Fate presents interim clinical data from ongoing Phase 1 stuty of FT576

Fate Therapeutics presented interim clinical data from the dose-escalation stage of its ongoing Phase 1 study of FT576 for patients with relapsed / refractory multiple myeloma at the 64th American Society of Hematology Annual Meeting and Exposition. The off-the-shelf product candidate, which is derived from a clonal master engineered induced pluripotent stem cell line, incorporates a chimeric antigen receptor targeting B-cell maturation antigen as well as a high-affinity, non-cleavable CD16 Fc receptor to maximize antibody-dependent cellular cytotoxicity and enable dual-antigen targeting of myeloma cells through combination with monoclonal antibody therapy. Preclinical data published last month in the journal Nature Communications demonstrated that single-dose administration of FT576 was effective at controlling tumor growth in vivo, with deeper and more sustained anti-tumor activity observed through multi-dose administration of FT576 as well as in combination with the CD38-targeted monoclonal antibody daratumumab. The multi-center Phase 1 clinical trial of FT576 is designed to assess its safety and clinical activity in adult patients with r/r MM, and to determine the recommended Phase 2 dose and schedule, as monotherapy and in combination with daratumumab to simultaneously target BCMA and CD38. As of the October 7, 2022 data cutoff date, 9 patients with r/r MM have been treated with a single dose of FT576, including 6 patients in Regimen A and 3 patients in Regimen B. Patients received standard conditioning chemotherapy consisting of cyclophosphamide at 300 mg/m2 and fludarabine at 30 mg/m2 for 3 days prior to the initiation of each regimen. Patients were heavily pre-treated having received a median of 5 prior lines of therapy, including 6 patients that were refractory to last therapy. In Regimen A, 6 patients were treated with a single dose of FT576 as monotherapy in the first dose cohort at 100 million cells and the second dose cohort at 300 million cells. In the second dose cohort, one patient, who had received 5 prior lines of therapy, was triple-refractory to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 mAb, and was refractory to last therapy, achieved a very good partial response with the other two patients showing stable disease. Further evidence of FT576 activity was observed in the second dose cohort, with two patients for whom serum BCMA levels were evaluable showing a substantial treatment-induced decrease in soluble BCMA. In Regimen B, 3 patients were treated with a single dose of FT576 in combination with daratumumab in the first dose cohort at 100 million cells, with one patient achieving a partial response and one patient achieving a minor response. All 3 patients showed a substantial treatment-induced decrease in soluble BCMA. The company has now initiated enrollment of two-dose escalation cohorts at 300 million cells per dose in both regimens. No dose-limiting toxicities, and no events of any grade of cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or graft-versus-host disease, were observed. Both FT576 treatment regimens were well tolerated. Two patients experienced Grade 3 or greater FT576-related adverse events (AEs), with one patient having Grade 3 diarrhea and one patient having two episodes of Grades 3 through 4 neutropenia and 3 episodes of Grade 3 anemia, all of which resolved. There were no serious AEs related to FT576. Grade 3 or greater treatment-emergent AEs not related to FT576 primarily included hematologic cytopenias associated with conditioning chemotherapy. There were no study discontinuations or deaths due to TEAEs. Under its collaboration with Janssen Biotech, one of the Janssen Pharmaceutical Companies of Johnson & Johnson (JNJ), the company is currently conducting preclinical development of FT555, a multiplexed-engineered CAR NK cell product candidate derived from a clonal master engineered iPSC line incorporating four functional components: a proprietary CAR optimized for NK cell biology that targets GPRC5D, an orphan G-protein-coupled receptor expressed on myeloma cells with a distribution that is similar to but independent of BCMA; a novel hnCD16 Fc receptor for enhanced ADCC; an IL-15 receptor fusion that augments NK cell activity; and the deletion of the CD38 gene, which promotes persistence and function in high oxidative stress environments. At ASH, scientists from the companies jointly presented preclinical data demonstrating that single-dose administration of FT555 as monotherapy resulted in robust and durable antigen-mediated tumor regression in two independent disseminated tumor models of aggressive myeloma, which activity was further improved in combination with daratumumab to simultaneously target GPRC5D and CD38 antigens. Administration of three doses of FT555 as monotherapy further improved tumor clearance and showed superior activity compared to single-dose primary CAR T cells.