Thank you all for joining us this afternoon. We're excited to share with you today interim phase I clinical data for our FT516 and FT538 off-the-shelf iPSC-derived NK cell programs in relapsed/refractory acute myeloid leukemia. Please note, as we discuss our FT516 and FT538 programs today, including clinical data and future plans for the programs, our comments will include forward-looking statements. These statements involve risks and uncertainties, and I refer you to our most recent Form 10-Q filed with the SEC for full disclosure of these risks and uncertainties. Note that undue reliance should not be placed on forward-looking statements, which speak only as of the date they are made, and the facts and circumstances underlying these forward-looking statements may change. Before we begin today, I would like to thank Dr. Jeff Miller for joining us this afternoon.
Dr. Miller is Professor of Medicine at the University of Minnesota and the Deputy Director of the Masonic Cancer Center. He is one of the founders of NK cell therapy, he is one of the foremost first persons to believe in our iPSC product platform and our potential to create NK cells from master engineered iPSC lines. Six years ago, we formed a collaboration together with a bold vision to bring off-the-shelf NK cell products to patients with cancer. His commitment, insights, and contributions over the years have been instrumental to our product design strategy, the first clinical successes we have achieved, and the therapeutic benefits being realized by patients in our clinical studies. In fact, the high-affinity non-cleavable CD16 Fc receptor incorporated into our FT516 and FT538 product candidates were conceived by inventors from the University of Minnesota, including Dr. Miller.
Additionally, Dr. Jeffrey Miller has played a leading role in our preclinical interrogation of FT538, which exhibits a unique metabolic and transcriptional profile that substantially increases cytokine production, enhances persistence, and induces potent serial cytotoxicity in preclinical models. Thank you, Jeff. Today, we will also hear from Dr. Sarah Cooley, who was also a leading clinical investigator in the NK cell therapy field before joining Fate Therapeutics in early 2019 as our Senior Vice President of Clinical Translation. Sarah will briefly review her experience as a clinician treating patients with relapse/refractory AML and discuss some of the opportunities for improving the patient experience and outcomes with an off-the-shelf iPSC-derived NK cell therapy. Following Sarah, Dr. Bob Valamehr, our Chief Research and Development Officer, will briefly discuss our iPSC product platform and describe the unique properties of FT538.
Finally, Dr. Yu-Waye Chu, our Senior Vice President of Clinical Development, and Dr. Jeffrey Miller will review our interim phase I clinical data of FT516 and FT538 in relapse/refractory AML. As a reminder, our FT516 and FT538 programs are being assessed as monotherapy in phase I clinical trials. Up to two cycles of treatment are administered, with each cycle consisting of three days of conditioning chemotherapy, followed by three weekly doses of the product candidate. One key difference between the phase I studies is that FT538, because of its incorporation of our novel IL-15 receptor fusion and knockout of CD38, is being investigated without the addition of IL-2 cytokine support, which is being administered to patients with each dose of FT516.
Today, we will share our clinical observations from nine patients in the first and second dose escalation cohorts of FT516 and three patients in the first dose escalation cohort of FT538 as of the data cutoff date of April 16th, 2021. We are pleased to announce that in these 12 patients, five patients achieved an objective response with complete leukemic blast clearance in the bone marrow based on the 2017 ELN response criteria. Of the five responding patients, two patients treated with FT516 in the second dose escalation cohort achieved complete remission with incomplete hematologic recovery and remained on study and in remission without further therapeutic intervention for more than six months as of the data cutoff. The five responding patients also include one patient treated with FT538 in the first dose escalation cohort.
This patient was refractory to their two most recent prior therapies, which included an investigational CD33-targeted tri-specific NK cell engager. The patient presented with approximately 30% leukemic blasts in the bone marrow and significant hematopoietic impairment. Achieved complete remission with incomplete hematologic recovery following the first FT538 treatment cycle, and remained on study and in remission without further therapeutic intervention as of the data cutoff. In both studies, no dose-limiting toxicities have been observed and no cases of any grade of cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or graft-versus-host disease have been reported. We are highly encouraged by these interim phase I data, which clearly indicate that off-the-shelf iPS-derived NK cells administered as monotherapy in the outpatient setting were well-tolerated and have the potential to induce complete leukemic blast clearance in the bone marrow and conferred durable remissions without further therapeutic intervention.
With that, it is my pleasure to introduce one of the most experienced clinicians in the field of NK cell therapy, Dr. Sarah Cooley.
Thank you, Scott. I'd like to begin with a brief overview of AML and some important clinical considerations in treating patients. The bone marrow is the site of hematopoiesis, where a self-renewing pool of CD34 positive hematopoietic stem cells differentiates into lymphoid and myeloid precursors, and eventually into mature blood cells, including white cells, red cells, and platelets, as appreciated in this image on the top of normal bone marrow. AML is an aggressive blood cancer that arises from clonal expansion of myeloid precursor cells that have acquired genetic mutations and become malignant. These malignant leukemic blasts are highly heterogeneous, as the phenotype depends upon the unique genetic mutations and upon the specific type of myeloid progenitor affected.
In all cases, rapidly proliferating leukemic blasts do not mature into functional blood cells, but rather they crowd out healthy blood cells and suppress normal hematopoiesis, as is seen in the bottom panel. As a result, the clinical presentation of AML generally reflects the cytopenias that result from impaired hematopoietic function, including anemia, thrombocytopenia, and neutropenia. Since AML is such an aggressive cancer, successful treatment requires complete clearance of leukemic blasts in the bone marrow. This is a prerequisite to a successful outcome, and complete marrow blast clearance has been shown to result in a statistically significant improvement in overall survival. Complete clearance of leukemic blasts also enables the bone marrow to recover and allows a restoration of normal hematopoietic function, often as assessed by evaluating neutrophil and platelet recovery, and thus resolution of the clinical symptoms.
It is important to recognize, though, especially in heavily pretreated, relapsed/refractory AML patients with significant disease burden, that the bone marrow may be permanently impaired despite leukemic blast clearance, and patients may never fully recover normal hematopoietic function. The majority of patients with AML are refractory to or will relapse after therapy. The prognosis for relapsed/refractory patients remains poor. As is shown in this cartoon, patients who remain fit are offered intensive salvage chemotherapy with the goal of bridging to an allogeneic transplant, which remains the only curative option. Patients who are older or unfit are offered milder therapies such as hypomethylating agents or venetoclax, with the goal of inducing responses that translate into overall improved survival. A subset of patients with targetable mutations may benefit from recently approved immune or molecular-based approaches such as IDH or FLT3 inhibitors.
Unfortunately, as Yu-Waye Chu will review in his presentation, response rates for relapsed/refractory AML patients remain low, and thus the NCCN guidelines recommend that patients enroll in clinical trials to help continue the quest for effective therapies. Developing effective treatments is challenging, though, for several reasons. First, the patients are often elderly and plagued by cytopenias, infections, or organ damage, which limits the intensity of therapy that can be delivered and the prospects for hematopoietic recovery. Second, as I mentioned, AML is a very heterogeneous disease, and patients often have several clonal populations. Therefore, there are no universal targets. Lastly, many of the emerging treatments are limited in their therapeutic reach. Targeted therapies only work for a select subset of patients.
The mechanism of immune engagers, such as monoclonal antibodies or bi and trispecifics, relies upon the patient's own immune cells, which, as I'll show you in a moment, are often dysfunctional. Current cell-based therapies are not easily scalable, as they are patient-specific and require costly and complex manufacturing at specialized centers. NK cells have been shown to effectively target and kill leukemic blasts. However, as in most cancers, a patient's NK cell compartment is often depleted and dysfunctional. As shown in the right, NK cells in patients with AML express an imbalanced profile of inhibitory versus activating receptors, suppressing NK cell activity. For example, the activating receptor CD16 is often downregulated. Additionally, regulatory T cells and myeloid-derived suppressor cells induced by the tumor microenvironment can further suppress NK cell function.
The dysfunction of the NK cell compartment in patients with AML has been correlated with disease progression. Additionally, leukemic blast targets have evolved mechanisms to evade recognition by the patient's NK cells. These evasion mechanisms include upregulation of ligands that inhibit NK cell recognition, such as class one HLA, or downregulation of ligands that activate NK cells, such as MICA. Given the significant impairment to a patient's NK cell compartment, investigators at the University of Minnesota, including Jeff Miller, hypothesized well over one decade ago that infusing healthy NK cells into a patient with relapsed refractory AML may provide therapeutic benefit. As many of you know, I spent the first 17 years of my career at the University of Minnesota, where I worked with Jeff Miller to develop NK cell-based therapies for AML and other cancers.
Jeff is credited as the pioneer of NK cell therapy, which all started with initial successes in treating AML. I'd like to take a moment to walk you through the treatment paradigm and initial trials that we pioneered together. While it was thrilling to establish clinical proof of concept for NK cell therapy, it was also a bit disheartening to realize the limitations that prevented our approach from reaching more patients, despite over a decade of hard work. The process of donor NK cell therapy that we pioneered is similar to that of a hematopoietic stem cell transplant. First, a related HLA haploidentical donor must be identified and screened for eligibility. Multiple clinic visits are required for the donor, culminating in a five-hour leukapheresis procedure on-site.
The apheresis product undergoes processing to enrich for NK cells, followed by overnight incubation in IL-2 or IL-15 or other complex multi-week expansion protocols. While the manufacture is underway, the patient is admitted to the hospital to receive lymphodepletion with high doses of fludarabine and cyclophosphamide, using a regimen initially developed by Steve Rosenberg at the NIH for TIL therapy. For patients with AML, who are already cytopenic, these high doses of Cy/Flu further impair hematopoiesis and cause a transfusion dependence, making discharge from the hospital near impossible until sufficient blood count recovery. Patient lymphodepletion must also be timed with the manufacture, as the NK cells are administered fresh to the patient. Following NK cell infusion, exogenous cytokines such as IL-2 are administered to the patient to support NK cell proliferation and function.
Patients are not discharged from the hospital until they have achieved clearance of leukemia and adequate blood count recovery. As you can appreciate, the treatment process is incredibly complex and can only be performed at specialty centers with on-site cell manufacturing facilities. From the time a patient with AML presented at our clinic, it took about three or four weeks, often longer, to identify a donor, process the cells, and proceed with patient treatment. Unfortunately, as is seen with patients awaiting autologous CAR T therapy, far too many progress or develop complications while waiting for treatment. Here, I have highlighted three landmark studies of donor-derived NK cell therapy reported out of the University of Minnesota. In the first study, published by Jeff Miller in 2005, peripheral blood apheresis collections from related haploidentical donors were used to treat highly refractory or multiply relapsed patients with AML.
About 8.5 million cells per kilo, or approximately 600 million NK cells, were infused after lymphodepletion, after which six doses of interleukin-2 were given subcutaneously over two weeks. There were no unexpected toxicities. Most importantly, no acute Graft-versus-host disease, cytokine release syndrome, or neurotoxicity. In this highly refractory population, 26% of patients attained a morphologic complete remission. The 26% remission rate was a remarkable advance, as the expected response rate to available salvage options for this patient population was about 10%. Building on this success, a second trial incorporating the use of an anti-CD25 diphtheria toxin to deplete suppressive host regulatory T cells was conducted in 15 patients. The results, reported in 2014, demonstrated improved responses, with 53% achieving complete remission. That same publication reported the ongoing experience with the IL-2 cytokine support alone, where an additional 42 patients were treated, with 21% achieving complete remission.
Again, the safety profile was favorable, with most Grade 3 to 5 toxicity related to the intensity of the lymphodepletion. Since IL-2 can drive the expansion of host regulatory T cells, we also explored the use of IL-15 cytokine support as an alternative to IL-2 to promote in vivo NK cell proliferation and function. We tested both IV and subcutaneous administration of a recombinant human IL-15 developed at the NCI. In both groups, about 1/3 of patients achieved complete remission. Note that the favorable safety profile was again seen in the 26 patients receiving IV IL-15. However, in the 16 patients receiving subcutaneous IL-15, for the first time, cytokine release syndrome and neurotoxicity were reported with an NK cell-based therapy.
Interestingly, the translational data showed extremely high, prolonged IL-15 PK with the subcutaneous administration and suggested that the toxicity was due to an IL-15-mediated activation of host T cells rather than by the NK cells. Several other groups have also investigated various forms of donor NK cell therapy, almost all studies rely on donor NK cells matched to the patient, the use of high-dose lymphodepletion as conditioning, and administration of fresh NK cells to the patient in a hospital setting. Generally speaking, these three studies are representative of the body of work in the field of donor NK cell therapy for patients with relapsed/refractory AML. Given the discouraging outcomes faced by these patients, the use of NK cells as a therapeutic modality has demonstrated encouraging potential. It's been a real privilege to help pioneer the field alongside with Jeff at the University of Minnesota.
As Scott mentioned, six years ago, Jeff and I began our collaboration with Fate Therapeutics. While Bob will tell you more about the advantages afforded by our iPSC product platform, I want to share with you a bit about what drove me as a clinician to continue this work by joining Fate Therapeutics. For me, I was compelled by the promise of an effective, truly off-the-shelf NK cell product that can improve the patient experience and provide increased patient access. I must reiterate that treating relapsed/refractory AML patients can be discouraging. They are very sick patients with few treatment options, and life expectancy is often short. I became inspired by what I refer to as a kinder, gentler cell therapy. The iPSC product platform offers the ability of an off-the-shelf product to eliminate treatment delays associated with donor identification, patient matching, and manufacture of individualized products.
The opportunity to reduce the intensity of the conditioning administered to patients, which avoids hospitalization and allows for them to be home with their families, and the hope that NK cells will one day be delivered in community-based settings to reach many more patients earlier in disease progression. I'm thrilled about the progress that we've made with our off-the-shelf iPSC-derived NK cells, about the initial clinical data we're seeing in patients with an aggressive disease, and by our potential to make a difference for many patients with cancer. Thank you, and I would like to now introduce Bob Valamehr, who has led the development of Fate's iPSC product platform for the past 11 years.
Thanks, Sarah. As Sarah alluded to, one of the challenges with donor NK cell therapy is that there is significant variability in the composition and functionality of the NK cell compartment from person to person. For example, as seen here, NK cells from three healthy donors were assessed for activity against primary AML blood, and you can see the heterogeneity in interferon gamma response across these donors. From our perspective, this heterogeneity is unacceptable and has the potential to limit efficacy. We believe our iPSC platform is uniquely positioned to deliver on the promise of cell therapy that Sarah spoke of. From our perspective, autologous and allogeneic cell therapy look remarkably similar. Whether patient or donor-derived, every manufacturing batch requires the sourcing of immune cells and the engineering of large population of immune cells.
This process is fraught with batch-to-batch and cell-to-cell variability that can affect product release, quality, safety, and efficacy. In contrast, our iPSC platform starts with one single engineered induced pluripotent stem cell, which we use to create a clonal master engineered iPSC line. Analogous to mastered cell lines using the manufacture of monoclonal antibodies, clonal master iPSC lines are a renewable source that we tap to mass produce immune cells. Importantly, unlike autologous and allogeneic approaches, our manufacturing process does not involve engineer, patient, or donor NK cell or T cell batch by batch. We engineer iPSCs in a one-time event and use the clonal master engineer iPSC line as a renewable source to make large quantities of off-the-shelf NK cells and T cells that are uniformly engineered, well-characterized, cryopreserved, and delivered on-demand to eliminate treatment delays and facilitate broad patient accessibility.
At the center of our novel iPSC product platform is a proprietary process that allows for the generation and single-cell selection of multiplex engineered iPSC clones that maintain the naive state of pluripotency and genomic integrity. These clones are expanded, banked, and rigorously tested for selection based on preferred attributes, including precision of selected genetic edits, uniformity of the product, and functionality of the manufactured immune cells. The winning clone, as a renewable cell source for mass production, serves as a renewable cell source for the mass production of a homogeneous cell product with ideal phenotype and functionality and off-the-shelf availability. We spent years optimizing our differentiation protocols to enable mass production of bona fide NK cells from our master iPSC lines.
Our manufacturing process consists of proprietary NK cell differentiation protocols, where iPSCs are precisely guided down the biological path to form fully functioning mature NK cells at large scale. Our iPSC-derived NK cells have high expression of prominent activating receptors, as seen on slide 18, and low expression of checkpoint inhibitory receptors, as seen on slide 19. Importantly, our iPSC-derived NK cells are mature effector cells and are packed with cytokine granule proteins, making them better primed for cytotoxicity compared to peripheral blood NK cells. As a result, our preclinical data has shown that iPSC-derived NK cells exhibit greater in vitro cytotoxicity compared to peripheral blood NK cells across a broad range of cancer cell lines and long-term killing assays. Additionally, as shown on slide 22, we demonstrate precise dose-dependent cytotoxicity, which we believe reflects our ability to consistently manufacture a homogeneous drug product.
With our unique ability to create a multiplex engineered NK cell products from master iPSC line, we have developed a deep pipeline of products, each with additional engineered functionality. FT538 is our 3rd- generation NK cell product candidate. It is the first ever CRISPR-edited iPSC-derived cell therapy. FT538 is engineered with three novel functional components, the high affinity non-cleavable CD16 Fc receptor, an IL-15 receptor fusion, and a knockout of CD38. As you can see on slide 24, single cell selection enables production of NK cells that have complete uniformity with respect to the engineered functionality, including complete silencing of the CD38 gene. Such uniformity of engineering has not been previously achieved with NK cell sourced from a patient or a donor.
As the field continues to develop multiplex engineered cell therapies, we think our approach has the potential to mass produce homogeneous products, establish and utilize well-defined release criteria that can consistently be met and confer improved safety and efficacy. In building FT538 off the FT516 backbone, our original intent in incorporating our novel IL-15 receptor fusion was to improve NK cell activity and avoid administration of exogenous cytokine support to patients. Additionally, in knocking out CD38, our original intent was to avoid NK cell fratricide as part of the combination strategy with the CD38 targeted monoclonal antibody as activated NK cells express CD38. Through studies conducted by Jeff, we became aware that CD38 expression also played a fundamental role in NK cell biology.
As illustrated by global assessment of the metabolic profile of FT538, the complete knockout of CD38 gene results in elevated levels of metabolites associated with glycolysis and sustained metabolism. This metabolic profile is significantly different than that of peripheral blood NK cells. In fact, the metabolic profile is uniquely associated with low frequency subset memory like NK cells first characterized by Jeff's group, referred to as adaptive NK cells. Adaptive NK cells have been shown to exhibit increased cytokine production, enhanced persistence, resistance to oxidative stress, and post-serial cytotoxicity.
In preclinical studies, we have shown that the metabolic trace of FT538 acquired through CD38 knockout result in iPSC-derived NK cells with the capacity to generate a higher oxygen consumption rate as a result, as illustrated in Figure A, to hold higher levels of ATP, as seen in Figure B, and to resist oxidative stress, often found in a tumor microenvironment that can result in stress-induced cell death, as highlighted in Figure C. This unique metabolic profile of FT538 is significantly different than that of peripheral blood NK cells. In in vivo studies, the unique metabolic profile of FT538 confers long-term persistence that has not been previously observed with NK cells. For example, on the left, at day 16 post-infusion, nearly 20% of the mouse blood system consists of FT538, whereas peripheral blood NK cells do not show persistence.
Additionally, as seen on the right, in comparing the additional engineered functionality of FT538 to FT516, while we do see persistence of FT516 beyond day 16, FT538 continues to be detected beyond day 60. Additionally, the unique metabolic and persistence profile of FT538 translates into unprecedented serial killing in a long-term serial pre-stimulation assay. Note that this assay is conducted without cytokine support and tumor cells are reintroduced every three days without the addition of new effector cells. While peripheral blood NK cells display exhaustion following a first round of killing, FT538 uniquely displays durable serial killing through all three rounds of tumor challenge. We think the metabolic and functional profile of FT538 is highly differentiated, and we are excited to be initiating broad clinical investigation of FT538 in hematologic diseases and solid tumors.
It is now my pleasure to introduce Waye and Jeff to discuss our interim phase I clinical data for our FT516 and FT538 programs in relapsed refractory AML.
Thanks, Bob, very much for that great presentation. As we review the interim clinical data from our ongoing phase I studies of FT516 and FT538 in relapsed refractory AML, it is important to understand the clinical context in which these product candidates are being tested. As Sarah mentioned, AML is a highly heterogeneous disease, and certain cytogenetic abnormalities and genetic mutations have been grouped into risk categories based on their associations with statistically significant differences in overall survival.
For example, in a study of over 1,000 patients with newly diagnosed AML who underwent standard induction chemotherapy, intermediate and adverse genetic risk strata, as defined by 2017 ELN criteria, are associated with statistically significant reduction in overall survival as well as relapse-free survival. Second, in the setting of relapse refractory disease, in particular, several survival outcomes remain extremely poor, with a median overall survival of 5.3 months and a five-year survival rate of less than 15%. Clearly, relapse refractory AML patients remains an area of high unmet medical need, necessitating the development of new therapies. Over the past several years, treatment options included those listed in this table, including those that target certain mutations such as FLT3 and IDH1 and IDH2, have been approved by the FDA. Two points worth highlighting here.
First, approvals have been secured based on response rates ranging between as low as 14% up to 35%, with durations of response ranging from 8 to 15 months. Clearly, despite their approval of these therapies, these are not curative therapies. Moreover, it's worth pointing out that three of the four recently approved agents listed here are restricted to diagnostically defined subsets based on FLT3 mutations or IDH1 or IDH2 mutations. Since these agents only target disease with these specific mutations, clinical benefit is limited only to a minority of patients. Even among patients who receive these agents, clinical benefit is modest. Beyond these agents, other non-cell-based immune therapies, such as exemplified by T-cell engagers, are also being actively investigated in relapsed refractory AML. Early clinical data from these T-cell engaging product candidates are notable for the following. First, efficacy is relatively modest.
As Sarah mentioned, this is likely reflective of the fact that the engager's mechanism of action is highly dependent on the patient's endogenous immune system. Given that patients with relapse refractory AML are generally profoundly cytopenic and/or immunosuppressed due to underlying disease and/or prior therapy, it's not surprising that T-cell engagers are limited with respect to their efficacy. Safety liabilities also remain a substantial barrier to the risk-benefit of T-cell engagers in relapse refractory AML, as evidenced by high rates of CRS, including CRS of Grade 3 or greater severity in 2%-20% of patients treated. Neurotoxicity, which is also a known toxicity with CAR T-cell therapy and T-cell engagers in other indications, including lymphoma and multiple myeloma, have also been observed in trials of relapsed refractory AML.
Together, these data serve to highlight the potential benefit, as was mentioned earlier, afforded by off-the-shelf iPSC-derived NK cell product candidates such as FT516 and FT538, including the ability to administer multiple doses of potent non-exhausted cell product that can lead to maximal antitumor activity, and the ability to administer these cell products that is safe and well-tolerated without the safety concerns of known T-cell based therapies. Before reviewing our interim phase I clinical data, I would like to take a moment to describe the response criteria we're using in dose escalation for our phase I studies. For our studies, we are rigorously following 2017 ELN response criteria in assessing objective anti-leukemic responses. Categorical objective responses are defined in the table on the left and include, complete remission, or CR, complete remission with incomplete hematologic recovery, or CRI, and morphologic leukemia-free state, or MLFS.
It is important to recognize that each of these response criteria requires complete clearance of leukemic blasts from the bone marrow. The criteria differ by the degree of hematologic recovery as measured by neutrophil and platelet count. It is also important to note that the definition of CR subcategories sometimes differ from study to study. While other clinical studies define CRi in a manner that only requires neutrophil count recovery to a level such as 500 cells per microliter in the absence of any assessment of platelet recovery, the 2017 ELN response criteria CRi requires recovery of neutrophils to 1,000 cells per microliter or platelets to 100,000 cells per microliter. The CRi response under the 2017 ELN response criteria is a high bar, as either neutrophils or platelets must recover to the same level as required to achieve a true CR.
Additionally, to achieve an objective response of MLFS, it's important to remember that it is not sufficient for the bone marrow simply to be aplastic. There must be evidence of normal hematopoietic recovery, defined by 2017 ELN criteria as a level of bone marrow cellularity of at least 10%. We believe that 2017 ELN response criteria is clinically rigorous and exemplifies the clinical importance of clearing leukemic blasts from the bone marrow with evidence of normal hematologic recovery.
This is exemplified by the Kaplan-Meier curve on the right from a retrospective analysis of patients with relapsed refractory AML who were treated with venetoclax combinations, which demonstrate that achieving CR, CRh, or MLFS based on 2017 ELN response criteria resulted in a statistically significant improvement in overall survival, with median overall survival not reached compared to 3.9 months for patients not attaining CR, CRh, or MLFS. Given the emerging association between the response of CR, CRh, or MLFS based on 2017 ELN response criteria and overall survival in relapsed refractory AML, we believe these response categories represent clear early indications of clinical benefit. Turning now to observations from our ongoing phase I clinical trials in relapsed refractory AML. We first start off with FT516. The phase I study of FT516 is a dose escalation study of FT516 administered as monotherapy in patients with relapsed refractory AML.
The treatment scheme is illustrated in this slide. Key elements of the study include the following. First, overall treatment consists of up to two treatment cycles, each cycle consisting of three consecutive days of conditioning chemotherapy comprised of cyclophosphamide of 500 milligrams per meter squared and fludarabine 30 milligrams per meter squared, followed by three weekly doses of FT516. IL-2 is administered with each FT516 dose to support NK cell activity. Second feature is that FT516 dose levels being tested range from 90 million to 900 million cells per dose. These are doses that are being currently tested in dose escalation. Importantly, as part of the study protocol, all study treatments are administered in the outpatient setting with no requirement for inpatient administration or monitoring. Dose escalation is currently enrolling in the third dose cohort of 900 million cells per dose.
On this slide, this slide shows the baseline characteristics of a total of nine patients who were enrolled into the study as of the data cutoff date of April 16th, 2021, including three patients in the first dose cohort of 90 million cells per dose and six patients in the second dose cohort of 300 million cells per dose. The nine patients had clinical and disease characteristics reflecting extremely poor prognosis in relapsed refractory AML. Key clinical and disease characteristics in this regard include the following. First, eight of nine patients had disease with known adverse genetic risk features per 2017 ELN criteria, as I alluded to in an earlier slide. Second, six of nine patients failed primary induction therapy. Third, eight of nine patients had disease that was refractory to last prior therapy, with some patients being refractory to multiple lines of prior therapy.
Treatment, safety and tolerability, and immunogenicity data are shown in this slide. The safety and tolerability profile of FT516 was extremely favorable. Through the 300 million cell dose level, there were no DLTs, Dose-Limiting Toxicities, observed. Importantly, known adverse events of CRS and ICANS, which is Immune Cell-Associated Neurotoxicity Syndrome, which have been associated with T-cell-directed therapies and relapsed refractory AML, were not observed. Additionally, no GvHD was observed. FT516 Grade 3 febrile neutropenia was observed in three patients, with no other FT516-related Grade 3 or greater adverse events observed. Additionally, no FT516 related serious adverse events were observed. Finally, there were no discontinuations of study treatments due to adverse events. Since FT516 is being assessed as a universal off-the-shelf cell therapy, it is administered without consideration for patient matching. In this respect, it is important that there was no observed evidence of T and B cell-mediated anti-product immunogenicity.
Together, these data strongly support the safety and tolerability of FT516 and the potential to administer multiple doses of FT516 in an outpatient setting. Antileukemic activity of FT516 is described in this slide. The median percent of leukemic blasts in the bone marrow at baseline was 39%, with two patients having extremely high leukemic blast burden at baseline in excess of 90%. Additionally, at baseline, and characteristic of patients with relapsed refractory AML, all nine patients had significant hematopoietic impairment. Eight patients had neutrophil counts below 1,000 per microliter with a median count of approximately 200 per microliter, and all nine patients had platelet counts below 100,000 per microliter with a median count of approximately 24,000 per microliter. These baseline characteristics of the bone marrow are reflective of a relapsed refractory AML population that has extremely poor prognosis.
Of the nine patients, four patients achieved an objective response based on 2017 ELN response criteria, including three patients who achieved CRi with neutrophil count recovery exceeding 1,000 per microliter. The additional responding patient achieved MLFS, and while not recovering neutrophils or platelets to a level required for CRI, the patient did have recovery of both neutrophils and platelets above pretreatment baseline level. As you can see on the next slide, which is the waterfall plot, six of nine patients showed anti-leukemic activity as evidenced by on-treatment reduction in bone marrow blast. The four patients showing complete clearance of leukemic blasts of the marrow are also shown.
In the second dose escalation cohort of 300 million cells per dose, shown in blue on the right-hand side, three of six patients achieved an objective response with complete clearance of leukemic blasts in the bone marrow, including two patients, subjects 1006 and 1007, who achieved CRI. I would also like to point out that the second dose escalation cohort included two subjects 1008 and 1011, both of whom did not respond to therapy. These two patients both had adverse disease risk features, failed primary induction therapy, were refractory to last prior therapy, and as I mentioned earlier, presented with extremely high leukemic blast burden in excess of 90% at baseline.
The next slide shows the swim lane plot, and as you can see, the two responding patients in the second dose escalation cohort who achieved CRI, subjects 1006 and 1007, have remained on study and in remission without further therapeutic intervention for a duration that exceeds six months. A third responding patient, subject 1001, who achieved a best overall response of CRI, subsequently experienced hematologic relapse. Of note, the measurable tumor burden at the time of hematologic relapse remained very low. This, combined with the fact that the patient did not experience any serious on-treatment safety events, allowed the patient to successfully bridge to allogeneic hematopoietic stem cell transplant. The fourth responding patient, subject 1012, who achieved a best overall response of MLFS, subsequently had progressive disease on study day 80.
For the next two slides, I just wanted to go into more detail of study vignettes for the two patients who had the durable CRI. On this slide, we describe the vignette from subject 1006, who is a 68-year-old patient unfit for standard 7+3 induction chemotherapy and who relapsed following treatment with venetoclax and decitabine combination. The patient's disease was significant for having an adverse genetic risk profile with 26% bone marrow blasts at baseline. Peripheral blood counts are shown here, characterized by both neutropenia and thrombocytopenia. The clinical course of the patient is summarized on the right-hand side. It's notable for the fact that the patient received the maximum planned six doses of FT516, did not experience any grade of CRS, ICANS, or GvHD, and did not experience any FT516-related grade 3 or greater Adverse Events.
The patient initially achieved a response of MLFS, which subsequently improved from MLFS to CRi as a result of continuing hematopoietic recovery. Neutrophils, of note, recovered to a level of over 1,000 per microliter, which is a level that is 4x greater than what the patient had at baseline prior to starting study treatment. As I mentioned earlier, the patient had an ongoing response of greater than six months as of the data cutoff. The second patient achieving durable CRI is subject 1007, who is an 85-year-old patient who was also considered unfit for standard 7+3 induction chemotherapy. Unlike subject 1006, this patient was refractory to primary induction therapy consisting of eight cycles of venetoclax plus decitabine. This patient's disease was also notable for having an adverse genetic risk profile with 12% bone marrow blasts at baseline.
The clinical course, as summarized on the right, was notable again for this patient receiving all six planned doses of FT516 without experiencing any grade of CRS, ICANS, or GvHD, or FT516 related greater than three adverse events. The patient achieved a response of CRi after FT516 treatment with neutrophil recovery exceeding 1,000 per microliter and ongoing thrombocytopenia. This patient also has an ongoing CRi of greater than six months as of the data cutoff. Together, the totality of the FT516 data suggests clear evidence of clinical benefit while we're still in dose escalation. Dose escalation continues. For our observations from our ongoing Phase I clinical trial of FT538, I now have the pleasure of turning it over to Dr. Jeff Miller.
Thank you, Waye. Good afternoon, everybody. As we can see here, the phase I study of FT538 is a dose escalation of FT538 administered as monotherapy in patients with relapsed/refractory AML. The treatment schema is illustrated on this slide, and some key elements will be highlighted. The overall treatment course consists of one cycle consisting of three consecutive days of conditioning chemotherapy comprised of cyclophosphamide at 500 milligram per meter squared and fludarabine at 30 milligram per meter squared, followed by three weekly doses of FT538. A second cycle may be given after FDA review and approval. In contrast to FT516, there is no exogenous IL-2 support administered with each dose of FT538, given its additional engineered functionality. FT538 dose levels range from 100 million cells to 1.5 billion cells per dose, and these are being tested in this dose escalation.
As with the FT516 study, all study treatments are administered in the outpatient setting with no requirement for inpatient administration or monitoring. Dose escalation is currently enrolling in the first cohort of 100 million cells per dose. I just want to highlight that this is significantly lower than what we gave with single-dose NK cell products that were outlined by Sarah Cooley earlier on in this presentation. This slide shows the baseline characteristics of the first three patients who were enrolled onto the study in the first dose escalation cohort as of the data cutoff of April 16th, 2021. The three patients had clinical and disease characteristics reflecting extremely poor prognosis. Key clinical and disease characteristics in this regard include the following, which are outlined here. Two patients had disease with known intermediate or adverse genetic risk features per 2017 ELN criteria.
All patients received greater than three lines of prior therapy, and all three patients had disease that was refractory to last prior therapy. Of note, two of these three patients were refractory to a previous investigational agent with a CD33-targeted NK cell engager. Clinical outcomes related to safety, immunogenicity, and best overall response per 2017 ELN criteria are summarized in this slide for patients in the first dose escalation cohort. Of the three patients in this first dose escalation cohort, two were evaluable for safety and anti-leukemic activity, and one patient discontinued from the study prior to completion of the first treatment cycle due to clinical evidence of failure to respond.
Both evaluable patients had received at least three prior lines of therapy, were refractory to the last prior therapy, and were significantly cytopenic, with neutrophil counts below 1,000 and platelet counts below 100,000 per microliter at baseline prior to conditioning chemotherapy. Similar to the interim results from the FT516 phase I study described earlier by Waye, the safety and tolerability profile were notable for no DLTs and no events for any grade of CRS, ICANS, or graft versus host disease. No CD38-related grade greater than or equal to three AEs or SAEs were observed, and there was no discontinuation of study treatment due to adverse events. There was no evidence of T or B cell mediated anti-product immunogenicity. Both evaluable patients showed anti-leukemic activity as evidenced by on-treatment reduction in bone marrow blast.
One subject 1003, showed complete clearance of leukemic blasts from the bone marrow and achieved a best overall response of CRi after the first FT538 treatment cycle. The course of patient 1003 is instructive both clinically and translationally. This was a 79-year-old gentleman who was refractory to multiple prior therapies, including an investigational CD33, IL-15, CD16 NK cell engager immunotherapy, and to their last prior therapy. He had intermediate genetic risk profile per ELN, with 30% bone marrow blast at baseline. At baseline, the patient presented with significant hematopoietic impairment, with neutrophil counts of approximately 100 per microliter and platelet counts of approximately 35,000 per microliter. The patient achieved a CRi following the first FT538 treatment cycle, with neutrophil recovery to over 1,000 per microliter.
The recovery of neutrophils far exceeded this baseline level, and the return of hematopoietic function is really remarkable in this patient, who had significant neutropenia for over 12 months prior to enrollment. He received a second treatment cycle with post-treatment follow-up that is still ongoing. There are additional comments from a translational perspective. We talked about the important role of CD16 in promoting antibody-dependent cellular cytotoxicity. We also know that there are significant limitations in the number and function of patient NK cells that limit their ability to maximize ADCC. Furthermore, wild type CD16 is shed after activation, as we described a number of years ago. Certainly when an ADCC competent monoclonal antibody or an NK cell engager is administered to the patient, you would prefer that the patient have a robust population of activated NK cells expressing CD16.
Therefore, the top right figure is really remarkable to me, as it represents the potential therapeutic value of administering engineered NK cells. Shown in the blue are the patient's NK cells, which are differentiated from the red population of FT538 cells based on expression using antibodies specific for patient HLA antigens, which are unique to separate the patient and the administered cells. As you could see, FT538 cells incorporate the high affinity non-cleavable CD16 Fc receptor, maintain uniform high expression of CD16 after seven days of in vivo circulation in the patient. This is really a marked contrast to the endogenous NK cell population, again, that's shown in blue, which exhibit heterogeneous and low expression levels of CD16. This underscores the importance of administering CD16 engineered cells alongside agents that rely on ADCC to maximize anti-tumor activity.
Additionally, in the bottom panel, in the lower right, we evaluated the peripheral blood PK profile of FT516 versus FT538 products using a Droplet Digital PCR targeting the high affinity CD16 transgene. Shown here are results from the patients enrolled in the first and second dose escalation cohorts of FT516, and from patients enrolled in the first dose escalation cohort of FT538. Recall that both products are dosed weekly on days one, eight, and 15 after the same Cytoxan and fludarabine lymphodepleting chemotherapy regimen. However, IL-2 cytokine support is administered to only patients who receive doses of FT516, where there is no exogenous cytokines administered to patients in the FT538 study. As you can see in the bottom right panel, at day eight, prior to the infusion of the second dose, FT538 exhibited superior in vivo persistence compared to FT516.
This provides us with initial confidence that engineered functionality of FT538 can augment NK cell PK without the need for exogenous cytokine support during the patient treatment. This really validates our preclinical data. Lastly, I would like to underscore these clinical studies that are assessing FT516 and FT538 as monotherapy, are testing the inherent capacity of iPSC derived NK cells to target and kill leukemic blasts without the aid of additional therapy. Recall that both FT516 and FT538 incorporate our novel high affinity non-cleavable CD16 Fc receptor, which has been modified to prevent its down-regulation and to enhance its binding to tumor targeting antibodies. Given this functionality, we think that there is a unique opportunity to combine these iPSC derived NK cells with monoclonal antibody therapy to target certain antigens that are expressed on leukemic blasts.
At the European Hematology Association meeting in 2020, a presentation caught our attention that highlighted the potential therapeutic role of CD38 targeted monoclonal antibody therapy in treating elderly patients with AML. An assessment of bone marrow samples from newly diagnosed elderly AML patients showed CD38 expression on leukemic blasts in 239 out of 241 samples tested, which is illustrated in the pie chart on the left panel there. This strongly indicates the potential of CD38 as a therapeutic target for AML. Our preclinical studies suggest that the combination with the CD38 targeted monoclonal antibody daratumumab can enhance the anti-tumor activity of FT538 against AML cell lines, as shown in the middle panel, or against patient derived AML samples, as shown in the right panel.
To exploit this potential, we are preparing to conduct a phase I clinical trial at the University of Minnesota Masonic Cancer Center, designed to assess three weekly doses of FT530, again in the absence of exogenous cytokines, in combination with daratumumab in patients with relapsed refractory AML. We expect this trial to initiate before the end of this quarter. Now, Scott, I will turn it back over to you for concluding remarks.
Thanks so much, Jeff. We're continuing to progress through dose escalation in our phase I clinical studies of FT516 and FT538 in relapse refractory AML, and we believe the objective responses we have observed at this interim stage are very encouraging. We've enrolled patients with clinical and disease characteristics that typically portend a dismal clinical outcome. Of the 12 patients, nine had adverse risk profile based on 2017 ELN risk category, 11 were refractory to their last prior therapy. 11 also had significant hematopoietic impairment at baseline with both low neutrophil and platelet counts. Five of 12 patients achieved an objective response with complete leukemic blast clearance in the bone marrow, including four patients that achieved CRi and one patient that achieved MLFS. Importantly, we have demonstrated that off-the-shelf iPSC-derived NK cells administered as monotherapy have the potential to confer durable remissions without further therapeutic intervention.
We've also observed initial clinical evidence that the additional engineered modalities of FT538 may confer therapeutic advantages, and we are pleased that the patient in the first dose cohort, who was refractory to multiple lines of therapy, achieved a CRi following the first treatment cycle. Relapse refractory AML is a devastating disease, and like other aggressive cancers, the patient's immune cells are often incapable of responding in a manner that is necessary to successfully combat cancer. While immunotherapies such as monoclonal antibodies and immune cell engagers have clearly shown activity, their therapeutic benefit can be significantly compromised by their reliance on the patient's own immune cells, which are often depleted in numbers and functionally impaired. The administration of multiple doses of optimized immune cells as monotherapy or in combination with other immunotherapies, has the potential to restore cellular function and transform patient outcomes.
We continue to believe our iPSC product platform will be the operating system for creating multiplex engineered off-the-shelf cell therapies for patients with cancer. With that, I want to thank you all for joining us this afternoon. We're happy to take a couple questions, and I'll turn it over to Edward Dulac, our CFO, who will moderate the Q&A session.
Great. Thank you, Scott and team. Just a reminder for those that are participants, you can submit questions in text format using the question and answer functionality of the webcast. We've got a number of questions. The first one coming from Yigal from Citi, there are a number of others that are common themed, which is, among the four patients that achieved CRi and the one patient that achieved MLFS, were any of these patients also MRD negative?
Sure. Waye, do you want to take that question?
Yeah, sure. MRD is something that we're monitoring with these patients. We're not ready to disclose that information at this time. We will present this information at upcoming medical conference. I will say that we monitor MRD both at the local level as well as in the case of FT538 phase I study, we do that centrally. I think it's instructive for everyone to know that as we monitor MRD, just like as we exemplified in that patient in FT516, responses evolve over time. It's worth mentioning that not being able to observe MRD early on doesn't preclude the possibility of MRD down the road as these responses evolve.
Okay, great.
Thanks, Waye.
Thanks, Waye. The next question will come from Michael Yee, and again, there are a number of questions, similar intent. Two-part question. We'll take the first part first. Question around 516 and observing a trend towards CRs having lower blast counts in patients that have fewer prior treatments, and comparing that to 538, where small patient numbers but a CR with a patient that has a higher blast count and four prior therapies. Just an overall question on those general trends, as well as does this suggest any promise for 538 versus 516 in AML?
I think they are fair observations. I think it's too early to extrapolate from that and form any definitive conclusions. I guess I would ask Sarah and Jeff, given their long history of treating relapse refractory AML patients, maybe you could characterize a little bit what it means to have 25%-30% blast in your marrow versus, we enrolled two patients, for instance, that had 90% blast in their marrow. Can you talk a little bit about that based on your experiences with respect to severity of disease? And again, in the context that these are, my gosh, relapse refractory patients, most of them refractory.
Sure. I'm happy to comment on that. I would reiterate, we're talking about four responses or five responses, and the patients are highly heterogeneous. It's really dangerous to extrapolate too much into this. In general, patients who come into treatment with whatever the therapeutic modality with marrows that are packed full of blasts tend to do worse. It correlates with a more rapidly proliferative phenotype, and it's harder to get control of those blasts in general. Patients who come into treatment with slightly less component of blasts in their marrow space have a lower leukemic burden, which can, again, it's not proliferating as rapidly, allow more time for the therapeutic modality to work. I don't know, Jeff, if you have any additional thoughts.
Yeah. I guess the only thing that, taking care of some of these patients that I'd like to just remind the group, we tend to take these cell therapies, and we test it on the worst of the worst. I think that the thing from my own personal experience with a patient treated at our site, which was 1003, is really the fact that this patient had failed so many things in the past. Seeing these very refractory patients, especially in this elderly age population, which tends to be particularly aggressive, seeing a response in them is, at least to me, a comforting signal knowing that we're on the right track. I agree with all the other comments and the question, and obviously it's early, but seeing responses early is really important to be excited about what the future will bring.
Thanks, Jeff.
Thank you. There are a number of questions around response criteria and specifically CRI versus CRh as it relates to regulatory preferences. Does regulators have one preference versus another? How do we think about the data presented today in the context of other studies in relapse refractory AML and the endpoints that were used, ostensibly not 2017 ELN criteria?
Yeah, I'll take.
Well, I'll start. I really don't want to comment.
I'll start. Go ahead.
It's hard to comment on other people's studies. I want to be careful about commenting on other studies and other criteria that people use, unless we're talking about a specific study that we can all have a meaningful conversation around where we're understanding the criteria. Generally, Waye, feel free to jump in, I think the criteria that we're using are very rigorous. To be clear, as Waye talked about, in order to achieve CRI, you have to recover either neutrophils or platelets to the level of CR. We tend to believe the 2017 ELN criteria is a high bar. We also, as we've talked about, CR, CRI, MLFS per the 2017 ELN criteria is clearly correlated with overall survival, and that's been shown in the study that Waye presented. I'd say lastly, I'll let Waye respond. Look, it's a dose escalation study.
Obviously, we're going to have conversations with the FDA as we advance and complete dose escalation to get their view on what is the proper criteria to use for registration studies. I don't know, Waye, do you want to add anything to that?
Yeah, not much. I think, Scott, you encapsulated the comments very, very well. I think going to the point around potential for registratability, of course, in the end, whether or not the product candidate gets approved will depend on the totality of the data that go well beyond these early response time points. I think it's also important to remember that we do not know today the correlations of these subcategories of CR with respect to overall clinical benefit based on duration or survival. I think these are things that still are pending further follow-up and further analysis. I think the important thing is that, particularly in the context of an early phase I dose escalation study. As we have said repeatedly through the presentation, complete clearance of bone marrow blasts is a prerequisite for anything related to longer-term clinical benefit.
What we've been seeing so far with various forms of this leukemic blast clearance, I think is very encouraging given the early stage of both studies.
Great. Thank you. Next question from Matthew Biegler, commenting on the safety profile for either FT 516 or 538 and any plans to go above the doses currently being considered as an attempt to get to the sicker patients with higher blast count.
Yeah, I'll start there. Obviously, we're moving through dose escalation. FT516 is going to explore and is exploring the highest dose level of 900 million cells where we're almost fully enrolled. FT538, clearly we are exploring very high doses. We'll move from 100 million cells to 300 million cells, then to a billion and potentially 1.5 billion. I think that's one of the benefits of our iPSC platform and the yield that we're able to generate at scale where we feel we can significantly increase dose so long as we are continuing to see a clean safety profile.
Okay. Thank you, Scott. Follow-on question about CRi and the decision to move to transplant, noting the CRIs that are still ongoing in terms of CRi response. Why are they not in transplant and just how does a physician make that decision to go to transplant from a CRi response?
Well, I could-
Yeah, Sarah, you want to talk about that?
Yeah.
Including sort of the baseline characteristics of the patient, whether they were or were not fit for transplant, and whether they did or did not have an eligible donor identified.
Yeah, exactly. I think, in general, speaking as a former transplanter, unfortunately, most patients with AML are not eligible for transplant due to age or comorbidities or being too unfit. That is absolutely the case with the patients described here coming onto this study, other than the initial patient with MLFS, who was younger and fitter and was able to bridge to transplant. These other patients were older and significantly impaired in their fitness. For them, this was the only option. The fact that they are remaining, at least at this point, in remission with no further therapy, really highlights the importance of this therapy to improve their quality of life. They're home living their life with their family without requiring additional treatment.
Thank you, Sarah. Questions on PK. The first one is about FT538 and asking to characterize 538 PK sort of pre-day eight and then post day eight following another round of therapy. That's the first question. A second one about the PK of 516 relative to what we may have seen with other donor-derived NK cell therapies and whether or not with 516 specifically, if it's a lower PK, then does that signal any need for different approaches to lympho-conditioning?
Sarah, do you want to talk about that? At least with respect to the data that's publicly disclosed.
Yep, exactly. What we showed here were the PK profiles from blood samples collected from the patient on day eight prior to the infusion of the second dose. This represents the status of the product in the peripheral blood after seven days of in vivo circulation prior to dose two. We're certainly monitoring the PK throughout the treatment course, cycle one and cycle two after each time point, comparing the profiles between 538 and 516 and trying to understand the relative benefit of the engineered IL-15 receptor fusion component, et cetera. These are data that we're continuing to evaluate and look forward to sharing, I think, in the future when we have a larger sample set. The other part of the question related to trying to compare the PK profile of FT516 with what's been reported previously with peripheral blood NK cells.
I would say again, at this point of dose escalation and what's been reported, we are continuing to monitor in the 516 product the potential contribution of the IL-2 to exogenous cytokine support and to understand whether at higher dose cohorts it will be necessary. That's what I can share with you at this time.
Thank you, Sarah.
One thing I'll say. We do think there's potentially a very different PK profile that may be dose-dependent, including based on the engineered features. For instance, FT538 may have a PK profile that's emerging already at 100 million cells, given that it's engineered with IL-15 and has a CD38 knockout. Whereas FT516, without those features, may have a PK profile that emerges at a higher dose level.
Yep.
I would also suggest that the PK profile, keep in mind this is monotherapy, and the addition of a monoclonal antibody may change the PK profiles that are observed.
Thanks, Scott. Couple questions on the classification of responses. There's some examples for patient 1011, for example, where they have progressive disease, but their blast count showed a modest reduction, or other examples where you have a modest positive change in blasts for patients that are classified as stable disease. Just sort of a better understanding of how those classifications are determined.
Sure. I can take that question. Recall that in the case of definitions of progressive disease, I think it's worth noting that the definition involves not only what happens with respect to the bone marrow, but also what happens outside of the bone marrow with respect to peripheral blood and other sites of extramedullary disease.
In the example of the patient who had progressive disease despite having a decrease in bone marrow blast, that was a manifestation of a significant increase in the number of peripheral circulating blasts that led to the designation of progressive disease. In the cases of patients who had modest reductions in the percentage of bone marrow blasts and were classified as stable disease, these patients were classified as stable disease per 2017 ELN criteria, because in order to achieve a partial response, you need to have a certain decrement in the percentage of bone marrow blasts that is at least 50% of what you started out with.
For a patient who may have a numerical drop in bone marrow blasts, if it does not constitute more than a 50% reduction from baseine, then it cannot be called a partial response, and it is classified as stable disease per 2017 ELN.
For instance, Waye, I think the second patient in the FT538 study, while they had a 40% reduction, it didn't meet the threshold of the 50% required.
That's correct.
Thank you, Waye. A clarification, I think we talked a tad about this briefly. We characterized the 4 CRIs that are either ongoing or transferring to a stem cell therapy, two with the six-month durability, but there's an additional CRI, which I think they're referencing the patient on the FT538-101 study and just asking to characterize the status of that CRI.
Yeah. Waye, you can answer this. As of the data cutoff, the patient was in flight with respect to the second cycle.
That's correct. As of the data cutoff, the patient was nearly complete second cycle, and it was in flight, and it still continued to be monitored.
Okay. Thank you.
I think we said remained in remission. I think we did say that, obviously, as the data cut off.
That's correct.
Thank you. Next question, early days, people wondering about FT538 versus FT516, whether or not we have any sufficient data today to make a determination, or if not, expectations for ASH as we get into the end of the year as it relates to these programs in AML?
Yeah, I think it's a great question. I think it's a question we have ourselves. I think it's a little bit too early to determine which is going to be the product candidate that we advance in relapse refractory AML. I will tell you that my suspicions are it is FT538 based on all the preclinical data that we have. As Bob mentioned, I think we're gaining a lot more confidence in the translatability of those preclinical models. We treated a handful of patients with FT538. We have to let that play out. I think probably as we get through dose escalation by ASH, we'll be in a much better position to have a more definitive view on that with respect to AML.
Okay. Thank you, Scott. Question about our confidence level that the treatment effect that we're seeing here in dose escalation is derived from NK cell therapy versus a preconditioning regimen.
I don't know. Sarah, Jeff, do you want to talk about that? It's a relatively light conditioning regimen as compared to what's been done historically in the donor-derived NK cell field, which I think, Sarah, you characterized more as lymphodepleting and required hospitalization.
Yes. Sarah, do you want me to make a comment and you can add?
Please. Absolutely.
Yeah. This has been a very much argued point in the field. I think the most interesting thing to me, remember in the studies that Sarah described from the single adult donor experience products, we were giving cyclophosphamide at 8 grams per patient over two days and five days of fludarabine. I think that even though there is no definitive way without a randomized trial to know the answer to that question, I think the speculation is even with the very high doses of cyclophosphamide, the responses are really low with chemotherapy alone, probably in the less than 10% range. Remember now with the trials that were discussed here today, we're even giving less chemotherapy, which I think gives us more confidence in the field that the cells are actually performing some of the activity. Sarah, anything you want to add to that?
No, I would agree. It's been a question with all of the peripheral blood and other NK-based therapies that require some sort of lympho-conditioning, and I agree exactly with your assessment that one would expect with these doses of Cy/Flu not to see the level of clinical activity that we're seeing.
Okay. Thank you. A couple questions here about the monotherapy data we're reviewing here and talking a little bit about potential beyond monotherapy, including the potential for future combinations like we talked about with daratumumab or other monoclonal antibodies. How do we think about development beyond monotherapy in the CD16 component of our NK cell platform?
Sure. I'll ask Jeff to talk a little bit about his excitement in combining with daratumumab, and then maybe Sarah, you can talk a little bit about your thoughts on other agents that we could combine with, for instance, azacitidine, which you've talked about historically in the past in terms of treating in earlier line of therapy.
Yeah, Scott. Thanks. As many of you know, the best antigen to target on AML blast, I think is very much in flux in the field. The fact that there has been good clinical development of daratumumab, which is an anti-CD38 antibody that is very capable and binds well to the high affinity non-cleavable CD16 receptor. We know this from the preclinical studies using both FT516 and FT538. We've been really interested in, remember, NK cells have two mechanisms of action, natural cytotoxicity, but the goal is to really use all the gene edits that are in there. Combining with daratumumab, especially with FT538, because we can avoid this phenomena of fratricide, since it's an anti-CD38 antibody in multiple myeloma patients, it's well documented that you give a dose of daratumumab, the NK cells go away for approximately six months.
The goal is to really now target the CD38 in a setting where we know we won't have fratricide, and we know that CD38 is a validated target on the slide that I showed you from the one study, which is really using daratumumab as monotherapy in elderly AML. There's growing anecdotal experience knowing how depressed NK cells are with active disease, it should only get better in combination with a product like FT538. Sarah?
To follow up on the opportunity for other combination therapies, ideally, we would love to be able to get an iPSC-derived cell-based therapy earlier into patients' treatment course when they are more fit, potentially could still be bridged to transplant, and are less refractory to treatment. Looking into opportunities to combine with other sort of upfront agents such as azacitidine or venetoclax is really intriguing to us. There are some data out there published on the interaction between those agents and peripheral blood NK cells, which we certainly would like to explore to confirm that the same things hold true with an iPSC-derived NK cell and the opportunity to use those drugs to, for example, increase the profile on the leukemic blast to make them better targets and/or to help clear post-immune cells which might compete with NK cells as part of an alternative lympho-conditioning strategy.
Just as a combination therapy with two modalities of mechanism of action. Something we're very interested in looking into exploring with further trials.
Thanks, Sarah.
Thank you.
Maybe last question, Ed. I think we're coming up on 90 minutes.
Yeah, we've gotten through most. The last question is really two parts. The first one just asking about, have we done this assessment using CR/CRh rate as historically has been done, but perhaps more importantly, how do you think about approvability or how do you know you have a viable product based on the data you presented and some of the other small molecules and other products that have been referenced throughout the presentation?
Sure. We're in a dose escalation study. We're using the criteria that we've set out in our dose escalation study of 2017 ELN response criteria. I think we continue to maintain that CRi is a higher bar than CRh because it requires either full recovery of neutrophils or platelets to the level that CR defines. Obviously, as we advance, as we see more activity, and clearly we're very encouraged by the clearance of leukemic blasts in the bone marrow in full, which is a prerequisite to any kind of response. We're very open to having conversations with the FDA around the appropriate criteria for a registration study. I don't know if, Waye, you want to add anything to that?
No. Other than the fact that, to emphasize and reiterate again, we are still in very early stages of dose escalation. As far as what are the appropriate endpoints for approvability, that's just something that's going to require additional follow-up and more patience, especially as we get to what we consider the recommended phase II dose and schedule. Again, I think just in the context of early phase I, what we are seeing with respect to our ability of FT516 and FT538 to clear out leukemic blasts, we're highly encouraged. We look forward to seeing additional data as we get to higher doses and with longer follow-up.
Thanks, Waye. Okay, since we're about 90 minutes.
Final comments.
I think I appreciate everyone's time today. Again, look forward to having follow-up conversations with you about our relapsed/refractory AML franchise. Talk to you soon. Thank you very much.