemotherapy into the community setting as an add-on to early-line standard of care rituximab-containing treatment regimens.
Based on the promising therapeutic profile that we observed with FT596, including its substantially differentiated safety profile supporting administration in the outpatient setting, and given that FT596 is specifically designed to synergize with monoclonal antibody therapy that is an essential component of early-line regimens for the treatment of B-cell lymphoma, we are aggressively pursuing the addition of FT596 to R-CHOP as a dual antigen-targeting treatment approach in patients with newly diagnosed aggressive lymphomas.
In the coming weeks, we plan to submit a clinical protocol to the FDA that adds FT596 to R-CHOP and expect to begin treating patients in the second half of 2022. We believe that demonstrating the ability to deliver off-the-shelf cell therapies in the community setting without Cy/Flu chemotherapy conditioning as an add-on to frontline immunotherapy regimens has the potential to transform outcomes for many patients with aggressive life-threatening disease. At this time, we continue to enroll patients with relapsed refractory B-cell lymphoma in the dose escalation stage of our FT516 phase I study and in the dose escalation stage of our FT596 phase I study.
With respect to FT516, we are enrolling patients into three disease-specific expansion cohorts, including patients with relapsed refractory B-cell lymphoma whose disease has progressed following autologous CD19 targeted CAR T-cell therapy, third line diffuse large B-cell lymphoma in patients that are naive to autologous CD19 targeted CAR T-cell therapy, and third line follicular lymphoma. We are also enrolling patients into a fourth expansion cohort without Cy/Flu conditioning chemotherapy, adding FT516 to the immunochemotherapy regimen of rituximab plus bendamustine. Importantly, in enrolling patients to these four dose expansion cohorts, we are including sites that serve patients in the community setting.
With respect to FT596, having observed that a single dose treatment schedule of FT596 at 900 million cells was well-tolerated with no dose-limiting toxicities, we have increased the frequency of FT596 dosing and initiated enrollment of a two-dose treatment schedule with FT596 administered on day one and day 15 at 900 million cells per dose, and with the potential to dose escalate to 1.8 billion cells per dose. Similar to FT516, we plan to initiate multiple disease-specific dose expansion cohorts for FT596. We expect to provide a clinical and regulatory update from our FT516 and FT596 programs in the second half of 2022.
I'd also like to take a moment to reiterate our excitement in conducting the first-ever clinical trial of an iPSC-derived T-cell therapy. FT819 is 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 biallelic disruption of T cell receptor expression and promoting uniform CAR expression. We believe FT819 is highly differentiated from patient and donor-derived CAR T cell therapies, both of which require the sourcing and engineering of large populations of immune cells and are fraught with batch-to-batch and cell-to-cell variability that can affect product quality, safety, efficacy, and patient reach. Instead, FT819 is mass-produced, uniformly engineered, and homogeneous in composition.
At ASH, we presented a poster demonstrating our capabilities relating to cGMP manufacturing of iPS-derived CAR T cells, including our ability to produce up to 1 × 10^13 FT819 cells in a single manufacturing campaign, with over 50% of FT819 cells exhibiting a memory T cell phenotype. Today, we are pleased to announce that the initial FT819 dose escalation cohort at a single dose of 90 million cells cleared with no dose-limiting toxicities and no FT819-related grade three or greater adverse events in patients with relapsed refractory DLBCL. Enrollment is now ongoing at five clinical sites in the U.S. in 3 treatment regimens: single-dose cohort at 180 million cells, single-dose cohort at 90 million cells administered with low-dose IL-2 cytokine support, and three-dose cohort at 30 million cells per dose.
In addition, enrollment is ongoing in the first single-dose escalation cohorts at 90 million cells for relapse refractory chronic lymphocytic leukemia and for relapse refractory acute lymphoblastic leukemia. Turning to our multiple myeloma disease franchise, I'm pleased to announce that the initial FT538 dose escalation cohort at three once-weekly doses of 100 million cells per dose in combination with the CD38-targeted monoclonal antibody daratumumab has cleared with no dose-limiting toxicities.
Our FT538 product candidate is engineered with three functional components to optimize innate immunity, and the preclinical studies have shown that FT538 exhibits enhanced serial killing, antibody-dependent cellular cytotoxicity, and functional persistence compared to peripheral blood NK cells. Enrollment in the FT538 phase I study is now ongoing in the second multi-dose escalation cohort of 300 million cells per dose at 8 U.S. sites.
Similar to our approach in lymphoma, where we are developing FT516 and FT596, we have further modified our FT538 product candidate to create FT576, our off-the-shelf iPSC-derived CAR NK cell product candidate designed to target multiple antigens, both through its high avidity BCMA-targeted CAR and its high-affinity non-cleavable CD16 Fc receptor. We have now treated the first patients in our phase I study of FT576, which is designed to assess both single-dose and multi-dose treatment regimens as monotherapy, as well as in combination with daratumumab, an approach that uniquely enables targeting of both BCMA and CD38 antigens. We expect to provide a clinical update from our FT538 and FT576 programs in the second half of 2022. Turning to our AML disease franchise, enrollment is currently ongoing in two phase I studies of FT538 for patients with relapsed refractory AML.
The company's phase I study of FT538 as monotherapy is preparing to initiate enrollment in the third multi-dose escalation cohort of one billion cells per dose as monotherapy. This is noteworthy as it represents the highest dose of iPS-derived NK cell therapy tested to date with any of our product candidates. In addition, an investigator-initiated study of FT538 in combination with daratumumab, which is designed to enable recognition, binding, and killing of CD38 leukemic blasts through ADCC, is currently enrolling patients in the second multi-dose escalation cohort at 300 million cells per dose. We will look to provide an update on our AML franchise as we generate additional dose escalation data with FT538, including in combination with daratumumab, so we're able to fully compare the safety, anti-leukemic activity, and durability response of our FT516 and FT538 phase I studies.
Turning to our solid tumor franchise, in November, we shared phase I data from our FT500 and FT516 pilot programs in heavily pretreated patients who had received multiple lines of prior systemic therapy, including at least one line of checkpoint inhibitor therapy. We are very pleased with our clinical observations from these pilot programs, both of which demonstrated a favorable safety profile and feasibility of a multi-dose, multi-cycle treatment schedule with outpatient administration. In addition, both pilot programs showed clinical evidence of antitumor activity. With respect to FT500, three of four non-small cell lung cancer patients treated in combination with checkpoint inhibitor therapy had reduction in target lesion burden from baseline, including one partial response in a heavily pretreated patient who was refractory to two prior lines of checkpoint inhibitor therapy.
With respect to FT516, five of nine solid tumor patients treated in combination with anti-PD-L1 checkpoint inhibitor therapy had reduction in target lesion burden from baseline, including one partial response in a heavily pretreated patient with advanced melanoma who was refractory to two prior lines of checkpoint inhibitor therapy. On the heels of these pilot programs, we are advancing a robust pipeline of five multiplexed engineered iPSC-derived NK and T cell product candidates for solid tumors.
We believe our product candidates' novel mechanisms of attack and ability to synergize with therapies that are used early and often in care can drive significantly improved outcomes for patients with solid tumors. For example, with FT538, we are leveraging the ability of NK cells to recognize, bind, and kill antibody-coated tumor cells and the potential to deliver a fully optimized NK cell compartment to patients to maximize ADCC.
Building off of FT538 as a foundation, we have created two additional wholly owned product candidates, FT536, which incorporates a CAR targeting the stress-induced proteins MICA and MICB and is designed to overcome prominent mechanisms of immune cell evasion. FT573, which incorporates a CAR targeting B7H3 and is designed to uniquely target the metabolic profile and metastasis of cancer. In addition, we are also developing multiplexed engineered CAR-NK and CAR T-cell product candidates for solid tumors alongside our two partners, Janssen and Ono.
I am pleased to announce that the first patients have been treated in our phase I study to assess three once-weekly doses of FT538 in combination with monoclonal antibody therapy for advanced solid tumors. The clinical protocol includes combination with each of four monoclonal antibodies, EGFR-targeted cetuximab, HER2-targeted trastuzumab, PD-1-targeted pembrolizumab, and PD-L1-targeted avelumab.
Each patient is eligible to receive up to two FT538 treatment cycles, and additional FT538 treatment cycles may be administered to patients that achieve initial clinical response. While the eligibility criteria enable the assessment of FT538 antibody combinations in a broad array of solid tumor indications, we are particularly interested in assessing various combinations in non-small cell lung cancer, given its immunological features, including that many tumor subsets express targets of interest for NK cell-based therapy.
We are also preparing to initiate a multicenter phase I clinical trial to assess a multi-dose, multi-cycle treatment schedule of FT536 as monotherapy and in combination with monoclonal antibody therapy for advanced solid tumors. FT536 is the company's off-the-shelf, multiplexed engineered, iPS-derived NK cell product candidate, which incorporates a novel CAR targeting the 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 one and alpha two 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 three domain of MICA and MICB and is designed to overcome tumor escape mechanisms mediated by loss of MHC class I expression and proteolytic shedding. We look forward to providing an initial update on our FT538 and FT536 solid tumor programs as we advance through dose escalation. I would now like to turn the call over to Ed to highlight our fourth quarter financial results.
Thank you, Scott, and good afternoon. Fate Therapeutics is in a strong financial position to advance our pipeline. Our cash equivalents, and investments at the end of 2021 were approximately $717 million. In the fourth quarter of 2021, our collaboration revenue derived from our partnerships with Janssen and Ono Pharmaceutical increased by $1.2 million to $17.1 million, compared to $15.9 million for the same period last year. Research and development expenses for the fourth quarter increased by $30.5 million to $69.5 million, compared to $39 million for the same period last year. The increase in our R&D expenses was attributable primarily to investments made in equipment and materials, increases in employee headcount and compensation, including share-based compensation and in expenses associated with R&D fees and third-party professional consultants.
General and administrative expenses for the fourth quarter of 2021 increased by $6.6 million to $16.9 million compared to $10.3 million for the same period last year. 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 fourth quarter were $86.4 million, which includes $14.6 million in non-cash share-based compensation expense. Note that in connection with the treatment of the first patient with our off-the-shelf iPSC-derived CAR T-cell product candidate FT819 in the third quarter of 2021, we achieved the clinical milestone set forth in our amended license agreement with Memorial Sloan Kettering Cancer Center.
This clinical milestone triggered a first milestone payment in the amount of $20 million to MSK, which we paid in the fourth quarter. Up to two additional milestone payments may be owed to MSK on subsequent trading values of the company's common stock, ranging from $100-$150 per share. We assess the fair value of these contingent milestone payments, currently valued at $24.2 million on a quarterly basis. In the fourth quarter, we recorded a non-cash $0.5 million non-operating benefit associated with the change in fair value. Our net loss for the fourth quarter of 2021 was $69.3 million or $0.72 per share. Finally, we expect to end this year with at least $400 million in cash equivalents, and investments.
This does not include potential success-based milestone payments from our collaborations with Janssen and Ono Pharmaceutical. With that, I would now like to open the call to questions.
Thank you. At this time, to ask a question, please press star one on your telephone. Again, that is star one to ask a question. To withdraw your question, just press the pound key. Please stand by while we compile the Q&A roster. Your first question comes from the line of Michael Yee from Jefferies. Your line is now open.
Hey, Scott, thank you for the update. Appreciate that. We think that solid tumor updates later this year could obviously be pretty important as you expand the power of the platform. Could you just maybe comment on how to think about the ongoing FT538 study in combination with antibodies and how to think about what that could show in terms of efficacy? Since you did comment that you've obviously now about to start the FT536 MICA/B study, would you have enough data later this year to talk about that in a solid tumor update? Thank you.
Sure. I mean, we're early in the FT538 study, but obviously there are four different escalation cohorts that are enrolling concurrently and independently. We do believe we're gonna get a very good early look here with respect to FT538's potential in combination with four different monoclonal antibodies, again, across several different solid tumors, but with an emphasis on non-small cell lung cancer. We can talk a little bit more about when we think that update it'll be, but we're striving to continue to work through dose escalation in the FT538 study and then provide an update, which we think, you know, can be in the second half of this year. That's what we're targeting currently with dose escalation. With FT536, the IND has obviously cleared with the FDA. Super excited about that.
It's another multiplexed engineered product that's pretty sophisticated that we cleared the IND in 30 days, and we expect to begin dosing the next, the first patients in that study in probably the middle of this year. I think what's important about the FT536 study is in addition to combination with monoclonal antibody, it includes a monotherapy arm. The monotherapy arm will kick off first, we'll start at 100 million cells. We'll start at multiple doses of that monotherapy arm. We think this will be, you know, an interesting first look at the CAR MICA/MICB construct and its ability to target certain solid tumors.
You know, we're relatively early with respect to the development of the solid tumor franchise, but look to provide an update as we work through dose escalation.
Thank you.
Your next question comes from the line of Yigal Nochomovitz from Citi. Your line is now open.
Hi, this is Ashiq Mubarack on for Yigal Nochomovitz. Thanks for taking my questions. For the post CD19 CAR T expansion study that you're initiating in B-cell lymphomas later this year, I guess what are some of the key factors you're considering in choosing between FT516 and FT596?
Yeah, there's a multitude of factors that will come into play. I think the two that I would highlight is number one, we're obviously continuing to generate data with both FT516 as well as FT596. So we'll certainly make a data-driven decision. We're also having conversations with the FDA with respect to clinical study design for that. So, you know, input from the FDA will also impact our decision with respect to what product candidate we'll ultimately select. I think, the one thing to note is, you know, certainly, FT596, we're doing a little bit more work with respect to its dose and schedule. And we've indicated that we potentially will even do a little bit of dose escalation work still with FT596 and go to 1.8 billion cells.
We think that's prudent, makes absolute sense. I think, you know, we will make the decision ultimately probably in the second half of the year based on a multitude of factors. We are prepared to move forward with either product candidate.
Okay, thank you very much.
Sure.
Your next question comes from the line of Tyler Van Buren from Cowen. Your line is now open.
Hi, guys. This is Tara on for Tyler. I wanna focus on this bendamustine combo that you're currently enrolling for 516 and the R-CHOP course for 596, which haven't been talked about too much yet. First, what proportion of patients are being treated in the community setting at least for the Benda cohort? And when can we expect data from that? Should it come along with the longer-term phase I data in August or at ASH? And if so, how many patients and where can we set expectations? Thanks.
I think in future updates, we'll provide clarity on when we might be able to provide data on both, 516 or Benda, as well as 596, obviously in combination with R-CHOP. I'll let Wayne talk about our strategy a little bit with 516 and 596 and our outreach into the community.
Sure. You know, when we think about, you know, these combinations of FT516 and FT596, you know, as Scott mentioned, we're highly interested in the ability to to use these cell products without flu/cy conditioning. The rationale for combinations with R-Benda and then R-CHOP, you know, are essentially twofold. One is, you know, to take a standard immuno-chemotherapy regimen that's used for the treatment of lymphoma and see whether or not, you know, by having complementary mechanisms of action that can translate into greater clinical benefit. The second question is really about the ability of regimens such as R-Benda or R-CHOP to also serve as conditioning regimens that can facilitate FT516 or FT596, you know, pharmacokinetics.
The purpose of doing both of these investigations is really to hone on those two different concepts. You know, with respect, specifically with respect to rituximab plus bendamustine, you know, R-Benda is a standard therapy that's used in a broad array of B-cell malignancies, both aggressive lymphomas as well as indolent lymphomas. You know, data from the University of Pennsylvania has demonstrated that single agent bendamustine could actually serve also as conditioning therapy for autologous CD19 CAR T. Our intention to combine FT516 with R-Benda is really to extend that concept. Certainly, you know, the same principles hold true when looking at combinations of FT596 with R-CHOP, right?
The implication there, of course, is that if you can demonstrate additive activity, as well as the ability of R-CHOP to serve as a conditioning regimen for cells, then that has significant implications with respect to how we treat patients with newly diagnosed disease.
Your next question comes from the line of Daina Graybosch from SVB Leerink. Your line is now open.
Yeah, I wanna ask a follow-up to Wayne, what you just said on the R-CHOP in particular. Can you talk about how you might design the trial to understand both of those goals over conditioning? Is there any other data in the community or in academic settings that talks about or shows how the CHOP part of R-CHOP could be a conditioning regimen for cell therapy?
I'll take the first part of the question, then I'll turn it to Wayne. Daina, I think it's a little bit early for us to talk about what our development strategy is with respect to R-CHOP. Obviously, we do have one, and we're thinking it through very carefully. I think the one thing that we're interested in demonstrating off the bat is. Do we see in the first couple of patients anything that is disqualifying? For instance, obviously this has not been done before. Almost all cell therapy has been delivered in conjunction with Cy/Flu.
We'll be looking carefully at the translational data, both safety and translational data, that would suggest or support the ability to deliver FT596 without Cy/Flu in combination with R-CHOP, where R-CHOP can provide the necessary sort of background for the cells to flourish and have potent activity. I think I'll turn it over to Wayne to answer the second part of that question.
Apologies. Could you just repeat that second part of the question so that I'm clear?
I just wondered if, like bendamustine, there's anything combined in cell therapies with CHOP that you can lean on or gives you confidence in your strategy.
Yeah. So as Scott mentioned, you know, this is the first time that we're kind of embarking on this with respect specifically to CHOP. I think the question is still, you know, a very valid one until we start generating clinical data. I would say that the. You know, conceptually, it's similar to that of R-Benda. And I think the key question is whether or not CHOP, when you give it, especially when you give it multiple cycles over, you know, over six cycles, whether or not that can achieve, you know, the same conditioning effect as what we typically see with flu/cy. It may be very different, and that's what the intention of this study is to really start, you know, interrogating those questions.
I mean, I think I'll pick up on that. I mean, think of it, this is a very different. Like, the idea of combining with R-CHOP or R-Benda is a very different paradigm than, for instance, the Cy/Flu paradigm, right? Obviously, standard of care R-CHOP, standard of care R-Benda are given in multiple cycles. For instance, with R-CHOP, the cycles are literally, I think, Wayne will correct me, 21 days apart. We're talking about being able to add 596 to each cycle of R-CHOP and assess, obviously, the cell's performance. Very, very different paradigm than what's currently utilized for cell therapy.
Great. Thank you.
Your next question comes from the line of Michael Schmidt from Guggenheim. Your line is now open.
Hey, this is Kelsey on for Michael. Thanks for taking our questions. On FT596, I guess you've noted you're treating patients in multi-dose, multi-cycle. I guess how many cycles are you planning to give there? And then regarding the decision in the second half of the year for pursuing either FT516 or FT596, I guess, is that specifically for the post CAR T patient cohort, or are you choosing the go-forward product, you know, more broadly? And then will early FT819 data inform that decision at all? Thanks.
Wow, there's a lot in there.
Sorry about that.
That's okay. That's okay. Look, the decision around the development of the lymphoma strategy is obviously multifactorial. There are lots of obvious considerations, but we are very comfortable that at the end of the day, there may in fact be a multi-product franchise in lymphoma. There are plenty of targets, plenty of opportunities, patients to serve in lots of different settings. We're very comfortable with the fact that there may be a multi-product franchise in lymphoma. How we make that decision, I'm not gonna get into it necessarily on the call, but it's certainly multifactorial. I don't know. Wayne, if you wanna add anything to that.
The only thing I would add to that is it's just to emphasize the fact that while, you know, we are aggressively pursuing a potential fast-to-market strategy in a specific population of patients who progress or relapse on prior CAR T, our clinical investigations for all of these products, you know, expand or extend well beyond that. We are looking at other patient populations in parallel with this potential fast-to-market approach. I think it's safe to assume that the broad development strategy will be reflected on, you know, what data we get from these other patient populations for all of our products. You know, you have not only multiple product candidates, but you have a multitude of B-cell indications, you know, in which these products can operate optimally.
Now, with all that said, I will continue to maintain that we are big believers in multi-antigen targeting. We think that will add significant value to patients. I will continue to maintain that at the end of the day, we believe FT596 is a best-in-class NK cell product candidate, and that includes with respect to FT516. We gotta generate more data. We're certainly now looking at the first multi-dose, multi-cycle experience with FT596. But today, we continue to maintain FT596 as a best-in-class product candidate, and if that becomes out, you know, for instance, our lead CD19, CD20 targeted strategy in lymphoma, and our best-in-class way to engage rituximab, not gonna apologize for that at the end of the day.
Got it. Okay. Thank you.
Your next question comes from the line of Nick Abbott from Wells Fargo. Your line is now open.
Good afternoon, Scott and co, and thanks for a terrific update as always. You know, maybe just starting on this post-CAR T, you know, clearly the data you've shown to date, the activity in patients who are primary failures is less durable than those who, you know, are not primary failures. I acknowledge these are still relatively low doses, but as you go forward here, do you look at both of these populations as one population or as discrete populations? I have a follow-up. Thanks.
Yeah. I think that's a fair question. I think it's one of the reasons, you know, I talked about continuing to generate data with both FT516 and FT596. We certainly are looking at patients downline of CAR T-cell therapy that have previously responded to CAR T, and we're certainly looking at patients that are refractory to CAR T. As we think about crafting ultimately our registration strategy and the pivotal trial design, we will continue to be guided by data.
Sure. Then I know there's been a couple of publications recently of patients who've failed CD19 CAR T following a CD19 bispecific, and it's pretty clear that that sort of epitope coating that's preventing that. Given likely uptake of CD19 bispecifics, is that a population that you think you can access with the, you know, rituximab combo while the old CD19 washes off?
Yeah. I mean, I'll let Wayne talk too, but I think that's one of the value propositions that we bring to the table with either FT516 or FT596. CD20 seems to be a very durable target throughout the lines of treatment. We certainly have seen terrific synergy between our hnCD16 receptor and rituximab, including, as you mentioned, demonstrating complete responses downline of CD19 targeted therapy. Yes, I continue to think the CD20 targeting strategy in combination with rituximab is definitely differentiated.
Only thing that I would add is, you know, specific to your question around T-cell engagers that we know where the target is CD19. You know, just keep in mind that most of these CD19 targeting T-cell engagers have relatively short half-lives because they're not of an antibody format that's, you know, similar to some of the CD20 engagers, which are more full length, you know, antibody structures. So in that context, there's still a possibility, you know, for the use of a CD19 targeted cell therapy, you know, with a relatively short washout from prior 19-engaging antibodies.
All right. Thanks. You know, just a last one for me and that is just going back to AML. That was kind of the first therapeutic franchise update you gave last year, Scott, around mid-year. Do we take it from your comments that you've sort of completed the 516 dose escalation now, perhaps some expansion, but the data there are not compelling enough to move forward? Have you considered looking at this in high-risk MDS being as that's sort of considered less aggressive than refractory AML? Thanks.
Yeah. I think our strategy has not changed at all. At the end of the day, we don't plan on advancing more than one product candidate in the relapsed refractory AML setting. We are making development decisions and bets on what we think are our best-in-class product candidates. We were always in the development mode, if you will, where we said we wanted to complete dose escalation with FT538, including up to 1.5 billion cells, and then make a further development decision. Nothing has changed there.
Thank you.
Your next question comes to the line of Matt Biegler from Oppenheimer. Your line is now open.
Oh, hey, guys. Perfect timing. I actually wanted to ask a follow-up on the prior AML question. And it might be philosophical at this point, but do you think that NK cell therapy can be curative on its own, or is it always going to need to be consolidated with a standard of care stem cell transplant? And if it's the case where you do need a stem cell transplant, have you guys considered exploring FT538 or one of the other products in an earlier treatment setting? I guess this kind of gets to what the broader corporate strategy is, but maybe looking at AML in like the MRD positive space, post-induction but pre-transplant. Thanks.
Yeah. We are doing a lot of work internally on a next step with respect to the development of the AML franchise. I think as you're alluding to, there are multiple development opportunities that exist in treating patients earlier in care. Treating multiply relapsed or refractory patients is obviously a difficult space given how sick these patients are, given the frailty that many of these patients are with respect to age and lines of treatment that they've gone through, given the fact that usually multiply relapsed refractory patients also the bone marrow has been permanently damaged. I think the curative potential in AML. You have to intervene earlier. I ultimately believe that most likely if you want to deliver cures in AML, you're probably best suited by a targeted strategy.
One of the challenges in an AML obviously is with targets. We're obviously really interested in what we're gonna see here with FT538 in combination with daratumumab. Certainly, I do think targeting leukemic blasts in the bone marrow, and intervening earlier in care, provides the best chance of a curative outcome.
Cool.
I don't know, Wayne, you wanna add up on that?
No, just exactly as Scott said. I think, you know, the value of going in early line is to try to provide some form of therapy where you can give it before the bone marrow gets totally obliterated by repeated rounds of treatment. That we're always cognizant about opportunities to go into earlier line. You know, of course, that's not just AML, that's even B-cell malignancies, you can make a similar argument in that regard.
Obviously in order to pursue that strategy, you know, one of the concerns with AML is the frailty of patients, so you have to have a pretty exquisite safety profile to enable that.
Yeah, fair point. Thanks.
Your next question comes to the line of Mara Goldstein from Mizuho. Your line is now open.
Hi. This is Mara. Thank you for taking the question. My question is on FT819. Can you expand a little bit on the, you know, the rationale behind its different cohorts exploring, you know, lower IL-2 and split dosing? And related to that, you know, with its unique design, perhaps the treatment regimen, do you expect FT819 to be differentiated from other allogeneic CAR T development, particularly on the durability? Thank you.
Thank you for the question. Regarding FT819, you know, the way I would look at FT819 is that it's. The nice thing about that study is that it is an opportunity to exploit a lot of the features of iPSC-derived CAR T cells that, you know, with the end goal of having a better therapeutic index or better clinical activity than current generation CD19-targeting CAR T. The reason for, you know, each of the different regimens in that study is to address specific components regarding the efficacy and safety of FT819. For example, the addition of IL-2, you know, is to really explore the value of that cytokine to promote T-cell persistence and function.
We know from multiple T-cell based therapies that you know of the importance of IL-2. We believe that assessing the addition of IL-2 is an important clinical experiment. Equally as important is the ability to take advantage of the off-the-shelf, on-demand features of a cell product like FT819 and see whether or not the flexibility around dose and schedule offers an opportunity to improve the clinical risk-benefit profile of the product. The purpose of the multiple dose regimen you know where FT819 is given on day one, day three, and day five of each treatment cycle is not only to evaluate the ability of multiple doses to drive deeper responses, but also to see whether or not flexibility with respect to individual day dose can lead to a better safety profile.
This is exemplified by, you know, by the experience from the University of Pennsylvania, where they were able to use a multi-dose cycle of their autologous CD19 CAR T product to actually improve the safety outcomes in patients with relapsed refractory ALL. We are looking at that as an opportunity to do the same thing here with FT819.
I'd also say just with respect to other programs, look, this is pretty novel. Sure, it's a CAR T-cell, and you can think about it that way, and you could say, "Gosh, it's gonna look like an autologous CAR T-cell or a donor-derived T-cell." There are some substantial differences here with respect to the targeted insertion of a CAR into the TRAC locus, with respect to the CAR construct we're using, which is a novel CAR construct, 1XX, with the perspective that we are making a fairly homogeneous patient cell type with that is majority of cells are of a memory phenotype. We do think that the outcomes with FT819 do have the potential to be very differentiated.
I think one of the challenges associated with, let's call it, even patient-derived CAR T-cell therapy, but certainly donor-derived CAR T-cell therapy, is the cells do go through an extensive period of manufacture and processing at the T-cell level, and that can cause T-cell exhaustion. I mean, even in the patient-derived CAR T-cell world, there was a desire. There is a desire to significantly reduce manufacture time, and that certainly has to do with vein-to-vein time to reach patients, but it also has to do with the potency of the cells, the T-cells themselves. I think one of the unique features of our iPSC-derived cell product is we create significant numbers of T-cells without actually, and for any significant time, expanding the T-cell population.
We think we are creating a very potent T-cell that has very low expression markers of exhaustion, and that can potentially be very differentiating.
Got it. Thank you.
Your next question comes from the line of Robyn Karnauskas from Truist Securities. Your line's now open.
Hi. Thanks, guys, and thanks for the great update. I guess one small one, probably a stupid question, and a bigger one. For the FT596, dose escalation to 1.8 billion, I know before you talked about 900 million times two and then maybe a third dose. Can you just clarify when you're dose escalating to 1.8 billion cells, would that be 1.8 at day one and day 15? Or are you talking about like another round of dosing? Then the second question, which is broad, is that I think last year in oncology in general, not just Fate, we're all plagued by expectations being so high, everyone wants to see very much more complete insights with longer durability.
You've said you're gonna give some updates in the second half of the year on a couple programs with, I think, a huge focus on your FT536 program. Have you set any changes in your internal bar as far as like what you will release or, you know, disclose and just say at some point we're, you know, we won't disclose data unless it's this mature given the environment we're in and given last year's debacle, I think with all of oncology shifting how much data is required for investors to make an assessment if something was real or not? Thanks.
The first one is pretty easy. The first one, we're doing two doses of 900 million cells, day one and day 15. We have the ability obviously to do two cycles now of day one and day 15 at 900 million cells, and actually we have the ability to do more than two cycles as well with FT596 under the protocol with the FDA. Certainly with a couple patients showing safety, we're able to expand that treatment schedule. While we're expanding, we will very likely explore a higher dose, where the dose, to be clear, is 1.8 at day one and 1.8 at day 15. Again, we could give a second cycle of that or even more than two cycles of that.
Yeah, we're gonna do a little bit more dose escalation here, and go to 1.8 billion cells delivered on day one and day 15. With respect to the sort of the broader environment, look, we're doing something at Fate Therapeutics that is incredibly novel, and I am gonna continue within all reason to be as transparent as possible with respect to what we're doing and what we're seeing. I, you know, get it's just my philosophical perspective.
Thank you. That's helpful just to hear it. Thank you so much.
Your next question comes from the line of David Dai from SMBC.
Hi, thanks for taking my questions. My question is on the FT516 plus R-Benda or R-CHOP without Cy/Flu conditioning. We have increasingly seen based on allogeneic CAR T data, that we need intense lymphodepletion in order to see CAR T expansion. Could you just provide some color as to what gives you the confidence that FT516, R-Benda or R-CHOP could expand in the absence of Cy/Flu? Thanks.
I think I'll let Wayne talk to it, but I think it's one of the reasons we're doing the study. I mean, certainly we've seen different environments that where cells can perform under. I think, you know, if I speak specifically about Cy/Flu or R-CHOP or we're not so sure with R-CHOP yet, but R-Benda. Certainly when you start thinking about delivering cells in multi-dose treatment schedules, the reality is that for instance, when you look at R-CHOP or you look at R-Benda, those treatment schedules, the window, for instance, that might exist with respect to lymphodepletion is only, you know, for instance, 20 days. So for instance, you give R-CHOP, and then 21 days later, you give R-CHOP again, and then 21 days later you give R-CHOP again.
We are not looking actually to achieve long-term persistence of a cell. We're looking to plug into multi-dose treatment schedules, including standard of care that exists for early line patients.
Let me ask-
The treatment paradigm we're pursuing is not with an NK cell, is not necessarily a patient-derived CAR T-cell paradigm of one dose, persistence of one dose. Quite frankly, I'm not even sure the persistence of a CAR T-cell, a patient-derived CAR T-cell is correlated with long-term outcomes. There's a tremendous amount of data to suggest that long-term durable responses have nothing to do with long-term persistence of cells. It's all about the killing capacity and potency during the first 14, 21, 30 days.
Thank you. Very helpful.
Your next question comes from the line of Peter Lawson from Barclays. Your line is now open.
Hey. Hey, Scott, just a follow-on question from David's question, just about kinda how many indications do you think you can use iPSCs where you can kinda skip the conditioning regimen? Should we be thinking about that as any indication that has things like R-CHOP or R-Benda?
I mean, we're gonna get a first look. I mean, to right now it's all speculation at some basic level. We're certainly encouraged by the fact that when we've looked at Novartis' data with respect to use of bendamustine with and not Cy/Flu. Certainly I think, you know, we've seen sort of evidence that you can move away from Cy/Flu and use R-Benda. I'll also say, I mean, keep in mind and this is really important, a big part of what Cy/Flu does is actually about cytokine spiking within the patient. If it was about, for instance, immunogenicity or alloreactivity, patient-derived CAR T-cell is delivered with Cy/Flu. It's delivered with Cy/Flu, or it's delivered with bendamustine because the cells that are being adoptively transferred love to go into a cytokine-rich environment.
Our cell therapy, starting with FT596, have cytokine support engineered into them, so they are less reliant, we believe, and less dependent on the conditioning regimen spiking cytokines because our cell therapies have cytokine support engineered into them.
Great. Thank you so much.
Sure.
There are no further questions at this time. I would now like to turn the conference back to Scott Wolchko.
Terrific. I wanna thank everyone for your participation in today's call and all the great questions. I look forward to providing you updates in the coming months. Be well. Take care.
This concludes today's conference call. Thank you for participating and have a wonderful day. You may all disconnect.
Thanks.