Orca-T / Orca Biosystems - LARVOL DELTA

Orca-T versus allogeneic hematopoietic stem cell transplantation (PRECISION-T): a multicenter, randomized phase 3 trial. (PubMed, Blood) - P3 | "To prevent graft-versus-host disease (GVHD) in patients undergoing myeloablative allogeneic hematopoietic stem cell transplantation (alloHSCT), a calcineurin inhibitor plus methotrexate is routinely used. Additionally, significantly less toxicity was observed with Orca-T patients including fewer serious infectious complications and less non-relapse mortality. (ClinicalTrials.gov number NCT05316701)."

Journal • P3 data • Bone Marrow Transplantation • Chronic Graft versus Host Disease • Graft versus Host Disease • Hematological Malignancies • Immunology • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation

Observational comparison of orca-T to registry-based post-transplant cyclophosphamide patients using matched unrelated donors (ASH 2025) - P3 | "Combined with single-agent tacrolimus, Orca-Thas shown superior survival free of moderate-to-severe cGVHD compared to conventional allograft plustacrolimus and methotrexate (Tac/MTX). Notably, these outcomes were achieved using only single-agent tacrolimus forpharmacological GVHD prophylaxis, in contrast to the triple-agent regimen used with PTCy, implicatingthe potential role of immune reconstitution in both disease control and mitigating posttransplantcomplications. Additional studies are needed to identify the specific clinical factors such as infection andorgan toxicity that may account for the potential differences in OS."

Clinical • Post-transplantation • Acute Graft versus Host Disease • Bone Marrow Transplantation • Chronic Graft versus Host Disease • Graft versus Host Disease • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Transplantation

FOXP3 and helios expressing CD4+ T conventional cells are a regulatory-like subset that is induced after orca-T allogeneic immunotherapy (ASH 2025) - "We therefore propose that CD4+CD25-FOXP3+Helios+ cellsare a regulatory-like subset of T cells which are induced by Orca-T immunotherapy and that thispopulation contributes to GVHD suppression in concert with other regulatory populations after leukemiatreatment. Overall, we hypothesize that the sequential addition of high-purity Tregs directs the immunereconstitution of CD4+CD25- Tcons towards a non-redundant, immunomodulatory, FOXP3+Helios+phenotype which may be predictive of long-term immune activation after T cell infusion."

IO biomarker • Bone Marrow Transplantation • Graft versus Host Disease • Hematological Malignancies • Immunology • Leukemia • CD4 • CD73 • CD8 • CTLA4 • ENTPD1 • FOXP3 • IL2RA • NT5E • TIGIT

Orca-T and CAR-T Combination Treatment Versus Autologous CAR-T (Businesswire) - "A second oral presentation compared the results from two separate Phase 1 trials in adults with high-risk relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL). The first trial evaluated OrCAR-T (n=16), a treatment that combines Orca-T and allogeneic CD19/CD22 CAR-T cells, and the second trial evaluated an autologous CD19/22 (n=17). At 18 months, progression-free survival (PFS) and OS were 100% and 100% with OrCAR-T, and 38.5% and 77% in the autologous cohort. Toxicities were mild across both cohorts, with no grade 3-4 CAR-related toxicities reported."

P1 data • B Acute Lymphoblastic Leukemia

Superior efficacy and persistence of Orca-T-allogeneic CAR19/22 versus autologous CAR19/22 in high-risk adult B-ALL (ASH 2025) - P1, P1/2 | "In adults with HR B-ALL, Orca-T-allogeneic CAR 19/22 resulted in superior relapse prevention,survival, and CAR persistence relative to autologous CAR 19/22. We hypothesize this is due to tolerancefor CAR molecules, resulting in persistent CAR expression and improved antitumor activity. Safety datawere comparable between the two cohorts."

Clinical • IO biomarker • Chronic Graft versus Host Disease • Graft versus Host Disease • Immunology • Infectious Disease • IL15 • KMT2A

Orca-T improves chronic graph-versus-host disease free in patients with a broad range of demographic and clinical variables: Results of randomized, Phase 3 trial (ASH 2025) - P3 | "The randomized phase 3 Precision-T trial (NCT05316701)showed improved moderate-to-severe chronic GvHD-free survival with Orca-T versus standard-of-caretransplantation with tacrolimus plus methotrexate prophylaxis...Patients received a myeloablative conditioning (MAC) regimen(busulfan/fludarabine/thiotepa [BFT] or a TBI-based regimen) and had an 8/8 HLA-matched donor...CONCLUSIONS Orca-T demonstrated improved clinical outcomes overall and across subgroups with varied demographicand clinical features. These data suggest that the benefit of Orca-T extends to older patients and thosewith high-risk disease."

Clinical • P3 data • Acute Graft versus Host Disease • Chronic Graft versus Host Disease • Graft versus Host Disease • Hematological Malignancies • Immunology • Leukemia • Myelodysplastic Syndrome

Orca-T demonstrates favorable quality of life and healthcare resource use compared to standard allohsct plus tac/MTX for GVHD prevention in a randomized Phase 3 clinical trial (Precision-T) (ASH 2025) - "Patients transplanted using Orca-T appear to have marked HRQoL advantages over unmanipulatedalloHSCT plus Tac/MTX recipients, with less decrement, faster recovery to baseline, higher rates ofimprovement above baseline, fewer ICU stays, lower likelihood of rehospitalization, lower total hospitaldays, and higher rehospitalization free survival potentially reflecting better early post-transplant recoveryand/or lower GVHD symptom burden."

Clinical • HEOR • P3 data • Bone Marrow Transplantation • Chronic Graft versus Host Disease • Graft versus Host Disease • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • Myelodysplastic Syndrome

Allogeneic HSC and regulatory T cell (Orca-T) engineered cell therapy following reduced intensity conditioning: Results of a single center Phase 1 study (ASH 2025) - P3 | "Fourteen subsequent patients received 10mg/kg of thiotepa instead of melphalan,with the same dosing of fludarabine and 4 Gy TBI. These early results demonstrate that Orca-T is a safe and feasible transplant strategy forRIC conditioning. The trial achieved the goal of identifying a lympho-depletive RIC conditioning regimentolerated in the outpatient setting. Patients showed robust engraftment and donor T cell chimerism."

Clinical • P1 data • Acute Graft versus Host Disease • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Chronic Graft versus Host Disease • Graft versus Host Disease • Hematological Malignancies • Hepatology • Immunology • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Myeloproliferative Neoplasm

Orca-T Improved GvHD-free Survival Across Patient Demographics (Businesswire) - "In subset analyses from the Precision-T Phase 3 study comparing Orca-T to a conventional alloHSCT plus tacrolimus and methotrexate (Tac/MTX), Orca-T demonstrated improved clinical outcomes overall and across subgroups with varied demographic and clinical features....Notably, OS and NRM were similar for patients aged 51-65 as in the entire safety population. For patients over the age of 50 at one year, OS was 94% (77%, 98%) for Orca-T patients (n=31) versus 80% (61%, 91%) for Tac/MTX patients (n=32) (HR=0.48 [0.12, 1.89]). Rates of NRM were 6.5% (1.1%, 19%) with Orca-T vs 16% with Tac/MTX (5.7%, 31%) (HR=0.49 [0.11, 2.06])."

P3 data • Acute Myelogenous Leukemia • B Acute Lymphoblastic Leukemia • Myelodysplastic Syndrome • Myeloproliferative Neoplasm

Orca Bio Presents New Clinical Data on Orca-T in Older Patients Using Reduced Intensity Conditioning Plus New Analyses from the Precision-T Phase 3 Study at the 67th ASH Annual Meeting (Businesswire) - "At one year, there was no aGvHD grade 3-4 observed, and the rate of aGvHD grade 2 was 12.3% (95% CI, 5-23%). The rate of moderate-to-severe cGvHD was 9.6% (95% CI, 3-21%). At one year, relapse-free survival (RFS) and graft versus host disease relapse-free survival (GRFS) were 82% (95% CI, 72-94%) and 72% (95% CI, 60-87%), respectively. The overall survival (OS) was 88% (95% CI, 79-98%) and non-relapse mortality (NRM) was 10% (95% CI, 4-20%)."

P3 data • Acute Myelogenous Leukemia • B Acute Lymphoblastic Leukemia • Myelodysplastic Syndrome • Myeloproliferative Neoplasm

Health-Related Quality of Life: Patient Reported Outcomes (Businesswire) - "FACT-BMT total scores were consistently higher for Orca-T recipients across all time points, with Orca-T recipients exceeding baseline scores across physical well-being, functional well-being and transplant-specific subscales by day 100, while the alloHSCT arm did not surpass baseline until day 365....Rehospitalizations due to adverse events occurred less frequently among Orca-T recipients (27.3% [24] vs. 45.7% [43]), with fewer total hospitalization days per patient (30.6 vs. 40.8)."

P3 data • Patient reported outcomes • Acute Myelogenous Leukemia • B Acute Lymphoblastic Leukemia • Myelodysplastic Syndrome • Myeloproliferative Neoplasm

New Analyses from the Precision-T Phase 3 Study (Businesswire) - "An observational analysis compared a dataset derived from patients who received Orca-T in the Precision-T Phase 3 study (n=45) to a historical PTCy patient cohort (n=475) derived from the Center for International Blood and Marrow Transplant Research (CIBMTR). At one year, OS was 94% with Orca-T compared to 81% with PTCy. RFS was 86% and 70% for Orca-T and PTCy, respectively. There was 0% NRM with Orca-T and 9.7% with PTCy, which achieved statistical significance. There was 13.8% relapse in the Orca-T cohort and 21% in the PTCy cohort."

Observational data • Acute Myelogenous Leukemia • B Acute Lymphoblastic Leukemia • Myelodysplastic Syndrome • Myeloproliferative Neoplasm

Optimizing Outcomes with Myeloablative Conditioning in Older Patients: Efficacy and Safety of Precision Engineered Orca-T in Patients > 55 Years Old with Hematologic Malignancies (ASH 2023) - P1 | "Patients received a myeloablative regimen consisting of intravenous busulfan, fludarabine, and thiotepa (BFT) prior to Orca-T, followed by single-agent GvHD prophylaxis with tacrolimus, and had an 8/8 related or unrelated matched donor. Remarkably, non-relapse mortality was zero at 1 year with excellent overall survival , suggesting that this regimen could potentially improve outcomes for older patients. An ongoing Phase 3 trial evaluating Orca-T vs. standard of care is currently enrolling throughout the United States."

Clinical • Acute Graft versus Host Disease • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Chronic Myeloid Leukemia • Graft versus Host Disease • Hematological Malignancies • Immunology • Leukemia • Mucositis • Myelodysplastic Syndrome • Myelofibrosis • Oncology • Transplantation • HLA-DRB1

Phase 1 Trial Results for Patients with Advanced Hematologic Malignancies Undergoing Reduced Intensity Allogeneic HCT with Orca-T Donor Cell Therapy Product and Single Agent Tacrolimus (ASH 2023) - "The first 11 patients on this arm were conditioned with fludarabine 40mg/m2, melphalan 50 mg/m2 and 4 Gy of total body irradiation (TBI), an additional 4 patients have been treated with thiotepa 10 mg/kg replacing the melphalan. These early results demonstrate that Orca-T is a safe and feasible transplant strategy in the RIC setting for patients with advanced hematological malignancies. Patients showed robust and early donor myeloid and eventual full donor T cell engraftment. The low incidence of acute and chronic GVHD with low rates of disease relapse, suggest retention of graft versus leukemia effect."

Clinical • Metastases • P1 data • Acute Graft versus Host Disease • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Chronic Graft versus Host Disease • Graft versus Host Disease • Hematological Malignancies • Hepatology • Immunology • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology • Transplantation

Observational Comparison of Overall Survival between Phase 1b Orca-T and Registry-Based Post-Transplant Cyclophosphamide Patients (ASH 2024) - P1 | "Additional inclusion criteria for the Ph1b' cohort were treatment between 2019-2024 and use of Bu/Flu/TT, TBI/Cy, or TBI/etoposide MAC regimen, consistent with the phase 3 protocol. Further analysis is needed to identify the specific clinical factors such as infection, relapse and organ toxicity including cardiotoxicity that may account for the differences in OS. A phase 3 prospectively randomized trial comparing Orca-T to Tac/MTX pharmacological GvHD control recently completed enrollment."

Clinical • P1 data • Post-transplantation • Bone Marrow Transplantation • Cardiovascular • Graft versus Host Disease • Hematological Malignancies • Immunology • Infectious Disease • Oncology • Transplantation

Kidney Function after Hematopoietic Cell Transplantation with Orca-T, Cyclophosphamide or Methotrexate GvHD Prophylaxis: a single-center retrospective study. (PubMed, Transplant Cell Ther) - No abstract available

Journal • Retrospective data • Graft versus Host Disease • Immunology • Transplantation

Preliminary Safety and Efficacy of Myeloablative Orca-Q with No GvHD Prophylaxis for Treatment of Advanced Hematologic Malignancies (ASH 2024) - P1 | "Prevention of GvHD after alloHSCT routinely necessitates multi-agent immunosuppression consisting of either methotrexate or post-transplant cyclophosphamide (PTCy) combined with a calcineurin inhibitor and additional drugs...All patients received myeloablative conditioning, either busulfan/fludarabine/thiotepa (BFT; n=11) or total body irradiation-based (TBI; n=3)...One patient received TBI/etoposide and experienced grade 3 aGvHD that was treated to resolution...BFT conditioning has shown promising disease control with Orca-T (Salhotra et al...Disease control may be further augmented by BFT conditioning. The Orca-Q Phase 1 study continues to enroll patients across the US."

Clinical • Metastases • Acute Graft versus Host Disease • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Chronic Graft versus Host Disease • Chronic Lymphocytic Leukemia • Chronic Myeloid Leukemia • Graft versus Host Disease • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • Myelofibrosis • Oncology • HLA-B • HLA-C • HLA-DRB1

Safety and Efficacy of Orca-Q with Haploidentical Donors for the Treatment of Advanced Hematologic Malignancies without the Use of Post-Transplant Cyclophosphamide (ASH 2023) - P1 | "RESULTS Orca-Q was successfully manufactured and delivered to all subjects with a vein-to-vein time (time between end of donor apheresis to start of recipient's Orca-T infusion) of < 72 hours...Sixteen patients received TBI-based MAC; 17 received busulfan-based MAC (Table)...With median follow-up of approximately 1 year, no patients experienced moderate or severe cGvHD, the low AE profile in the haplo setting remains favorable, and 1 year GvHD-free, relapse-free survival of 83% is very encouraging. This phase 1 study continues to enroll patients across the US."

Clinical • Metastases • Post-transplantation • Acute Graft versus Host Disease • Cardiovascular • Chronic Graft versus Host Disease • Graft versus Host Disease • Hematological Malignancies • Immunology • Infectious Disease • Mucositis • Oncology • Transplantation • CD34 • HLA-DRB1

Kidney Function After Allogeneic Hematopoietic Cell Transplantation in Patients Treated with Orca-T Cell Therapy, Post-Transplant Cyclophosphamide, or Methotrexate Graft vs. Host Disease Prophylaxis (KIDNEY WEEK 2025) - "Conclusion In the one year following alloHCT, patients experienced substantial eGFR decline. ORCA-T shows potential as a therapy to slow the decline in eGFR compared with methotrexate and PTCy."

Clinical • Post-transplantation • Acute Graft versus Host Disease • Chronic Graft versus Host Disease • Graft versus Host Disease • Immunology • Transplantation

Safe and Effective Combination of Donor-Derived, Allogeneic CD19/CD22-CAR T Cells with Myeloablative Graft-Engineered Allo-HCT for High-Risk B-ALL (ASH 2024) - P1 | "Myeloablative conditioning with cyclophosphamide and total body irradiation precede infusion of investigational Orca-T, which consists of infusions of HSPCs and Tregs on Day 0 and an infusion of T conventional (Tcon) cells on Day 2. This paradigm shifting combination of allogeneic CAR T and allo-HCT resulted in 100% MRD- CR with full donor chimerism but without GVHD or severe CAR-mediated toxicity. These data, which demonstrate antigen-specific anti-tumor benefit of allogeneic CAR T cells in combination with GVHD prophylaxis mediated by Tregs and tacrolimus, have potential implications that could benefit patients with other hematologic diseases."

CAR T-Cell Therapy • IO biomarker • Acute Graft versus Host Disease • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Chronic Graft versus Host Disease • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Oncology • ABL1 • CD22 • TP53

732. Allogeneic Transplantation: Disease Response and Comparative Treatment Studies: Finding the Ideal Donor and Graft: Going Beyond HLA (ASH 2024) - "The studies include optimizing donor selection using new molecular techniques, comparing outcomes between MMUD and MUD, investigating whether the probability of finding an 8/8 MUD affects prognosis, examining the impact of Orca-T infusion on post-transplant outcomes, and conducting an RCT comparing peripheral blood plus cord blood or bone marrow in Haplo-HSCT. Through this section, we hope clinicians can choose the most suitable donors and grafts from the currently available multiple donor options for each patient."

Bone Marrow Transplantation • Transplantation

High Disease-Free Survival in Patients with High-Risk MDS Treated with Orca-T (ASH 2023) - P3 | "Patients received a busulfan-based myeloablative chemotherapy regimen prior to Orca-T, followed by single-agent GvHD prophylaxis with tacrolimus. CONCLUSIONS Orca-T demonstrated promising results in this HR-MDS patient population, including high RFS, low incidence of GvHD, and very high OS at 1 year. A randomized controlled phase 3 multi-center trial comparing Orca-T to SOC in patients with MDS, AML, and ALL is currently enrolling across the US (NCT05316701)."

Clinical • Acute Graft versus Host Disease • Acute Myelogenous Leukemia • Chronic Graft versus Host Disease • Graft versus Host Disease • Hematological Malignancies • Immunology • Myelodysplastic Syndrome • Oncology • TP53

Orca Bio to Present New Clinical Data on Its High-Precision Cell Therapies at the 67th American Society of Hematology Annual Meeting (Businesswire) - "New data evaluating Orca-T with reduced intensity conditioning for the treatment of hematological malignancies in patients 60 to 75 years of age; Clinical findings of Orca-Q with and without the use of GvHD prophylaxis in patients with hematological malignancies including AML, ALL and MDS; Expanded feasibility data on the combination of Orca-T and an allogeneic CAR-T (OrCAR-T) in patients with high-risk B-ALL; Additional presentations will highlight overall survival and non-relapse mortality with Orca-T versus PTCy, and additional subsets from the pivotal Phase 3 study including relapse-free survival and patient-reported outcomes....Orca-T is currently under Priority Review with the FDA with a PDUFA target action date of April 6, 2026."

Clinical data • PDUFA • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • B Acute Lymphoblastic Leukemia • Myelodysplastic Syndrome

Reduced Intensity or Nonmyeloablative Conditioning With Orca-T for Acute Myelogenous Leukemia and Myelodysplastic Syndrome (clinicaltrials.gov) - P2 | N=80 | Recruiting | Sponsor: Orca Biosystems, Inc.

New P2 trial • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation

Orca Bio Announces FDA Acceptance and Priority Review of the Biologics License Application (BLA) for Orca-T to Treat Hematological Malignancies (Businesswire) - "The FDA granted the BLA Priority Review with a Prescription Drug User Fee Act (PDUFA) target action date of April 6, 2026....The BLA submission for Orca-T is supported by positive results from the pivotal Phase 3 study, Precision-T (NCT04013685), a randomized, open-label multi-center study that evaluated the safety, efficacy and tolerability of Orca-T compared to conventional allogeneic hematopoietic stem cell transplant (alloHSCT) in patients with AML, ALL and MDS."

FDA filing • PDUFA • Priority review • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Myelodysplastic Syndrome