Thank you all for joining us this afternoon. We are excited to share with you today interim Phase I clinical data for FT516 and FT538 off the shelf iPS derived NK cell programs in relapsedrefractory 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 if I refer 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 Doctor. Jeff Miller for joining us this afternoon. Doctor. 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. And he is one of the foremost persons 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 Doctor.
Miller. Additionally, Doctor. 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 Doctor.
Sarah Cooley, who was also a leading clinical investigator in the NK cell therapy field before joining Fate Therapeutics in early twenty nineteen as our Senior Vice President of Clinical Translation. Sarah will briefly review her experience as a clinician treating patients with relapsedrefractory AML and discuss some of the opportunities for improving the patient experience and outcomes with an off the shelf iPS derived NK cell therapy. Following Sarah, Doctor. Bob Valemir, our Chief Research and Development Officer, will briefly discuss our iPSC product platform and describe the unique properties of FT538. And finally, Doctor.
Wayne Chew, our Senior Vice President of Clinical Development, and Doctor. Miller will review our interim Phase I clinical data of FT516 and FT538 in relapsedrefractory 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-fifteen receptor fusion and knockout of CD38 is being investigated without the addition of IL-two 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 04/16/2021. 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 twenty seventeen 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. Importantly, this patient was refractory to their two most recent prior therapies, which included an investigational CD33 targeted trispecific 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 recorded. We are highly encouraged by these interim phase one data, which clearly indicate that off the shelf ITS 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 confer durable remissions without further therapeutic intervention. And with that, it is my pleasure to introduce one of the most experienced clinicians in the field of NK cell therapy, Doctor. 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 blast 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 leukemias blast also enables the bone marrow to recover and allows a restoration of normal hematopoietic function often assessed by evaluating neutrophil and platelet recovery and thus resolution of the clinical symptoms.
It is important to recognize though, especially in heavily pretreated relapsedrefractory 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 Wayne 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. And 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. And 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 c d 16 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 MYC A. Given the significant impairment to a patient's NK cell compartment, investigators at the University of Minnesota, including Jeff Miller, hypothesized well over a 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 seventeen 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. So 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-two or IL-fifteen or other complex multi week expansion protocols. While manufacturer 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 Till therapy. For patients with AML who are already cytopenic, these high doses of CyFlu 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 manufacturer as the NK cells are administered fresh to the patient.
Following NK cell infusion, exogenous cytokines such as IL-two 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 2,000 collections from related haploidentical donors were used to treat highly refractory or multiply relapsed patients with AML. About 8,500,000 cells per kilo or approximately 600,000,000 NK cells were infused after lymphodepletion, after which six doses of interleukin two were given subcutaneously over two weeks. There were no unexpected toxicities, and most importantly, no acute graft versus host disease, cytokine release syndrome, or neurotoxicity. In this highly refractory population, twenty six percent of patients attained a morphologic complete remission.
The twenty six percent remission rate was a remarkable advance as the expected response rate to available salvage options for this patient population was about ten percent. 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 fifteen patients. The results reported in 2014 demonstrated improved responses with fifty three percent achieving complete remission. That same publication reported the ongoing experience with the IL-two cytokine support alone, where an additional forty two patients were treated with twenty one percent achieving complete remission. Again, the safety profile was favorable with most grade three to five toxicity related to the intensity of the lymphodepletion.
Since IL-two can drive the expansion of host regulatory T cells, We also explored the use of IL-fifteen cytokine support as an alternative to IL-two to promote in vivo NK cell proliferation and function. We tested both IV and subcutaneous administration of a recombinant human IL-fifteen developed at the NCI. In both groups, about one third of patients achieved complete remission. Note that the favorable safety profile was again seen in the twenty six patients receiving IV IL-fifteen. However, in the sixteen patients receiving subcutaneous IL-fifteen, 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-fifteen PK with the subcutaneous administration and suggested that the toxicity was due to an IL-fifteen mediated activation of host T cells rather than by the NK cells. While 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 fields 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. And while Bob will tell you more about the advantages afforded by our iPSC product platform, I wanna 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 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. So thank you, and I would like to now introduce Bob Valemir who has led the development of Fate's iPSC product platform for the past eleven years.
Thanks, Sarah. As Sarah alluded to, one of the challenges with donor NK cell therapy 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 blast. 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 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, and this process is fraught with batch 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 patch. We engineer iPSCs in a onetime event and use the clonal master engineer iPSC line as a renewable source to make large quality quant large quantities of off the shelf NK cells and T cells that are uniformly engineered, well characterized, cryopreserved, and deliver 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 regeneration and single cell selection of multiplex engineered iPSC clones that maintain the naive state of polypotency and genomic integrity. These clones are expanded, banked, and regularly 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 the renewable cell source for mass production, and the winning clone 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 bonafide NK cells from our master iPSC lines. Our manufacturing process consists of proprietary NK cell differentiation protocols where iPSCs are precisely guide 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 granular 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 NA 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 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 third generation NK cell product candidate, and it is the first ever CRISPR edited iPSC derived cell therapy. FT538 is engineered with three novel functional components, the high affinity nonclinical CD 16 Fc receptor, an IL 15 receptor fusion, and the knockout of CD 38. As you can see on slide 24, single cell selection enables production of NK cells have complete uniformity with respect to the engineered functionality, including complete silencing of the c d 38 g.
Such uniformity of engineering has not been previously achieved with NK cells sourced from the 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 consistently be met, 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 knock it out CD38, our original intent was to avoid NK cell fracture site as part of the combination strategy with the CD38 targeted monoclonal antibodies antibody as activated NK cells express CD38. Through studies conducted by Jeff, we became aware that CD38 expression also play also played a fundamental role in NK cell biology.
As illustrated by global assessment of the metabolic profile of f t five three eight, the complete knockout of c d 38 gene results in elevated levels of metabolites associated with glycolysis and cystic metabolism. This metabolic profile is significantly different than that of peripheral blood NK cell. 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 potent serial cytotoxicity. In a preclinical in preclinical studies, we have shown that the metabolic trace of s t five three eight 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 into a microenvironment that can result in stress induced cell death as highlighted in figure two.
This unique metabolic profile of f t five three eight is significantly different than that of peripheral blood NK cells. In in vivo studies, the unique metabolic profile of f d five three eight confers long term persistence that has not been previously observed with NK cells. For example, on the left, at day sixteen post infusion, nearly 20 of the mouse blood systems consist of f t five three eight, whereas peripheral blood NK cells do not show persistence. Additionally, as seen on the right, in comparing the additional engineered functionality of f t five three eight to f t five one six, while we do see persistence of f t five one six beyond day sixteen, f t five three eight continues to be detected beyond day sixteen. Additionally, the unique metabolic and persistent persistence profile of f t five three eight translates into unprecedented serial killing in a long term serial restimulation 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 for a first round of killing, f t five three eight uniquely displays durable serial killing through all three rounds of tumor challenge. We think the metabolic and functional profile of f t five 38 is highly differentiated, and we are excited to be initiating broad clinical investigation of FT538 in heme malignancies and solid tumors. It is now my pleasure to introduce Wayne and Jeff to discuss our interim phase one clinical data for our FT516 and FT538 programs in relapsedrefractory AML.
Thanks, Bob, very much for that great presentation. As we review the interim clinical data from our ongoing phase one studies of FT516 and FT538 in relapsedrefractory AML, it is important to understand the clinical context in which these product candidates are being tested. First, 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 a thousand patients with newly diagnosed AML who underwent standard induction chemotherapy, intermediate and adverse genetic risk strata as defined by twenty seventeen 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 five point three months and a five year survival rate of less than fifteen percent.
Clearly, relapsedrefractory 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 IDH one and IDH two 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 fourteen percent, up to thirty five percent with durations of response ranging from eight to fifteen months. So 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 subset based on FLT3 mutations or IDH one or IDH two mutations. Since these agents only target disease with these specific mutations, clinical benefit is limited only to a minority of patients. And even among patients who receive these agents, clinical benefit is modest. Beyond these agents, other non cell based immune therapies such as as exemplified by T cell engagers are also being actively investigated in relapsedrefractory 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 engagers mechanism of action is highly dependent on the patient's endogenous immune system. Given that patients with relapsedrefractory 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. Moreover, safety liabilities also remain a substantial barrier to the risk benefit of T cell engagers in relapsedrefractory AML as evidenced by high rates of CRS, including CRS of grade three or greater severity in two to twenty percent of patients treated. Additionally, neurotoxicity, which is also a known toxicity with CAR T cell therapy and T cell engagers and other indications including lymphoma and multiple myeloma, have also been observed in trials of relapsedrefractory 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 nonexhausted 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 therapy. Before reviewing our interim phase one clinical data, I would like to take a moment to describe the response criteria we're using in dose escalation for our phase one study. For our studies, we are rigorously following twenty seventeen 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 twenty seventeen ELN response criteria of CRI requires recovery of neutrophils to a thousand cells per microliter or platelets to a 100,000 cells per microliter. The CRI response under the twenty seventeen 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 twenty seventeen ELN criteria as a level of bone marrow cellularity of at least 10%. We believe that twenty seventeen ELN response criteria is clinically rigorous and exemplify the clinical importance of clearing leukemic blast from the bone marrow with evidence of normal hematic recovery. This is exemplified by the Kaplan Meier curve on the right from a retrospective analysis of patients with relapsedrefractory AML who are treated with venetoclax combinations, which demonstrate that achieving CR, CRI, or MLFS based on twenty seventeen ELN response criteria resulted in a statistically significant improvement in overall survival with median overall survival not reached compared to three point nine months for patients not obtaining CR, CRI, or MLFS. Given the emerging association between the response of CR, CRI, or MLFS based on twenty seventeen ELN response criteria and overall survival in relapsedrefractory AML, we believe these response categories represent clear early indications of clinical benefit. Turning now to observations from our ongoing phase one clinical trials in relapsed refractory AML.
We first start off with FT516. The phase one 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 five hundred milligrams per meter squared and fludarabine thirty milligrams per meter squared, followed by three weekly doses of FT516.
IL two is administered with each f t five one six dose to support NK cell activity. Second feature is that f t five one six dose levels being tested range from 90,000,000 to 900,000,000 cells per dose. These are 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. And dose escalation is currently enrolling in the third dose cohort of 900,000,000 cells per dose.
On this slide, this slide shows the baseline characteristics of a total of nine patients who were who were enrolled into the study as of the data cutoff date of sixteen April twenty twenty one, including three patients in the first dose cohort of 90,000,000 cells per dose and six patients in the second dose cohort of 300,000,000 cells per dose. The nine patients had clinical and disease characteristics reflecting extremely poor prognosis in relapsedrefractory 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 twenty seventeen ELN criteria as I alluded to in an earlier slide. Second, six of nine patients failed primary induction therapy.
And 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 f t five one six was extremely favorable. Through the three hundred million cell dose level, there were no DLT 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 relapsedrefractory AML were not observed.
Additionally, no GVHD was observed. FT516 grade three febrile neutropenia was observed in three patients with no other FT516 related grade three or greater adverse events observed. Additionally, no FT516 related serious adverse events were observed. Finally, there were no discontinuations of study treatment 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. Anti leukemic activity of FT516 is described in this slide. The median percent of leukemic blasts in the bone marrow at baseline was thirty nine percent, with two patients having extremely high leukemic blast burden at baseline in excess of ninety percent. Additionally, at baseline and characteristic of patients with relapsedrefractory AML, all nine patients had significant hematopoietic impairment.
Eight patients had neutrophil counts below a thousand per microliter with a median count of approximately 200 per microliter, and all nine patients had platelet counts below a 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 relapsedrefractory AML population that has extremely poor prognosis. Of the nine patients, four patients achieved an objective response based on twenty seventeen ELN response criteria, including three patients who achieved CRI with neutrophil count recovery exceeding a thousand 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, is the water plot 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 blast of the marrow are also shown. In the second dose escalation cohort of 300,000,000 cells per dose shown in blue on the right hand side, three of six patients achieved an objective response with complete clearance of leukemic blast in the bone marrow, including two patients, subjects one zero zero six and one zero zero seven, who achieved CRI. I would also like to point out that the second dose escalation cohort included two subjects, subjects 1008 and one zero one one, both of whom did not respond to therapy. These two patients both had adverse disease fee 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 ninety percent 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 one zero zero seven have remained on study and in remission without further therapeutic intervention for duration of 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 the best overall response of MLFS subsequently had progressive disease on study day 80.
So for the next two slides, I just wanted to go into more detail on, of study vignettes for the two patients who had the durable CRI. On this slide, we describe a vignette from subject 1006 with a 68 year old patient unfit for standard seven plus three induction chemotherapy and who relapsed following treatment with venetoclax and the cetabene combination. The patient's disease was significant for having an adverse genetic risk profile with twenty six percent bone marrow blast 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 plan six doses of f t five one six, did not experience any grade of CRS, ICANS, or GVHD, and did not experience any FT516 related grade three 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 a thousand per microliter, which is a level that is four times greater than what the patient had at baseline prior to starting study treatment. And as I mentioned before 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 is also considered unfit for standard seven plus three induction chemotherapy.
Unlike subject 1006, this patient was refractory to primary induction therapy consisting of eight cycles of venetoclax plus dacitabine. This patient's disease was also notable for having an adverse genetic risk profile with 12% bone bone marrow blast at baseline. The clinical course, as summarized on the right, was notable, again, for this patient receiving all six planned doses of f t five one six without experiencing any grade of CRS, ICANS, or GVHD, or five one six related grade greater than three adverse events. And the patient achieved a response of CRI after FT516 treatment with neutrophil coverage, exceeding a thousand per microliter and ongoing thrombocytopenia. This patient also has an ongoing CRI of greater than six months as of the data cutoff.
So together, the totality of the f t five one six data suggests, clear evidence of clinical benefit. Why we're still in dose escalation? Dose escalation continues. And so for our observations from our ongoing phase one clinical trial of FT538, I now have the pleasure of turning it over to doctor Jeff Miller.
Thank you, Wayne. Good afternoon, everybody. So as we can see here, the phase one study of FT538 is a dose escalation of FT538 administered as monotherapy in patients with relapsedrefractory 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 weeks sorry, three consecutive days of conditioning chemotherapy comprised of cyclophosphamide at five hundred milligram meter squared and fludarabine at thirty 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-two support administered with each dose of FT538 given its additional engineered functionality. FT538 dose levels range from 100,000,000 cells to 1,500,000,000 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 100,000,000 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 04/16/2021. 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 twenty seventeen 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 twenty seventeen ELN criteria are summarized patients in the first dose escalation cohort. 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 their 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 one study described earlier by Wayne, 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 TRB cell mediated anti product immunogenicity. Both evaluable patients showed anti leukemic activity as evidenced by on treatment reduction in bone marrow blast. One subject, subject 1,003, showed complete clearance of leukemic blast from the bone marrow and achieved a best overall response of CRI after the first FT538 treatment cycle.
The first course the first the course of patient one zero zero three is instructive both clinically and translationally. This was a 75 year old 79 year old gentleman with who was refractory to multiple prior therapies, including an investigational c d thirty three, IL fifteen, c d sixteen, NK cell engager immunotherapy, into their last prior therapy. They 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 refunction is really remarkable in this patient who had significant neutropenia for over twelve 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, but we also know that there are significant limitations in the number and function of patient encasal 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 c d 16. 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 patients' 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 c d 16 Fc receptor, maintain uniform high expression of c d 16 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 c d 16.
This underscores the importance of administering CD16 engineered cells alongside agents that rely on ADCC to maximize antitumor activity. Additionally, in the bottom panel in the lower right, we evaluated the peripheral blood PK profile of FT516 versus FT538 products using a digital droplet PCR targeting the high affinity CD 16 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 cytotoxin and pleuribian odepleting chemotherapy regimen. However, IL two 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, and this really validates our preclinical data. Lastly, I would like to underscore these clinical studies are assessing FT516 and FT538 as monotherapy, are testing the inherent capacity of iPS derived NK cells to target and kill leukemoplasts without the aid of additional therapy. But recall that both FT516 and FT538 incorporate our novel high affinity non cleavable c d 16 Fc receptor, which has been modified to prevent its sound regulation and to enhance its binding to tumor targeting antibodies. Given this functionality, we think there is a unique opportunity to combine these iPS derived NK cells with monoclonal antibody therapy to target certain antigens that are expressed on leukemic blast.
At the European Hematology Meeting in 2020, a presentation caught our attention that highlighted the potential therapeutic role of c d thirty eight targeted monoclonal antibody therapy in treating elderly patients with AML. An assessment of bone marrow samples from newly diagnosed elderly AML patients showed c d 38 expression on leukemiblast in two hundred and thirty nine out of two hundred and forty one samples tested. This 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, geratumumab, can enhance the antitumor 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 one 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 relapsedrefractory AML, and we expect this trial to initiate before the end of this quarter. And 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 relapsedrefractory 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 twelve patients, nine had adverse risk profile based on twenty seventeen ELN risk category, eleven were refractory to their last prior therapy, and eleven also had significant hematopoietic impairment at baseline with both low neutrophil and platelet counts.
Five of twelve 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 iPS 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. Relapsedrefractory 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. And 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. And 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 Ed Dulock, our CFO, who will moderate the Q and A session.
Great. Thank you, Scott and team. And just a reminder, for those that are participants, you can submit questions in text format using the question and answer functionality of the webcast. So we've got a number of questions. The first one coming from Ugallit City, but there are a number of others that are common themes, which is among the four patients that achieved CRI and one patient that achieved MLFS, were any of these patients also MRD negative?
Sure. Wayne Wayne, do you wanna take that question?
Yeah. Sure. So 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, you know, we monitor MRD. So for we monitor for MRD both at the local level as well as in the case of f t five thirty eight phase one study, we do that centrally. I think it's instructive to to you know, for everyone to know that as we monitor MRD, just like as we exemplified in that patient in FT516, you know, responses evolve over time. And so 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.
K. Great. Thanks, Wayne. The next question then will come from Michael Yee. And again, there are a number of questions, similar intent.
So two part question. We'll take the first part first. Question around five sixteen and observing a trend towards CRs having lower blast counts in patients that have fewer prior treatments and comparing that to five thirty eight where small patient numbers, but a CR with a patient that has a higher blast count and four prior therapies. So just an overall question on those general trends as well as does this suggest any promise for five thirty eight versus five sixteen 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 relapsedrefractory AML patients, what is maybe you could characterize a little bit what it means to have twenty five percent to thirty percent blast in your marrow versus we enrolled two patients, for instance, that had ninety percent blast in their marrow. Could you talk a little bit about that based on your experiences with respect to severity of disease? And again, in the context these are my gosh, relapsedrefractory patients, most of them refractory.
Sure. I'm happy to comment on that. And I would reiterate, this is we're talking about four responses or five responses, and the patients are highly heterogeneous. So it's really dangerous to extrapolate too much into this. But 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. So patients who come into treatment with slightly less component of blasts in their marrow space have a lower leukemic burden, can, which again, if 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, you know, taking care of some of these patients that I'd like to just remind the group, you know, we tend to take these, cell therapies, and we test it on the worst of the worst. I think the thing from my own personal experience with a patient treated at our site, which was 01/2003, is really the fact that this patient had failed so many things in the past. And 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. So I agree with all the other comments in 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, you know, regulatory preferences? You know, does regulators have one preference versus another? And then how do we think about the data presented today in the context of other studies in relapsedrefractory AML and the endpoints that were used ostensibly not twenty seventeen ELN criteria?
Yeah. Take a look. Well,
I'll start. I mean, I really don't want to comment. It's hard to comment on other people's studies, So 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. You know, generally, and Wayne feel free to jump in, I think the criteria that we're using are very rigorous. To be clear, as Wayne talked about, in order to achieve, CRI, you have to recover either neutrophils or platelets to the level of CR.
And so we tend to believe the twenty seventeen ELN criteria is a high bar. We also, you know, as we've talked about, CR, CRI, MLFS per the twenty seventeen ELN criteria is clearly correlated with overall survival. And that's been shown in the study that Wayne presented. I'd say lastly, and then I'll let Wayne respond, look, it's a dose escalation study. Obviously we're going 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.
Don't know.
Wayne, do want
to add anything to that? Yeah. Not much. I mean, I think, Scott, you encapsulated, you know, the comments, you know, very, very well. You know, I think going to the point around potential for registratability, of course, in the end, whether or not, you know, the product candidate gets approved will depend on the totality of the data that go well beyond these early, response time points.
And I think it's also important to remember that, you know, we do not know today the correlations of these subcategories of CR with respect to overall clinical benefit based on duration or survival. So I think these are things that are still, you know, are pending, you know, further follow-up and and further analysis. But I think the important thing is that it's particularly in the context of an early phase one dose escalation study. Right? As we have said, you know, repeatedly through the presentation, complete clearance of bone marrow blast is a prerequisite for anything related to, you know, longer term clinical benefit.
And so what we've been seeing so far with various forms of this leukemic blast clearance, I think it's very encouraging giving you early stage of both studies.
Great. Thank you. Next question from Matt Begler commenting on the safety profile for either FT516 or five thirty eight, 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 mean, I'll start there. Obviously, you know, we're moving through dose escalation. FT516 is going to explore and is exploring the highest dose level of 900,000,000 cells where we're almost fully enrolled. FT538, clearly, we have are exploring very high doses.
We'll move from one hundred million cells to 300,000,000 cells, then to 1,000,000,000 and potentially 1,500,000,000. And 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. Thanks, Scott. Follow on question about CRI and the decision to move to transplant, noting, you know, the CRIs that are still ongoing in terms of CRI response. Why are they not in transplant, and just how does the physician make that decision to go to transplant from a CRI response?
Can Sarah, you want to talk about that? 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, you know, speaking as a former transplanter, unfortunately, most patients with AML are not eligible for transplant due to age or comorbidities or being too unfit. And 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.
And so for them, this was the only option. And then 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, you know, their 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 five thirty eight PK sort of pre day eight and then post day eight following another round of therapy? That's the first question. And then a second one about the PK of five sixteen relative to what we may have seen with other donor derived NK cell therapies and whether or not with five sixteen specifically, if it's a lower PK, then does that signal any need for different approaches to lympho conditioning?
Sarah, do wanna talk about that? At least with respect to the data that's that's publicly disclosed.
Yep. Exactly. So what 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. So this represents the status of the product in the peripheral blood after seven days of in vivo circulation prior to dose two. And we're certainly monitoring, you know, the PK throughout the treatment course, cycle one and cycle two after each time point, and comparing the profile between five three eight and five one six and trying to understand, you know, the relative benefit of the engineered IL-fifteen receptor fusion component, etcetera.
And so 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. And I would say, again, at this point of dose escalation and what's been reported, we are continuing to monitor in the five one six product the potential contribution of the IL, to exogenous cytokine support and to understand whether at higher dose cohorts, it will be necessary. So that's what I can share with you at this time.
Thank you, Sarah. It
is Another I mean, one thing I'll say, you know, we do think there's potentially a very different PK profile that may be dose dependent, including based on the engineered features. So for instance, FT538 may have a PK profile that's emerging already at 100,000,000 cells, given that it's engineered with IL-fifteen and has a CD38 knockout, whereas FT516 without those features may have a PK profile that emerges at a higher dose level.
Yep.
And 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. A couple of questions on the classification of responses. There's some examples for patient ten eleven, for example, where they have progressive disease but their blast count showed a modest reduction, or other examples where you have, you know, positive some 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. So 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 extra you know, outside of the bone marrow with respect to peripheral blood and other sites of extramedullary disease. So in the example of that 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 reduction in the percentage of bone marrow blasts and were classified as stable disease, these patients were classified as stable disease per twenty seventeen ELN criteria because in order to achieve a partial response, you need to have a certain decrement in the percentage of bone marrow blast that is at least 50% of what you started out with.
So for a patient who may have a numerical drop in bone marrow blast, if it it's not constitute more than a 50% reduction from baseline, then it cannot be called a partial response, and it is classified as stable disease per twenty seventeen ELN.
So for instance, Wayne, I think the second patient in the FT538 study, right, had a while they had a 40% reduction, it didn't meet the threshold of the 50% required.
That's correct.
Thank you, Wayne. Clarification, I think we talked about this briefly. We characterized the four CRIs that are either ongoing or transferring to a stem cell therapy, two with a six month durability, but there's an additional CRI, which I think they're referencing the patient on the FT538101 study. And just asking to characterize the status of that CRI?
Mean, Wayne, you can answer this. I mean, as of the data cutoff, the patient was in flight with respect to the second cycle.
That's correct. So as of the data cutoff, the patient was, nearly complete in second cycle, and it was in flight, and it's it's still continuing to be monitored.
And I think we and I we said
I think we said remained in remission. I think we did say that. Obviously, it's the data cutoff.
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, 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 relapsedrefractory AML. I will tell you that my suspicions are it is five thirty eight based on all the preclinical data that we have.
And as Bob mentioned, I think we're gaining a lot more confidence in the translatability of those preclinical models. But 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?
Don't know. Sarah or Jeff, do you want to talk about that? I mean, it's a relatively light conditioning regimen as compared to what's been done historically in derived NK cell field, which I think Sarah you characterized more as lymphodepleting and required hospitalization. Sarah, do
you want me to make a comment and you can add? Please. Absolutely. Yes. So, you know, this has been a very much argued point in the field.
I think, you know, the most interesting thing to me, remember in the studies that Sarah described, you know, from the single adult donor experience products, we were giving cyclophosphamide at, like, eight grams per patient over two days and five days of fludarabine. And I think 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, really low with chemotherapy alone, probably in the less than ten percent range. And remember, now with the trials that were discussed here today, we're even getting 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 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 CyFlu 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? So how do we think about development beyond monotherapy in the CD16 component of our INK cell platform?
Sure. I mean, 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.
Yes, Scott, so thanks. You know, as many of you know, the best antigen to target on AML blast I think is very much in flux in the field. You know, 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, and we know this from the preclinical studies using both FT516 and FT538. You know, we've been really, interested in remember, NK cells have two mechanisms of action, natural cytotoxicity, but the goal is to gain, you know, to really use all the gene edits that are in there. So combining with daratumumab, especially with FT538 because we can avoid this phenomena of fratricide, you know, 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.
And 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?
And to 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 patient's treatment course when they are more fit, potentially could still be bridged to transplant, and are less refractory to treatment. So looking into opportunities to combine with other sort of upfront agents such as azacitidine or venetoclax is really intriguing to us. And 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 care the profile on the leukemic blast to make them better targets and or to help clear host immune cells, which might compete with NK cells as part of a alternative lympho conditioning strategy, and then just as a combination therapy with two modalities of mechanism of action. So something we're very interested in looking into exploring with further trials.
Thanks, Sarah.
Thank you.
Last question, Ed. I think we're coming up on ninety minutes.
Yes, we've gotten through most. The last question is really two parts. The first one just asking about have we done this assessment using CRCRH rate as historically has been done? But perhaps more importantly, how do you think about approvability or how do you know you have 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 twenty seventeen 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. But obviously, you know, 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, Wayne, you wanna add anything to that.
No. I mean, other than the fact that, you know, to emphasize and reiterate again, you know, we are still in very early stages of dose escalation. So as far as what are the appropriate endpoints for approvability, you know, that's just something that's gonna require additional follow-up and more patients, especially as we get to, you know, what we consider the recommended phase two dosing schedule. But, you know, again, I think just in the context of early phase one, what we are seeing with respect to our, ability of FT516 and FT538 to clear out leukemic blast, we're highly encouraged. And so we look forward to seeing additional data as we get to higher doses and with longer follow-up.
Thanks, Wayne. Since we're about ninety minutes
final comments.
No. Think yeah. No. I think, I appreciate everyone's time today. And, again, look forward to having follow-up conversations with you about, our relapsedrefractory AML franchise.
Talk to you soon. Thank you very much.