Omisirge
omidubicel
Sources:FDA pharmacology/toxicology review ↗FDA summary basis for approval ↗US prescribing information ↗
Species
Mouse
Longest study
12 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Immunodeficient irradiated NOD/SCID mouse only (xenogeneic human cells)
“In vivo pharmacology, pharmacokinetic, and toxicology studies were conducted to evaluate the activity, distribution, and safety of the product in immunocompromised, irradiated mice.”
Why that species
NOD/SCID chosen for human cell engraftment over other strain in pilot; limited relevance to human homing
“Results showed that NOD/SCID mice were preferable over mice based on cell engraftment levels.”
Surrogate molecule
No surrogate; clinical-like human CF + NF cells tested in immunodeficient mice
“Like omidubicel-onlv, this test article consisted of cells that were expanded for with cytokines and NAM”
Species: general tox
Irradiated NOD/SCID mouse only (single-dose GLP toxicity study)
“The following toxicology study was conducted to evaluate the safety of the test article following administration in the NOD/SCID mouse.”
Species: DART
Not conducted; no reproductive organ findings in mouse toxicity study and conditioning regimen affects fertility
“Per the applicant, developmental and reproductive toxicology studies were not conducted because there were no test article-related toxicity findings in reproductive organs as assessed by histopathological analyses”
Species: carcinogenicity
Not conducted (not warranted based on product characteristics and safety profile)
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with omidubicel-onlv. These studies are not warranted based on the product characteristics and safety profile.”
Surrogate used in
No surrogate used; human CF + NF cells expanded with cytokines and NAM tested in mice
“Like omidubicel-onlv, this test article consisted of cells that were expanded for with cytokines and NAM”
Study lengthopen answer page →
Longest pivotal study
12 weeks
“Scheduled Sacrifice Time Points Day 1, Week 4, and Week 12 post-transplantation”
Pivotal GLP studies
One GLP single-dose IV toxicity/biodistribution study in irradiated NOD/SCID mice, sacrifices Day 1, Week 4, Week 12
“The following toxicology study was conducted to evaluate the safety of the test article following administration in the NOD/SCID mouse.”
Route in tox
Intravenous (tail vein), single infusion after total body irradiation
“NOD/SCID mice were administered the product via tail vein injection 24 hours after a TBI dose of 300 cGy according to the study groups below.”
Skipped studiesopen answer page →
Genotoxicity
No standard genotox; cytogenetic/karyotype analyses of CF and NF showed no clonal aneuploidy
“The genomic integrity was evaluated using cytogenic and karyotype analysis. Results showed no difference in the occurrence of chromosomal abnormalities between the CF, NF, and control cells and no evidence of clonal aneuploidy.”
Carcinogenicity
Not conducted (not warranted based on known safety profile)
“No carcinogenicity/tumorgenicity studies were conducted with the test article and were not warranted based on the known safety profile.”
Reproductive & developmental
Not conducted (no reproductive organ findings; conditioning regimen already affects fertility)
“Per the applicant, developmental and reproductive toxicology studies were not conducted because there were no test article-related toxicity findings in reproductive organs as assessed by histopathological analyses”
Safety pharmacology
Not conducted
“No safety pharmacology studies with omidubicel-onlv were conducted.”
Genotox: Ames
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.
Genotox: in vitro mammalian
Cytogenetic and karyotype analysis of CF and NF cells: no clonal aneuploidy, no difference from controls
“The genomic integrity was evaluated using cytogenic and karyotype analysis. Results showed no difference in the occurrence of chromosomal abnormalities between the CF, NF, and control cells and no evidence of clonal aneuploidy.”
Genotox: in vivo
Not conducted
“No in vivo carcinogenicity, mutagenicity and fertility studies were conducted to evaluate the effects of OMISIRGE.”
Carcinogenicity model
Not conducted (not warranted); single-dose mouse toxicity and genetic stability data showed no tumorigenic concern
“No carcinogenicity/tumorgenicity studies were conducted with the test article and were not warranted based on the known safety profile. Genetic stability and single-dose toxicity were assessed in Study No. 10 (GAM-066-AIT-BIO) and did not reveal specific tumorigenic or oncogenic concerns.”
Carcinogenicity timing
Not required: not warranted based on product characteristics and safety profile
“No carcinogenicity or reproductive and developmental toxicity studies were conducted with OMISIRGE. These studies are not warranted based on the product characteristics and safety profile.”
hERG / QT
Not conducted (no safety pharmacology studies)
“No safety pharmacology studies with omidubicel-onlv were conducted.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Omisirge don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for cell therapies
FDA expects preclinical proof-of-concept and toxicology studies to identify active dose levels and support the choice of starting dose and escalation. The 2013 guidance gives no numeric formula or scaling rule for the starting dose.
“Selection of potential starting dose level, dose-escalation schedule, and dosing regimen for clinical trials.”
✓ VerifiedFDA 2013: Preclinical Assessment of Investigational Cellular and Gene Therapy…, p. 7Source ↗
This product's starting point
NOAEL / key findings: No NOAEL stated; no test article-related adverse effects at up to 10x10^6 CF + 5x10^6 NF cells/mouse; deaths attributed to irradiation (FDA pharmacology/toxicology review, p. 28)
NOAEL / key findings
No NOAEL stated; no test article-related adverse effects at up to 10x10^6 CF + 5x10^6 NF cells/mouse; deaths attributed to irradiation
“No test article-related adverse effects were observed in body weights, food consumption, clinical pathology, or histopathology assessments.”
Risksopen answer page →
Immune & cytokine safety
Not assessed nonclinically (immunodeficient model); clinically GvHD dose-safety relationship flat
“The dose-safety relationship is essentially flat suggesting that an increase in dose did not result in an increase in adverse events of interest such as aGvHD and cGvHD.”
Biodistribution & persistence
GLP mouse qPCR: human DNA in all tissues through Week 12, highest femur, spleen, lung, liver, kidney
“At Week 12, relatively high quantities of human DNA were found in femur, spleen, lung, liver, and kidney in the high dose group.”
Modality-specific risk
Genomic instability/tumorigenicity of ex vivo expanded HPCs; engraftment efficacy
“This study indicates that the CF manufacturing procedure, including NAM culture, does not appear to generate chromosomal abnormalities in the regions analyzed when compared to unmanipulated UCB.”
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
Boxed warning: GRAFT VERSUS HOST DISEASE, INFUSION REACTIONS, AUTOIMMUNE CYTOPENIAS, GRAFT FAILURE, and ENGRAFTMENT SYNDROME
- Graft-versus-Host Disease
- Hypersensitivity and Infusion-Related Reactions
- Autoimmune Cytopenias
- Graft Failure
- Malignancies of Donor Origin
- Engraftment Syndrome
- Transmission of Serious Infections
- Transmission of Rare Genetic Diseases
CytopeniasHypersensitivity & infusion reactionsImmune-mediated reactionsSecondary malignancyInfections
US prescribing information, Boxed Warning and 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
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.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Omisirge don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for cell therapies
FDA expects preclinical proof-of-concept and toxicology studies to identify active dose levels and support the choice of starting dose and escalation. The 2013 guidance gives no numeric formula or scaling rule for the starting dose.
“Selection of potential starting dose level, dose-escalation schedule, and dosing regimen for clinical trials.”
✓ VerifiedFDA 2013: Preclinical Assessment of Investigational Cellular and Gene Therapy…, p. 7Source ↗
This product's starting point
NOAEL / key findings: No NOAEL stated; no test article-related adverse effects at up to 10x10^6 CF + 5x10^6 NF cells/mouse; deaths attributed to irradiation (FDA pharmacology/toxicology review, p. 28)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (single IV infusion in irradiated NOD/SCID mice)
“To assess the safety of the CF + NF cells following a single intravenous infusion into irradiated NOD-SCID mice.”
Pivotal GLP studies
One GLP single-dose IV toxicity/biodistribution study in irradiated NOD/SCID mice, sacrifices Day 1, Week 4, Week 12
“The following toxicology study was conducted to evaluate the safety of the test article following administration in the NOD/SCID mouse.”
DART package
Species: DART
Not conducted; no reproductive organ findings in mouse toxicity study and conditioning regimen affects fertility
“Per the applicant, developmental and reproductive toxicology studies were not conducted because there were no test article-related toxicity findings in reproductive organs as assessed by histopathological analyses”
Reproductive & developmental
Not conducted (no reproductive organ findings; conditioning regimen already affects fertility)
“Per the applicant, developmental and reproductive toxicology studies were not conducted because there were no test article-related toxicity findings in reproductive organs as assessed by histopathological analyses”
PPND / ePPND: when
Not conducted: no reproductive organ findings in mouse toxicity study; conditioning regimen already affects fertility
“Per the applicant, developmental and reproductive toxicology studies were not conducted because there were no test article-related toxicity findings in reproductive organs as assessed by histopathological analyses”
Carcinogenicity
Species: carcinogenicity
Not conducted (not warranted based on product characteristics and safety profile)
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with omidubicel-onlv. These studies are not warranted based on the product characteristics and safety profile.”
Carcinogenicity model
Not conducted (not warranted); single-dose mouse toxicity and genetic stability data showed no tumorigenic concern
“No carcinogenicity/tumorgenicity studies were conducted with the test article and were not warranted based on the known safety profile. Genetic stability and single-dose toxicity were assessed in Study No. 10 (GAM-066-AIT-BIO) and did not reveal specific tumorigenic or oncogenic concerns.”
Carcinogenicity timing
Not required: not warranted based on product characteristics and safety profile
“No carcinogenicity or reproductive and developmental toxicity studies were conducted with OMISIRGE. These studies are not warranted based on the product characteristics 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 stated; no test article-related adverse effects at up to 10x10^6 CF + 5x10^6 NF cells/mouse; deaths attributed to irradiation
“No test article-related adverse effects were observed in body weights, food consumption, clinical pathology, or histopathology assessments.”
Efficacy evidenceopen answer page →
Efficacy evidence
Human bone marrow engraftment of NAM-cultured cord blood cells in irradiated NOD/SCID mice; in vitro migration and phenotype assays
“Studies evaluating cells cultured with NAM and cytokines in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice at 1.2 x 106 to 1 x 107 cells/mouse (approximately 4.8 x 107 to 4 x 108 cells/kg) showed an increased overall engraftment”
Why that model
NOD/SCID chosen over another strain based on human cell engraftment levels in a pilot study
“Results showed that NOD/SCID mice were preferable over mice based on cell engraftment levels.”
Reviewer's view of the efficacy data
Engraftment claims unsubstantiated: the >0.5% human-cell cutoff was not validated; NOD/SCID not expected to mimic human homing
“However, data was not provided to confirm the validity of the cutoff limit of >0.5%, therefore the claims of “engraftment” are unsubstantiated.”
Flexibilityopen answer page →
Flexibility accepted
GLPCriticised but acceptedBeyond the letter
In vivo studies described as GLP lacked QA statements, facility information and deviation reports
“The applicant states that some of their in vivo studies were conducted under GLP conditions. However, in these study reports, there are missing pieces of information that should be part of any GLP-compliant study.”
“There are no nonclinical deficiencies identified in this submission.”
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity or tumorigenicity studies; genetic stability and single-dose toxicity used instead
Why: Not warranted given product characteristics and known safety profile; genetic stability and single-dose toxicity showed no tumorigenic concern · Weight of evidence · Other reason
“No carcinogenicity/tumorgenicity studies were conducted with the test article and were not warranted based on the known safety profile. Genetic stability and single-dose toxicity were assessed in Study No. 10 (GAM-066-AIT-BIO) and did not reveal specific tumorigenic or oncogenic concerns.”
“No carcinogenicity or reproductive and developmental toxicity studies were conducted with OMISIRGE. These studies are not warranted based on the product characteristics and safety profile.”
DARTAcceptedBeyond the letter
No developmental and reproductive toxicity studies
Why: No reproductive organ findings in mouse toxicity study; not warranted given product characteristics and safety profile · Weight of evidence · Other reason
“Per the applicant, developmental and reproductive toxicology studies were not conducted because there were no test article-related toxicity findings in reproductive organs as assessed by histopathological analyses performed on male and female mice in Study No. 14 (GAM-066-AIT-BIO).”
“No carcinogenicity or reproductive and developmental toxicity studies were conducted with OMISIRGE. These studies are not warranted based on the product characteristics and safety profile.”
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