On January 5, 2023 Fate Therapeutics, Inc. (NASDAQ: FATE), a clinical-stage biopharmaceutical company dedicated to bringing a first-in-class pipeline of induced pluripotent stem cell (iPSC)-derived cellular immunotherapies to patients with cancer and autoimmune disorders, reported that it has declined a proposal from Janssen Biotech, Inc. ("Janssen") for continuation of the collaboration and option agreement between the parties on revised terms and conditions and, as a result, the agreement has been terminated and all collaboration activities will be wound down in the first quarter of 2023 (Press release, Fate Therapeutics, JAN 5, 2023, View Source [SID1234625921]). In addition, the Company has completed a strategic review of its natural killer (NK) cell product pipeline and has elected to focus on advancing its most innovative and differentiated programs, which have a multiplexed-engineered cellular framework of novel synthetic controls designed to promote multi-antigen targeting, increase potency, extend functional persistence, and enable patient dosing with reduced conditioning chemotherapy. The Company ended the fourth quarter with approximately $475 million in cash, cash equivalents, and receivables and, based on its pipeline prioritization and expense reduction, the Company expects to have sufficient financial resources through the end of 2025 to capitalize on its iPSC-derived chimeric antigen receptor (CAR) NK and CAR T-cell programs.

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"We are disappointed that we were not able to align with Janssen on their proposal for continuation of our collaboration, where two product candidates targeting high-value, clinically-validated hematology antigens were set to enter clinical development in 2023," said Scott Wolchko, President and Chief Executive Officer of Fate Therapeutics. "As a consequence, in keeping with the Company’s commitment to develop disruptive product candidates, programs and technologies with the potential to address large, unmet clinical needs, we have prioritized our clinical programs and substantially reduced operating expenses, including taking the difficult and painful step of reducing our workforce, to ensure that we have a three-year cash runway. We are greatly saddened to move in this direction as our employees have continually demonstrated the highest level of dedication and commitment in pioneering iPSC-derived cell therapy for patients with cancer. I want to extend my deepest appreciation to all of our employees for their tremendous efforts and wish those employees who will be departing great success in the future."

"Our second-generation CD19-targeted CAR NK cell program incorporates CD38 knock-out and can be effectively combined with B cell-targeted monoclonal antibody therapy, including those targeting CD20 and CD38, to direct a multi-antigen attack on target cells. This broadens the program’s therapeutic application to include both hematologic malignancies, including non-Hodgkin’s lymphoma and multiple myeloma, and severe autoimmune disorders, and has the potential to enable patient dosing with reduced conditioning chemotherapy. In 2023, we plan to initiate clinical development and assess the potential of this highly-differentiated program with five novel synthetic controls of cell function, rather than commit our resources to an expansive, registrational-directed effort for our FT596 program which does not benefit from certain attributes that we believe are critical for expanded disease application and broad patient reach," continued Mr. Wolchko. "We also expect initial clinical data from high-dose, multi-dose treatment cohorts in multiple myeloma for our FT576 BCMA-targeted CAR NK cell program, which in combination with CD38-targeted monoclonal antibody therapy is designed to enable dual-antigen targeting and to extend functional persistence by selectively depleting activated host immune cells. In addition, we look forward this year to the further emergence of our iPSC-derived CAR T-cell programs for the treatment of hematologic malignancies and solid tumors. Dose and dose schedule optimization is ongoing for FT819, our first iPSC-derived CAR T-cell program, where we continue to assess single-dose and novel split-dose treatment schedules to compare pharmacokinetic, safety, and response profiles for non-Hodgkin’s lymphoma. We also plan to submit an IND application to the FDA for FT825/ONO-8250, our first multiplexed-engineered, CAR T-cell solid tumor program under our collaboration with ONO Pharmaceutical, which incorporates seven novel synthetic controls designed to overcome treatment challenges specific to solid tumors."

NK Cell Programs

First IND Submission Planned in Mid-2023 for Second-generation CD19-targeted CAR NK Cell Program. The Company has applied its unique ability to create multiplexed-engineered iPSC lines to improve upon its first-generation FT596 program, incorporating five novel synthetic controls designed to increase NK cell potency, enhance functional persistence, and reduce or eliminate the need to administer conditioning chemotherapy to patients. The additional features, including the knock-out of CD38, have the potential to significantly improve safety and clinical benefit, facilitate ease of combination with standard-of-care regimens including CD20- and CD38-targeted monoclonal antibody (mAb) therapy, and enable use in the treatment of non-Hodgkin’s lymphoma (NHL), multiple myeloma (MM), and severe autoimmune disorders. The program also incorporates the Company’s proprietary alloimmune defense receptor (ADR) technology for which the Company presented preclinical data at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in December 2022, which data indicated that ADR-armed, iPSC-derived CAR NK cells have the potential to proliferate, functionally persist, and durably kill tumor cells while resisting rejection by allo-reactive immune cells. The Company intends to submit an Investigational New Drug (IND) application to the U.S. Food and Drug Administration (FDA) in mid-2023 to commence a Phase 1 study of its second-generation program in combination with CD20-targeted mAb therapy for the treatment of NHL, including without administration of intensive conditioning chemotherapy to patients.
Ongoing Phase 1 Study of FT576 BCMA-targeted CAR NK Cell Program to Accrue Higher-dose, Multi-dose Treatment Cohorts. At the 2022 ASH (Free ASH Whitepaper) Annual Meeting, the Company presented interim Phase 1 clinical data from the low-dose escalation cohorts of single-dose administration of FT576 as monotherapy and in combination with CD38-targeted mAb therapy for the treatment of MM, which showed encouraging clinical evidence of BCMA-targeted activity in heavily pre-treated patients and a favorable safety profile indicating its potential to be administered in the outpatient setting. Moreover, Phase 1 translational data from the combination arm showed that CD38-positive patient immune cells were rapidly and selectively depleted through the first month of therapy, suggesting that iPSC-derived NK cells incorporating CD38 knock-out, such as FT576, may be combined with CD38-targeted mAb therapy to promote dual-antigen targeting of plasma cells and mitigate the risk of rejection. Preclinical data published in November 2022 in the journal Nature Communications (Cichocki et al. 2022, 13:7341) demonstrated that, while single-dose administration of FT576 was effective at controlling tumor growth in vivo, deeper and more sustained anti-tumor activity was observed through multi-dose administration. Dose escalation assessing multi-dose administration of FT576 as monotherapy and in combination with CD38-targeted mAb therapy is currently ongoing at 300 million cells per dose.

T-cell Programs

Ongoing FT819 Phase 1 Study Assessing Single-dose and Novel Split-dose Treatment Schedules. The landmark clinical trial, which is the first-ever clinical investigation of a T-cell product candidate manufactured from a clonal master iPSC line, is assessing conventional single-dose and novel split-dose treatment schedules of FT819 to compare pharmacokinetics, safety, and efficacy. Dose escalation is currently ongoing in a single-dose treatment regimen at 360 million cells and in a split-dose treatment regimen at 60 million cells per dose. At the 2022 ASH (Free ASH Whitepaper) Annual Meeting, the Company presented interim clinical data from its ongoing Phase 1 study, which showed a favorable safety profile and demonstrated objective responses in heavily pre-treated patients with aggressive large B-cell lymphoma, including in patients who were not eligible for or had previously failed autologous CD19-targeted CAR T-cell therapy.
2023 IND Submission Planned for Multiplexed-engineered CAR T-cell Therapy FT825/ONO-8250. Under the Company’s collaboration with ONO Pharmaceutical Co., Ltd. (ONO), the parties are conducting IND-enabling activities for FT825/ONO-8250, a multiplexed-engineered, iPSC-derived CAR T-cell product candidate targeting human epidermal growth factor receptor 2 (HER2)-expressing solid tumors. The product candidate incorporates seven novel synthetic controls designed to enhance effector cell function and overcome unique challenges in treating solid tumors with cell-based cancer immunotherapies, including cell trafficking, tumor infiltration, and immune cell suppression in the tumor microenvironment. At the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 37th Annual Meeting held in November 2022, the Company presented preclinical data of FT825/ONO-8250, which highlighted the differentiated targeting profile of the novel HER2-targeted binding domain, functional activity of its synthetic CXCR2 receptor to promote cell trafficking, its synthetic TGFβ receptor to redirect immunosuppressive signals in the tumor microenvironment, and its synthetic interleukin-7 receptor fusion protein to induce T-cell activation. The parties expect to submit an IND application to the FDA in 2023 to commence a Phase 1 study of FT825/ONO-8250 for patients with HER2-positive solid tumors.
Preclinical Development to Focus on Multiplexed-engineered, Multi-antigen Targeted CAR T-cell Programs. The Company’s proprietary iPSC product platform enables the selective design of multiplexed-engineered, CAR T-cell product candidates which incorporate novel synthetic controls of cell function and can deliver multiple mechanisms of action. Through the application of its platform, the Company is developing multiplexed-engineered, multi-antigen targeted CAR T-cell product candidates utilizing its library of novel binding domains targeting hematologic malignancy and solid tumor antigens.

Wind Down of Janssen Collaboration

During the fourth quarter of 2022, the FDA allowed an IND application for a first collaboration product for the treatment of B-cell lymphoma, for which the Company expects to receive a $3 million milestone payment, and Janssen exercised its second commercial option for a collaboration product, for which the Company expects to receive a $10 million milestone payment. As a result of the collaboration’s termination, during the first quarter of 2023, the Company will wind down its activities with Janssen, including discontinuing development of all collaboration products, at the expense of Janssen. As a result of such termination, all licenses and other rights granted pursuant to the agreement terminate; neither party has any right to continue to develop, manufacture or commercialize any collaboration product or use the other party’s materials; and neither party is restricted from independently developing, manufacturing, or commercializing any product, including any product directed to any antigen targeted by a collaboration product.

3-year Operational Runway

The Company ended the fourth quarter of 2022 with unaudited cash, cash equivalents, and receivables totaling approximately $475 million. The Company is reducing its headcount to approximately 220 employees in the first quarter of 2023, and is discontinuing clinical development of its FT516 and FT538 NK cell programs in acute myeloid leukemia, its FT516 and FT596 NK cell programs in B-cell lymphoma, and its FT538 and FT536 NK cell programs in solid tumors. Based on its current operating plan, the Company expects to have sufficient financial resources to fund operations through 2025.

About Fate Therapeutics’ iPSC Product Platform

The Company’s proprietary induced pluripotent stem cell (iPSC) product platform enables mass production of off-the-shelf, multiplexed-engineered cell products that are selectively designed, incorporate novel synthetic controls of cell function, and can deliver multiple mechanisms of therapeutic importance to patients. 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 combines multiplexed-engineering of human iPSCs with single-cell selection to create clonal master iPSC lines. 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 multiplexed-engineered cell 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 to maximize patient reach. As a result, the Company’s platform is uniquely designed to overcome 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.