On November 4, 2021 Fate Therapeutics, Inc. (NASDAQ: FATE), a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for patients with cancer, reported business highlights and financial results for the third quarter ended September 30, 2021 (Press release, Fate Therapeutics, NOV 4, 2021, View Source [SID1234594414]).

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"The interim Phase 1 data from our FT516 and FT596 programs in relapsed / refractory lymphoma demonstrate that our off-the-shelf, iPSC-derived NK cell product candidates have the potential to deliver substantial therapeutic benefit for patients along with a differentiated safety profile that supports outpatient treatment. We look forward to sharing additional clinical data from both of these programs at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December," said Scott Wolchko, President and Chief Executive Officer of Fate Therapeutics. "We also continue to be pleased with the clinical advancement of our multiplexed-engineered, iPSC-derived NK cell pipeline, where we have now successfully treated the first patients with FT516 in disease-specific expansion cohorts for lymphoma and with FT538 in combination with daratumumab for multiple myeloma. Additionally, we have successfully completed GMP manufacture and release of FT576, our multi-antigen targeted, CAR BCMA product candidate for multiple myeloma, and have initiated enrollment in our Phase 1 study."

B-cell Malignancy Disease Franchise

Positive FT596 Interim Phase 1 Clinical Data Observed in Single-dose Treatment Regimens. In August, the Company highlighted interim clinical data from its dose-escalating Phase 1 study of FT596 as monotherapy and in combination with rituximab for the treatment of relapsed / refractory (r/r) B-cell lymphoma (BCL). As of the data cutoff date of June 25, 2021, in the second (90 million cells) and third (300 million cells) dose cohorts of the single-dose monotherapy and combination regimens, 10 of 14 patients (71%) achieved an objective response (ORR), including seven patients (50%) that achieved a complete response (CR), on Day 29 as assessed by PET-CT scan per Lugano 2014 criteria. Treatment with FT596 was well tolerated, with two reported low-grade adverse events (one Grade 1, one Grade 2) of cytokine release syndrome (CRS) and no reported adverse events of immune effector cell-associated neurotoxicity syndrome (ICANS) or graft-versus-host disease (GVHD). Dose escalation is ongoing with enrollment in the fourth (900 million cells) single-dose cohorts. In addition, the Company has initiated enrollment of a two-dose treatment schedule in both regimens, with FT596 administered on Day 1 and Day 15 at 300 million cells per dose with the potential to dose escalate to 900 million cells per dose.
Encouraging Safety Profile with Second FT596 Cycle Supports Re-treatment. The FT596 Phase 1 clinical protocol allows for the re-treatment of eligible patients with a second FT596 cycle. As of the June 25, 2021 data cutoff date, in the second (90 million cells) and third (300 million cells) dose cohorts, eight of 10 patients responding after the first single-dose cycle were re-treated with a second single-dose cycle. Of these eight re-treated patients, four patients with CR at the end of the first cycle remained in CR following disease assessment at the end of the second cycle, and the other four patients had not yet been assessed for response following the end of the second cycle. The second cycle was well tolerated, and no adverse events of CRS, ICANS, or GVHD were observed.
Positive FT516 Interim Phase 1 Clinical Data Reported in Multi-dose, Multi-cycle Treatment Regimen. In August, the Company updated interim clinical data from its dose-escalating Phase 1 study of FT516 in combination with rituximab for the treatment of r/r BCL. As of the data cutoff date of July 7, 2021, in the second and third multi-dose cohorts (90 million cells per dose and 300 million cells per dose, respectively), eight of 11 patients (73%) achieved an objective response, including six patients (55%) that achieved CR, on Day 29 of the second FT516 treatment cycle as assessed by PET-CT scan per Lugano 2014 criteria. Five of the 11 patients (45%) maintained their response without further therapeutic intervention, including four patients that remained in CR (4.6-9.5 months) and one patient that remained in partial response (6.1 months). The multi-dose, multi-cycle treatment regimen was well tolerated, and no adverse events of CRS, ICANS, or GVHD were reported.
Dose-expansion Stage of FT516 Phase 1 Study Initiated. The Company has completed enrollment in the dose-escalation stage of its Phase 1 study of FT516 in combination with rituximab for the treatment of r/r BCL, and has initiated enrollment in the study’s dose-expansion stage at 900 million cells per dose. The Company plans to enroll patients in three disease-specific expansion cohorts using cyclophosphamide (Cy) and fludarabine (Flu) as conditioning chemotherapy: patients with r/r aggressive lymphomas who have previously been treated with CD19-targeted CAR T-cell therapy; patients with r/r aggressive lymphomas who are naïve to treatment with CD19-targeted CAR T-cell therapy; and patients with r/r follicular lymphoma. In addition, the Company plans to enroll an expansion cohort without Cy / Flu conditioning chemotherapy, combining FT516 with rituximab and bendamustine, a standard-of-care treatment regimen for lymphoma.
Landmark Phase 1 Study of Off-the-shelf, iPSC-derived CAR T-cell Therapy Ongoing at Multiple Sites. In July, the first patient was treated in the Company’s landmark Phase 1 clinical trial of FT819, the first-ever T-cell therapy manufactured from a clonal master induced pluripotent stem cell (iPSC) line to undergo clinical investigation. The product candidate’s clonal master iPSC line is created from a single iPSC that has a novel CD19-targeted 1XX CAR construct (1XX-CAR19) integrated into the T-cell receptor alpha constant (TRAC) locus, ensuring complete bi-allelic disruption of T-cell receptor expression and promoting uniform CAR expression. The first patients have been treated with a single FT819 dose of 90 million cells for r/r acute lymphoblastic leukemia (ALL) and for r/r BCL, and the study is open to patient recruitment at three U.S. sites.
AML Disease Franchise

FT538 Phase 1 Study Enrolling in Dose Cohort 2. The Company is currently enrolling patients in the second multi-dose cohort (300 million cells per dose) in its dose-escalating Phase 1 study of FT538 as monotherapy for the treatment of r/r acute myeloid leukemia (AML). In addition, enrollment has commenced in an investigator-initiated Phase 1 clinical trial of FT538 in combination with the CD38-targeted monoclonal antibody daratumumab in patients with r/r AML, a therapeutic strategy designed to exploit the product candidate’s proprietary high-affinity, non-cleavable (hnCD16) receptor and CD38 knock-out (CD38KO) to recognize, bind, and kill CD38+ leukemic blasts through antibody-dependent cellular cytotoxicity (ADCC).
Dose-escalation Stage of FT516 Phase 1 Clinical Trial Completed. The Company completed enrollment in the dose-escalation stage of its Phase 1 study of FT516 as monotherapy for the treatment of r/r AML, having enrolled seven patients in the third multi-dose cohort (900 million cells per dose). The maximum tolerated dose was not established with the third multi-dose cohort, and treatment with FT516 was well-tolerated.
Multiple Myeloma Franchise

First Patient Treated in Phase 1 Study of FT538 in Combination with Daratumumab. The Phase 1 clinical trial is designed to assess three once-weekly doses of FT538 in combination with daratumumab for patients with r/r multiple myeloma (MM). The first patient has been treated in the first multi-dose cohort (100 million cells per dose), and the study is open to patient recruitment at seven U.S. sites.
Initiated Enrollment in FT576 Phase 1 Study. FT576 is derived from a clonal master iPSC line engineered with four functional components (CAR-BCMA + hnCD16 + IL-15RF + CD38KO) designed to enable multi-antigen targeting of myeloma cells, augment ADCC, promote NK cell activation without exogenous cytokine support, enhance NK cell persistence and prevent anti-CD38 monoclonal antibody-induced fratricide. The Company has initiated enrollment of a multi-center Phase 1 clinical trial to assess single-dose and multi-dose treatment regimens of FT576 as monotherapy and in combination with daratumumab for the treatment of r/r MM.
Solid Tumor Franchise

Initiated Enrollment in Phase 1 Study of FT538 in Combination with Monoclonal Antibody Therapy. The Phase 1 clinical trial is designed to assess the safety and activity of three once-weekly doses of FT538 in combination with monoclonal antibody therapy for the treatment of a broad array of solid tumors. The clinical protocol includes combination with each of three monoclonal antibodies: EGFR-targeted cetuximab; HER2-targeted trastuzumab; and PDL1-targeted avelumab. Each patient is eligible to receive up to two FT538 treatment cycles, with each cycle consisting of three days of outpatient lympho-conditioning, three once-weekly infusions of FT538, and monoclonal antibody therapy.
FT536 Preclinical Data to be Featured at SITC (Free SITC Whitepaper) in Oral Presentation. At the 36th Annual Meeting of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper), the Company plans to present IND-enabling preclinical data for FT536, its off-the-shelf, multiplexed-engineered, iPSC-derived NK cell product candidate that incorporates a novel CAR targeting the alpha-3 domain of the pan-tumor associated stress antigens MICA and MICB. The clonal master iPSC bank for FT536 was created from a single iPSC engineered with four functional elements, including the CAR which has a novel binding domain designed to overcome common tumor escape mechanisms mediated by loss of MHC Class I expression and by shedding of MICA and MICB. The Company expects to submit an Investigational New Drug (IND) application for FT536 in the fourth quarter of 2021 for the treatment of advanced solid tumors, including in combination with monoclonal antibody therapy to promote multi-antigen targeting.
Other Corporate Highlights

Peer-Reviewed Cell Stem Cell Publication Highlights Adaptive Phenotype and Functionality of FT538. The peer-reviewed article entitled "Harnessing features of adaptive NK cells to generate iPSC-derived NK cells for enhanced immunotherapy" describes preclinical studies showing that FT538 shares metabolic, transcriptional, and functional features with adaptive NK cells, a rare subset of NK cells with memory-like properties that have a genome-wide epigenetic profile and recall response that parallel cytotoxic effector CD8+ T cells. The published data demonstrate that FT538 exhibits significantly enhanced serial killing and functional persistence compared to peripheral blood NK cells. The superior anti-tumor activity of FT538 was attributable to its novel engineered components, including the knockout of CD38 and the expression of IL-15/IL-15R fusion protein, which were shown to improve metabolic fitness, increase resistance to oxidative stress, and induce transcription of proteins that control NK cell activation and effector function. The studies in the Cell Stem Cell publication were conducted as part of a collaboration between scientists at Fate Therapeutics and the laboratory of Jeffrey S. Miller, M.D., University of Minnesota, and were led by Frank Cichocki, Ph.D., University of Minnesota.
Third Quarter 2021 Financial Results

Cash & Investment Position: Cash, cash equivalents and investments as of September 30, 2021 were $803.6 million.
Total Revenue: Revenue was $14.2 million for the third quarter of 2021, which was derived from the Company’s collaborations with Janssen and Ono Pharmaceutical.
R&D Expenses: Research and development expenses were $53.1 million for the third quarter of 2021, which includes $8.6 million of non-cash stock-based compensation expense.
G&A Expenses: General and administrative expenses were $15.7 million for the third quarter of 2021, which includes $5.0 million of non-cash stock-based compensation expense.
Shares Outstanding: Common shares outstanding were 95.4 million, and preferred shares outstanding were 2.8 million, as of September 30, 2021. Each preferred share is convertible into five common shares.
Today’s Conference Call and Webcast
The Company will conduct a conference call today, Thursday, November 4, 2021 at 5:00 p.m. ET to review financial and operating results for the quarter ended September 30, 2021. In order to participate in the conference call, please dial 877-303-6235 (toll free) or 631-291-4837 (toll) and refer to conference ID 9459084. The live webcast can be accessed under "Events & Presentations" in the Investors section of the Company’s website at www.fatetherapeutics.com. The archived webcast will be available on the Company’s website beginning approximately two hours after the event.

About Fate Therapeutics’ iPSC Product Platform
The Company’s proprietary induced pluripotent stem cell (iPSC) product platform enables mass production of off-the-shelf, engineered, homogeneous cell products that can be administered with multiple doses to deliver more effective pharmacologic activity, including in combination with other cancer treatments. Human iPSCs possess the unique dual properties of unlimited self-renewal and differentiation potential into all cell types of the body. The Company’s first-of-kind approach involves engineering human iPSCs in a one-time genetic modification event and selecting a single engineered iPSC for maintenance as a clonal master iPSC line. Analogous to master cell lines used to manufacture biopharmaceutical drug products such as monoclonal antibodies, clonal master iPSC lines are a renewable source for manufacturing cell therapy products which are well-defined and uniform in composition, can be mass produced at significant scale in a cost-effective manner, and can be delivered off-the-shelf for patient treatment. As a result, the Company’s platform is uniquely capable of overcoming numerous limitations associated with the production of cell therapies using patient- or donor-sourced cells, which is logistically complex and expensive and is subject to batch-to-batch and cell-to-cell variability that can affect clinical safety and efficacy. Fate Therapeutics’ iPSC product platform is supported by an intellectual property portfolio of over 350 issued patents and 150 pending patent applications.

About FT516
FT516 is an investigational, universal, off-the-shelf natural killer (NK) cell cancer immunotherapy derived from a clonal master induced pluripotent stem cell (iPSC) line engineered to express a novel high-affinity 158V, non-cleavable CD16 (hnCD16) Fc receptor, which has been modified to prevent its down-regulation and to enhance its binding to tumor-targeting antibodies. CD16 mediates antibody-dependent cellular cytotoxicity (ADCC), a potent anti-tumor mechanism by which NK cells recognize, bind and kill antibody-coated cancer cells. ADCC is dependent on NK cells maintaining stable and effective expression of CD16, which has been shown to undergo considerable down-regulation in cancer patients. In addition, CD16 occurs in two variants, 158V or 158F, that elicit high or low binding affinity, respectively, to the Fc domain of IgG1 antibodies. Numerous clinical studies with FDA-approved tumor-targeting antibodies, including rituximab, trastuzumab and cetuximab, have demonstrated that patients homozygous for the 158V variant, which is present in only about 15% of patients, have improved clinical outcomes. FT516 is being investigated in a multi-dose Phase 1 clinical trial as a monotherapy for the treatment of acute myeloid leukemia and in combination with CD20-targeted monoclonal antibodies for the treatment of advanced B-cell lymphoma (NCT04023071). Additionally, FT516 is being investigated in a multi-dose Phase 1 clinical trial in combination with avelumab for the treatment of advanced solid tumors resistant to anti-PDL1 checkpoint inhibitor therapy (NCT04551885).

About FT596
FT596 is an investigational, universal, off-the-shelf natural killer (NK) cell cancer immunotherapy derived from a clonal master induced pluripotent stem cell (iPSC) line engineered with three anti-tumor functional modalities: a proprietary chimeric antigen receptor (CAR) optimized for NK cell biology that targets B-cell antigen CD19; a novel high-affinity 158V, non-cleavable CD16 (hnCD16) Fc receptor, which has been modified to prevent its down-regulation and to enhance its binding to tumor-targeting antibodies; and an IL-15 receptor fusion (IL-15RF) that augments NK cell activity. In preclinical studies of FT596, the Company has demonstrated that dual activation of the CAR19 and hnCD16 targeting receptors enhances cytotoxic activity, indicating that multi-antigen engagement may elicit a deeper and more durable response. Additionally, in a humanized mouse model of lymphoma, FT596 in combination with the anti-CD20 monoclonal antibody rituximab showed enhanced killing of tumor cells in vivo as compared to rituximab alone. FT596 is being investigated in a multi-center Phase 1 clinical trial for the treatment of relapsed / refractory B-cell lymphoma as a monotherapy and in combination with rituximab, and for the treatment of relapsed / refractory chronic lymphocytic leukemia (CLL) as a monotherapy and in combination with obinutuzumab (NCT04245722).

About FT538
FT538 is an investigational, universal, off-the-shelf natural killer (NK) cell cancer immunotherapy derived from a clonal master induced pluripotent stem cell (iPSC) line engineered with three functional components: a novel high-affinity 158V, non-cleavable CD16 (hnCD16) Fc receptor, which has been modified to prevent its down-regulation and to enhance its binding to tumor-targeting antibodies; an IL-15 receptor fusion (IL-15RF) that augments NK cell activity; and the deletion of the CD38 gene (CD38KO), which promotes persistence and function in high oxidative stress environments. FT538 is designed to enhance innate immunity in cancer patients, where endogenous NK cells are typically diminished in both number and function due to prior treatment regimens and tumor suppressive mechanisms. In preclinical studies, FT538 has shown superior NK cell effector function, as compared to peripheral blood NK cells, with the potential to confer significant anti-tumor activity to patients through multiple mechanisms of action. FT538 is being investigated in a multi-dose Phase 1 clinical trial for the treatment of acute myeloid leukemia (AML) and in combination with daratumumab, a CD38-targeted monoclonal antibody therapy, for the treatment of multiple myeloma (NCT04614636). FT538 is also being investigated in a multi-dose Phase 1 clinical trial in combination with one of an array of tumor-targeting monoclonal antibodies for the treatment of advanced solid tumors (NCT05069935).

About FT819
FT819 is an investigational, universal, off-the-shelf, T-cell receptor (TCR)-less CD19 chimeric antigen receptor (CAR) T-cell cancer immunotherapy derived from a clonal master induced pluripotent stem cell (iPSC) line, which is engineered with the following features designed to improve the safety and efficacy of CAR19 T-cell therapy: a novel 1XX CAR signaling domain, which has been shown to extend T-cell effector function without eliciting exhaustion; integration of the CAR19 transgene directly into the T-cell receptor alpha constant (TRAC) locus, which has been shown to promote uniform CAR19 expression and enhanced T-cell potency; and complete bi-allelic disruption of TCR expression for the prevention of graft-versus-host disease. FT819 demonstrated antigen-specific cytolytic activity in vitro against CD19-expressing leukemia and lymphoma cell lines comparable to that of primary CAR T cells, and persisted and maintained tumor clearance in the bone marrow in an in vivo disseminated xenograft model of lymphoblastic leukemia (Valamehr et al. 2020). FT819 is being investigated in a multi-center Phase 1 clinical trial for the treatment of relapsed / refractory B-cell malignancies, including B-cell lymphoma, chronic lymphocytic leukemia, and acute lymphoblastic leukemia (NCT04629729).