Tregzi
allogeneic Treg immunotherapy with HSPC and T cells (Orca-T)
Sources:FDA pharmacology/toxicology review ↗US prescribing information ↗FDA summary basis for approval ↗
Species
no relevantMouse
Longest study
n/a
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Partial / alternative Partly stated
Speciesopen answer page →
Species
No tox species; sublethally irradiated immunodeficient mice (xenogeneic GVHD proof-of-concept) plus published murine literature
“In the applicant’s POC studies using xenogeneic models, co-administration of human donor Tregs with Tcons demonstrated dose-dependent GVHD inhibition in sub-lethally irradiated immunodeficient mice.”
Why that species
Immunodeficient mice allow human Tcon-induced xenogeneic GVHD and Treg mitigation; no relevant tox species stated
“evaluating the ability of human Tcons to induce xenogeneic GVHD”
Surrogate molecule
Yes: published murine HSC, Treg, Tcon studies used as mechanism-of-action support; human cells tested in mouse xenograft
“Instead, in Module 4 of the BLA, the applicant submitted 45 publications delineating the MOAs of HSCs (mouse and human), Tregs (mouse), Tcons (mouse), and their combinations (mouse).”
Species: general tox
None; no toxicology studies
“No toxicology studies were conducted for TREGZI.”
Species: DART
Not conducted; not warranted based on product characteristics, biological activity and safety profile
“No genotoxicity, carcinogenicity, and developmental and reproductive toxicity (DART) studies were conducted for TREGZI. These studies are not warranted based on the product characteristics, biological activity, and safety profile.”
Species: carcinogenicity
Not conducted; not warranted
“No genotoxicity, carcinogenicity, and developmental and reproductive toxicity (DART) studies were conducted for TREGZI. These studies are not warranted based on the product characteristics, biological activity, and safety profile.”
Surrogate used in
Published murine HSC, Treg and Tcon studies (45 publications) supported mechanisms of action
“Instead, in Module 4 of the BLA, the applicant submitted 45 publications delineating the MOAs of HSCs (mouse and human), Tregs (mouse), Tcons (mouse), and their combinations (mouse).”
Study lengthopen answer page →
Longest pivotal study
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Pivotal GLP studies
No toxicology studies; xenogeneic GVHD POC study OBS-24-001 (18 studies, sublethally irradiated immunodeficient mice, human Tcons +/- Tregs)
“No toxicology studies were conducted for TREGZI.”
Route in tox
Intravenous (clinical; mouse POC IV)
“HSPC DP (dose level: ≥1.0 x106 viable HSPCs/kg per patient) followed by Treg DP (dose level range: x 106 to 3.5 x 106 viable Tregs/kg per patient) are intravenously (IV) administered on day 0”
Skipped studiesopen answer page →
Genotoxicity
Not conducted
“No nonclinical studies were conducted to evaluate genotoxicity of TREGZI.”
Carcinogenicity
Not conducted
“No nonclinical studies were performed to evaluate the effect of TREGZI on carcinogenesis, mutagenesis, or impairment of fertility.”
Instead of genotoxicity
Not applicable: cells not genetically modified
“No genotoxicity, carcinogenicity, and developmental and reproductive toxicity (DART) studies were conducted for TREGZI.”
Reproductive & developmental
Not conducted
“No animal reproductive and developmental toxicity studies have been conducted with TREGZI to assess whether it can cause fetal harm when administered to a pregnant woman.”
Safety pharmacology
Not conducted (omission acceptable given product characteristics and clinical safety data)
“No nonclinical studies were conducted to evaluate safety pharmacology of TREGZI.”
Genotox: Ames
Not conducted
“No nonclinical studies were conducted to evaluate genotoxicity of TREGZI. Given the characteristics and biological activity of TREGZI, together with the clinical safety data for TREGZI, this omission is acceptable.”
Genotox: in vitro mammalian
Not conducted
“No nonclinical studies were conducted to evaluate genotoxicity of TREGZI. Given the characteristics and biological activity of TREGZI, together with the clinical safety data for TREGZI, this omission is acceptable.”
Genotox: in vivo
Not conducted
“No nonclinical studies were conducted to evaluate genotoxicity of TREGZI. Given the characteristics and biological activity of TREGZI, together with the clinical safety data for TREGZI, this omission is acceptable.”
Carcinogenicity model
Not conducted; omission acceptable given product characteristics, biological activity and clinical safety data
“No nonclinical studies were conducted to evaluate carcinogenicity/tumorigenicity of TREGZI. Given the characteristics and biological activity of TREGZI, together with the clinical safety data for TREGZI, this omission is acceptable.”
Carcinogenicity timing
Not required (not warranted based on product characteristics, biological activity and safety profile)
“No genotoxicity, carcinogenicity, and developmental and reproductive toxicity (DART) studies were conducted for TREGZI. These studies are not warranted based on the product characteristics, biological activity, and safety profile.”
hERG / QT
Not conducted (no safety pharmacology studies; omission acceptable)
“No nonclinical studies were conducted to evaluate safety pharmacology of TREGZI. Given the characteristics and biological activity of TREGZI, together with the clinical safety data for TREGZI, this omission is acceptable.”
First doseopen answer page →
First-in-human starting dose
No nonclinical basis; Phase 1/2 clinical safety data with a similar product supported the Phase 1b dose levels
“This omission is acceptable, as the applicant provided safety data from a Phase 1/2 clinical study with a similar clinical product to support initiation of the Phase 1b study”
NOAEL / key findings
No NOAEL; no tox studies; in mice Tcons alone caused dose-dependent GVHD with T-cell infiltration of liver and intestine, attenuated by Tregs
“Histopathological examination revealed dose-dependent T cell infiltration in hepatic periportal regions and parenchyma, thickening of intestinal lamina propria, and atrophy of subcutaneous fat and hair follicles”
Risksopen answer page →
Immune & cytokine safety
Tregs suppress Tcon activation via contact and IL-2 inhibition; GVHD and weight loss in mice from Tcons; no cytokine release or immunotoxicity studies
“No safety/toxicology studies were conducted to assess additional safety endpoints, such as immunotoxicity and local tolerance, for TREGZI.”
Biodistribution & persistence
No cell distribution studies conducted
“No nonclinical studies were conducted to evaluate cell distribution of TREGZI.”
Modality-specific risk
GVHD from donor Tcons and preservation of graft-versus-leukemia; Treg:Tcon ratio and timing; leachables from bags
“Data from this study provided the scientific rationale for administering Tregs two days earlier than Tcons clinically.”
Anti-drug antibodies: animals
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Anti-drug antibodies: patients
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Label warnings
- Graft Failure
- Graft-Versus-Host Disease
- Infusion Reactions
- Secondary Malignancies and Malignancies of Donor Origin
- Transmission of Infectious Agents
Hypersensitivity & infusion reactionsSecondary malignancy
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
None; first clinical study supported by clinical safety data from a similar product instead of toxicology studies
“No toxicology studies were conducted for TREGZI. This omission is acceptable, as the applicant provided safety data from a Phase 1/2 clinical study with a similar clinical product to support initiation of the Phase 1b study”
First-in-human starting dose
No nonclinical basis; Phase 1/2 clinical safety data with a similar product supported the Phase 1b dose levels
“This omission is acceptable, as the applicant provided safety data from a Phase 1/2 clinical study with a similar clinical product to support initiation of the Phase 1b study”
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No toxicology studies (no repeat-dose study); clinical data from a similar product used instead
“No toxicology studies were conducted for TREGZI. This omission is acceptable, as the applicant provided safety data from a Phase 1/2 clinical study with a similar clinical product to support initiation of the Phase 1b study”
Pivotal GLP studies
No toxicology studies; xenogeneic GVHD POC study OBS-24-001 (18 studies, sublethally irradiated immunodeficient mice, human Tcons +/- Tregs)
“No toxicology studies were conducted for TREGZI.”
DART package
Species: DART
Not conducted; not warranted based on product characteristics, biological activity and safety profile
“No genotoxicity, carcinogenicity, and developmental and reproductive toxicity (DART) studies were conducted for TREGZI. These studies are not warranted based on the product characteristics, biological activity, and safety profile.”
Reproductive & developmental
Not conducted
“No animal reproductive and developmental toxicity studies have been conducted with TREGZI to assess whether it can cause fetal harm when administered to a pregnant woman.”
PPND / ePPND: when
No DART studies; not warranted based on product characteristics, biological activity and safety profile
“No genotoxicity, carcinogenicity, and developmental and reproductive toxicity (DART) studies were conducted for TREGZI. These studies are not warranted based on the product characteristics, biological activity, and safety profile.”
Carcinogenicity
Species: carcinogenicity
Not conducted; not warranted
“No genotoxicity, carcinogenicity, and developmental and reproductive toxicity (DART) studies were conducted for TREGZI. These studies are not warranted based on the product characteristics, biological activity, and safety profile.”
Carcinogenicity model
Not conducted; omission acceptable given product characteristics, biological activity and clinical safety data
“No nonclinical studies were conducted to evaluate carcinogenicity/tumorigenicity of TREGZI. Given the characteristics and biological activity of TREGZI, together with the clinical safety data for TREGZI, this omission is acceptable.”
Carcinogenicity timing
Not required (not warranted based on product characteristics, biological activity and safety profile)
“No genotoxicity, carcinogenicity, and developmental and reproductive toxicity (DART) studies were conducted for TREGZI. These studies are not warranted based on the product characteristics, biological activity, and safety profile.”
Safety marginopen answer page →
Safety margin at NOAEL
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
NOAEL / key findings
No NOAEL; no tox studies; in mice Tcons alone caused dose-dependent GVHD with T-cell infiltration of liver and intestine, attenuated by Tregs
“Histopathological examination revealed dose-dependent T cell infiltration in hepatic periportal regions and parenchyma, thickening of intestinal lamina propria, and atrophy of subcutaneous fat and hair follicles”
Efficacy evidenceopen answer page →
Efficacy evidence
Xenogeneic GVHD model in sub-lethally irradiated immunodeficient mice: human Tcons with human Tregs gave dose-dependent GVHD inhibition
“In the applicant’s POC studies using xenogeneic models, co-administration of human donor Tregs with Tcons demonstrated dose-dependent GVHD inhibition in sub-lethally irradiated immunodeficient mice.”
Why that model
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Reviewer's view of the efficacy data
FDA: reproducible murine GVHD model; Tregs showed clear dose-response in GVHD prevention, supporting therapeutic potential
“The Follow-on Study demonstrated that Tregs co-administered with Tcons exhibited a clear dose-response relationship in GVHD prevention by delaying disease onset, prolonging survival, and reducing tissue damage through suppression of inflammatory CD8⁺ T cell responses. Together, these studies supported the therapeutic potential of Tregs in preventing GVHD following administration of human HSPC and Tcons.”
Test articleopen answer page →
Test article vs clinical lot
Human Tregs and Tcons manufactured similarly to intended clinical DP lots. Bridging: Manufactured similarly to clinical lots; unclear dose basis limits comparison of biological activity with clinical doses
“Although the human Tregs and Tcons administered in the nonclinical studies were manufactured similarly to the intended clinical DP lots, this lack of clarity limits the ability to determine whether nonclinical dose levels (cells/mouse) reflect comparable biological activity to clinical Treg DP and Tcon DP dose levels in TREGZI.”
Genetically modified?
Allogeneic HSPC and T-cell immunotherapy
“TREGZI (Orca-T) is an allogeneic hematopoietic stem and progenitor cell (HSPC), and T-cell immunotherapy designed to improve survival free of cGVHD in adult patients with hematologic malignancies undergoing a myeloablative preparative regimen.”
First approval
2026 (FDA)
“Summary Basis for Regulatory Action Date: June 30, 2026”
Flexibilityopen answer page →
Flexibility accepted
OtherAcceptedBeyond the letter
No nonclinical toxicology studies; safety supported by clinical data with a similar cell product
Why: Clinical safety data from a study with a similar cell product · Human data
“No toxicology studies were conducted for TREGZI. This omission is acceptable, as the applicant provided safety data from a Phase 1/2 clinical study with a similar clinical product to support initiation of the Phase 1b study”
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity/tumorigenicity studies with the cell product
Why: Not warranted based on product characteristics, biological activity and safety profile · Other reason
“No nonclinical studies were conducted to evaluate carcinogenicity/tumorigenicity of TREGZI.”
“These studies are not warranted based on the product characteristics, biological activity, and safety profile.”
BiodistributionAcceptedBeyond the letter
No cell distribution studies
Why: Product characteristics and biological activity, together with clinical safety data · Human data
“No nonclinical studies were conducted to evaluate cell distribution of TREGZI. Given the characteristics and biological activity of TREGZI, together with the clinical safety data for TREGZI, this omission is acceptable.”
DARTAcceptedBeyond the letter
No developmental and reproductive toxicity studies
Why: Product characteristics and biological activity, together with clinical safety data · Human data
“DART Studies: No nonclinical studies were conducted to evaluate DART of TREGZI. Given the characteristics and biological activity TREGZI, together with the clinical safety data for TREGZI, this omission is acceptable.”
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