Rethymic
allogeneic processed thymus tissue
Sources:FDA pharmacology/toxicology review ↗FDA summary basis for approval ↗US prescribing information ↗
Species
no relevantRat
Longest study
39 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
No relevant species; nude rat pharmacology studies only, no tox
“Based on the acceptable clinical safety profile of RVT-802 and the lack of relevant animal species/models, no nonclinical toxicology studies with RVT-802 were performed.”
Why that species
Nude rats used to model engraftment and thymopoiesis of allogeneic thymus; no relevant tox species
“Studies were conducted in nude rats to to identify potentially optimal culture conditions of allogeneic neonatal thymus that result in engraftment and development of an endogenous T cell population”
Surrogate molecule
No surrogate; human product tested in athymic nude rats (pharmacology only)
“Allogeneic Thymus Transplantation in Nude Rats RVT-802-001”
Species: general tox
None; no toxicology studies (no relevant animal species/models)
“Based on the acceptable clinical safety profile of RVT-802 and the lack of relevant animal species/models, no nonclinical toxicology studies with RVT-802 were performed.”
Species: DART
Not conducted; published mouse thymectomy literature reviewed instead
“No DART studies were conducted. To assess the DART potential of RVT-802, the applicant examined published assessments of DART outcomes in mice following thymectomy.”
Species: carcinogenicity
Not conducted; published mouse thymus-transplant literature reviewed instead
“No carcinogenicity/tumorigenicity studies were conducted. To assess the carcinogenicity/tumorigenicity potential of RVT-802, the applicant examined published assessments of carcinogenicity outcomes in mice following thymus transplantation.”
Surrogate used in
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.
Study lengthopen answer page →
Longest pivotal study
39 weeks
“thymopoiesis was observed at the pre-specified time points (1 and 9 months”
Pivotal GLP studies
No toxicology studies; pharmacology only (in vitro thymus organ culture, nude rat transplants to 9 months)
“no nonclinical toxicology studies with RVT-802 were conducted.”
Route in tox
Implantation (nude rat; clinical use is quadriceps muscle implant)
“RVT-802 is surgically implanted into the quadriceps muscle.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted
“No genotoxicity studies were conducted.”
Carcinogenicity
Not conducted; published mouse thymus-transplant literature reviewed
“No carcinogenicity/tumorigenicity studies were conducted.”
Instead of genotoxicity
Not applicable: cells not genetically modified
“No in vitro or in vivo genotoxicity, carcinogenicity, or developmental and reproductive toxicity (DART) studies were conducted with RVT-802.”
Reproductive & developmental
Not conducted; published thymectomy literature suggests minimal risk
“No DART studies were conducted.”
Safety pharmacology
Not conducted
“No safety pharmacology studies were conducted.”
Genotox: Ames
Not conducted
“No in vitro or in vivo genotoxicity, carcinogenicity, or developmental and reproductive toxicity (DART) studies were conducted with RVT-802.”
Genotox: in vitro mammalian
Not conducted
“No in vitro or in vivo genotoxicity, carcinogenicity, or developmental and reproductive toxicity (DART) studies were conducted with RVT-802.”
Genotox: in vivo
Not conducted
“No in vitro or in vivo genotoxicity, carcinogenicity, or developmental and reproductive toxicity (DART) studies were conducted with RVT-802.”
Carcinogenicity model
Not conducted; literature on thymus transplantation in tumor-bearing mice reviewed; risk considered minimal
“Although the thymus products administered were not identical to RVT-802 and the studies were conducted in tumor-bearing mice (which does not reflect the clinical scenario), these data combined with the existing clinical safety data for RVT-802, indicate that the risk of carcinogenicity after RVT-802 transplantation in humans appears to be minimal.”
Carcinogenicity timing
Not required: carcinogenicity studies not conducted and not indicated
“In vitro or in vivo genotoxicity, carcinogenicity, or developmental and reproductive toxicity studies were not conducted with RETHYMIC, nor were they indicated.”
hERG / QT
Not conducted (no safety pharmacology studies)
“No safety pharmacology studies 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 Rethymic 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; no toxicology studies; dose range from clinical use (FDA pharmacology/toxicology review, p. 2)
NOAEL / key findings
No NOAEL; no toxicology studies; dose range from clinical use
“The recommended dose range is to 22,000 mm2”
Risksopen answer page →
Immune & cytokine safety
Donor-derived T cells declined as endogenous recipient T cells developed in rats; no dedicated immunotoxicity study
“there was a time-dependent decrease in donor-derived T cells in the peripheral blood as the endogenous T cell population developed.”
Biodistribution & persistence
No cell distribution studies conducted
“No cell distribution studies were conducted.”
Modality-specific risk
Alloreactivity and tumorigenicity risk assessed only through literature; considered minimal
“these data combined with the existing clinical safety data for RVT-802, indicate that the risk of carcinogenicity after RVT-802 transplantation in humans appears to be minimal.”
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
- Infection Control and Immunoprophylaxis
- Graft versus Host Disease
- Autoimmune Disorders
- Renal Impairment
- Cytomegalovirus Infection
- Malignancy
- Transmission of Serious Infections and Transmissible Infectious Diseases
- Vaccine Administration
- Anti-HLA Antibodies
- HLA Typing
InfectionsImmune-mediated reactionsNephrotoxicitySecondary 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
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 Rethymic 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; no toxicology studies; dose range from clinical use (FDA pharmacology/toxicology review, p. 2)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (no nonclinical toxicology studies conducted)
“Per the applicant, based on the acceptable clinical safety profile of RVT-802 and the lack of relevant animal models, no nonclinical toxicology studies with RVT-802 were conducted.”
Pivotal GLP studies
No toxicology studies; pharmacology only (in vitro thymus organ culture, nude rat transplants to 9 months)
“no nonclinical toxicology studies with RVT-802 were conducted.”
DART package
Species: DART
Not conducted; published mouse thymectomy literature reviewed instead
“No DART studies were conducted. To assess the DART potential of RVT-802, the applicant examined published assessments of DART outcomes in mice following thymectomy.”
Reproductive & developmental
Not conducted; published thymectomy literature suggests minimal risk
“No DART studies were conducted.”
PPND / ePPND: when
Not conducted and not indicated
“In vitro or in vivo genotoxicity, carcinogenicity, or developmental and reproductive toxicity studies were not conducted with RETHYMIC, nor were they indicated.”
Carcinogenicity
Species: carcinogenicity
Not conducted; published mouse thymus-transplant literature reviewed instead
“No carcinogenicity/tumorigenicity studies were conducted. To assess the carcinogenicity/tumorigenicity potential of RVT-802, the applicant examined published assessments of carcinogenicity outcomes in mice following thymus transplantation.”
Carcinogenicity model
Not conducted; literature on thymus transplantation in tumor-bearing mice reviewed; risk considered minimal
“Although the thymus products administered were not identical to RVT-802 and the studies were conducted in tumor-bearing mice (which does not reflect the clinical scenario), these data combined with the existing clinical safety data for RVT-802, indicate that the risk of carcinogenicity after RVT-802 transplantation in humans appears to be minimal.”
Carcinogenicity timing
Not required: carcinogenicity studies not conducted and not indicated
“In vitro or in vivo genotoxicity, carcinogenicity, or developmental and reproductive toxicity studies were not conducted with RETHYMIC, nor were they indicated.”
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 toxicology studies; dose range from clinical use
“The recommended dose range is to 22,000 mm2”
Efficacy evidenceopen answer page →
Efficacy evidence
Allogeneic neonatal thymus transplanted into nude rats (engraftment, endogenous T cell development)
“Studies were conducted in nude rats to to identify potentially optimal culture conditions of allogeneic neonatal thymus that result in engraftment and development of an endogenous T cell population (i.e., thymogenesis) following transplantation.”
Why that model
Lack of relevant animal species/models cited; no toxicology studies done
“Per the applicant, based on the acceptable clinical safety profile of RVT-802 and the lack of relevant animal models, no nonclinical toxicology studies with RVT-802 were conducted.”
Reviewer's view of the efficacy data
Supportive proof-of-concept only; studies not robust, so no Section 13.2 in label; data support approval
“Section 13.2 (‘Animal Toxicology and/or Pharmacology’) is not included in the label. However, this is appropriate because the data generated were primarily proof-of-concept data and the studies conducted were not robust in nature.”
Test articleopen answer page →
Test article vs clinical lot
Allogeneic neonatal thymus under candidate culture conditions, implanted in nude rats
“Animal studies were conducted in nude rats to identify potentially optimal culture conditions of allogeneic neonatal thymus that result in engraftment and development of an endogenous T cell population (i.e., thymogenesis) following transplantation.”
Genetically modified?
Allogeneic processed postnatal thymus tissue
“RVT-802 is an allogeneic, processed postnatal thymus tissue product that is administered via surgical implantation.”
First approval
Flexibilityopen answer page →
Flexibility accepted
SpeciesAccepted
No nonclinical toxicology studies: no relevant animal species or model
Why: Acceptable clinical safety profile; lack of relevant animal species or models · No relevant species · Within the guideline · Human data
“Based on the acceptable clinical safety profile of RVT-802 and the lack of relevant animal species/models, no nonclinical toxicology studies with RVT-802 were performed.”
“PHARMACOLOGY/TOXICOLOGY RECOMMENDATION: There were no nonclinical deficiencies identified in this submission.”
DARTAcceptedBeyond the letter
No DART studies; published mouse thymectomy literature used instead
Why: Published thymectomy and thymus-grafting data in mice indicate minimal DART risk · Weight of evidence
“While the thymus product administered is not identical to RVT-802, these data indicate that the risk of DART after RVT-802 transplantation in humans appears to be minimal.”
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity or tumorigenicity studies; published thymus-transplant studies in tumour-bearing mice used instead
Why: Published mouse data combined with existing clinical safety data indicate minimal risk · Weight of evidence · Human data
“Although the thymus products administered were not identical to RVT-802 and the studies were conducted in tumor-bearing mice (which does not reflect the clinical scenario), these data combined with the existing clinical safety data for RVT-802, indicate that the risk of carcinogenicity after RVT-802 transplantation in humans appears to be minimal.”
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