Tregzi
allogeneic Treg immunotherapy with HSPC and T cells (Orca-T)
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).”
Study lengthopen answer page →
Longest pivotal study
Not stated in public reviews
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.”
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.”
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.”