Tudriqev
vusolimogene oderparepvec
Sources:FDA summary basis for approval ↗
Species
RatMouse
Longest study
26 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Tumor-bearing immunocompetent mice (TUDRIQEV, mRP1) and healthy rats (murine surrogate mRP1)
“Toxicology studies evaluating TUDRIQEV and mRP1 were conducted in tumor-bearing immunocompetent mice and healthy rats, respectively.”
Why that species
Not stated in public reviews
The reviews list the species but not why. For biologics, ICH S6(R1) asks for species in which the product is pharmacologically active (target binding and activity), usually a cynomolgus monkey.
“A relevant species is one in which the test material is pharmacologically active due to the expression of the receptor or an epitope (in the case of monoclonal antibodies).”
✓ VerifiedICH 2011: ICH S6(R1): Preclinical Safety Evaluation of Biotechnology-Derived…, p. 7Source ↗
Surrogate molecule
Yes: mRP1, identical to clinical product except murine GM-CSF replaces human GM-CSF
“a murine surrogate product, mRP1 (identical to TUDRIQEV, except that human GM-CSF is replaced by murine GM-CSF)”
Species: general tox
Healthy rats (murine surrogate mRP1) and tumor-bearing immunocompetent mice (TUDRIQEV)
“Toxicology studies evaluating TUDRIQEV and mRP1 were conducted in tumor-bearing immunocompetent mice and healthy rats, respectively.”
Species: DART
Pregnant rat (repeat IV mRP1, GD 4 to 16, embryofetal)
“Developmental and reproductive toxicology studies were conducted in pregnant rats following repeat IV administrations of between 9x104 - 1x106 PFU mRP1/animal/injection over gestation days (GD) 4 to 16 corresponding to early- and mid-organogenesis.”
Species: carcinogenicity
Not conducted (not warranted based on product characteristics and safety profile)
“Studies to evaluate the safety pharmacology, genotoxicity, and carcinogenicity of TUDRIQEV were not conducted. These studies are not warranted based on the product characteristics and safety profile.”
Surrogate used in
Yes: murine surrogate mRP1 (murine GM-CSF in place of human GM-CSF) for in vivo pharmacology
“In vivo pharmacology studies were conducted with a murine surrogate product, mRP1 (identical to TUDRIQEV, except that human GM-CSF is replaced by murine GM-CSF)”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“No adverse findings were observed up to 6 months following repeat administration of mRP1 (16 total doses; up to 1x106 PFU/animal/injection) in healthy rats.”
Pivotal GLP studies
Single and repeat-dose mRP1 studies in healthy rats (16 doses, 6-month follow-up); repeat IT TUDRIQEV in tumor-bearing mice (5 doses)
“Toxicology studies evaluating TUDRIQEV and mRP1 were conducted in tumor-bearing immunocompetent mice and healthy rats, respectively.”
Route in tox
Intratumoral (mice) and intravenous/other routes (rats); IV in embryofetal study
“Repeat IT administration of TUDRIQEV batches manufactured at two different sites”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (not warranted based on product characteristics and safety profile)
“Studies to evaluate the safety pharmacology, genotoxicity, and carcinogenicity of TUDRIQEV were not conducted.”
Carcinogenicity
Not conducted (not warranted)
“Studies to evaluate the safety pharmacology, genotoxicity, and carcinogenicity of TUDRIQEV were not conducted.”
Reproductive & developmental
Embryofetal study in pregnant rats (mRP1 IV, GD 4-16): no malformations or growth effects; minimal placental transfer
“no embryofetal structural abnormalities or adverse effects on embryofetal growth were observed following repeat IV mRP1 administration.”
Safety pharmacology
Not conducted (not warranted)
“Studies to evaluate the safety pharmacology, genotoxicity, and carcinogenicity of TUDRIQEV were not conducted.”
Genotox: Ames
Not conducted (not warranted)
“Studies to evaluate the safety pharmacology, genotoxicity, and carcinogenicity of TUDRIQEV were not conducted. These studies are not warranted based on the product characteristics and safety profile.”
Genotox: in vitro mammalian
Not conducted (not warranted)
“Studies to evaluate the safety pharmacology, genotoxicity, and carcinogenicity of TUDRIQEV were not conducted. These studies are not warranted based on the product characteristics and safety profile.”
Genotox: in vivo
Not conducted (not warranted)
“Studies to evaluate the safety pharmacology, genotoxicity, and carcinogenicity of TUDRIQEV were not conducted. These studies are not warranted based on the product characteristics and safety profile.”
Carcinogenicity model
Not conducted (not warranted based on product characteristics and safety profile)
“Studies to evaluate the safety pharmacology, genotoxicity, and carcinogenicity of TUDRIQEV were not conducted. These studies are not warranted based on the product characteristics and safety profile.”
Carcinogenicity timing
Not required (not warranted based on product characteristics and safety profile)
“Studies to evaluate the safety pharmacology, genotoxicity, and carcinogenicity of TUDRIQEV were not conducted. These studies are not warranted based on the product characteristics and safety profile.”
hERG / QT
Not conducted (safety pharmacology not warranted)
“Studies to evaluate the safety pharmacology, genotoxicity, and carcinogenicity of TUDRIQEV were not 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 Tudriqev 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 gene 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: NOAEL = highest dose tested of mRP1 in rats, 1x10^7 PFU/animal/injection; no adverse findings (FDA summary basis for approval, p. 13)
NOAEL / key findings
NOAEL = highest dose tested of mRP1 in rats, 1x10^7 PFU/animal/injection; no adverse findings
“was 1x107 plaque-forming units (PFU)/animal/injection, which was the determined no-observed-adverse-effect level for all studies.”
Risksopen answer page →
Immune & cytokine safety
No test-article-related adverse findings in tumor-bearing mice; RNAseq showed immune infiltration/inflammation genes in injected tumors
“showed increased expression of genes associated with immune cell infiltration and inflammation in injected tumors compared to non-injected tumors”
Biodistribution & persistence
Viral genomes mainly at injection site; mRP1 DNA in blood, organs, ovaries, neural tissue in rats to Day 71; no latency/reactivation at 6 months
“viral genomes were predominantly present at the injection sites (i.e., tumor), irrespective of the route of administration.”
Modality-specific risk
HSV-1 latency/reactivation, neural tissue distribution and viral shedding; minimal risk seen at 6 months
“indicating minimal risk of latency and reactivation of mRP1.”
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
- Accidental Exposure
- Herpetic Infection or Reactivation
- Injection Procedure Complications
- Immune-Mediated Events
InfectionsImmune-mediated reactions
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 Tudriqev 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 gene 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: NOAEL = highest dose tested of mRP1 in rats, 1x10^7 PFU/animal/injection; no adverse findings (FDA summary basis for approval, p. 13)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
Rat repeat-dose mRP1 study (16 doses every 3 days for 7 weeks) with follow-up up to 6 months after final dose
“In a follow-up study, 16 doses (every 3 days for 7 weeks) of mRP1 were administered to healthy rats. mRP1 DNA was not detected in any neurologic tissues and there was no evidence of viral reactivation at any time point up to 6 months post-final dosing, indicating minimal risk of latency and reactivation of mRP1.”
Pivotal GLP studies
Single and repeat-dose mRP1 studies in healthy rats (16 doses, 6-month follow-up); repeat IT TUDRIQEV in tumor-bearing mice (5 doses)
“Toxicology studies evaluating TUDRIQEV and mRP1 were conducted in tumor-bearing immunocompetent mice and healthy rats, respectively.”
DART package
Species: DART
Pregnant rat (repeat IV mRP1, GD 4 to 16, embryofetal)
“Developmental and reproductive toxicology studies were conducted in pregnant rats following repeat IV administrations of between 9x104 - 1x106 PFU mRP1/animal/injection over gestation days (GD) 4 to 16 corresponding to early- and mid-organogenesis.”
Reproductive & developmental
Embryofetal study in pregnant rats (mRP1 IV, GD 4-16): no malformations or growth effects; minimal placental transfer
“no embryofetal structural abnormalities or adverse effects on embryofetal growth were observed following repeat IV mRP1 administration.”
PPND / ePPND: when
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.
Carcinogenicity
Species: carcinogenicity
Not conducted (not warranted based on product characteristics and safety profile)
“Studies to evaluate the safety pharmacology, genotoxicity, and carcinogenicity of TUDRIQEV were not conducted. These studies are not warranted based on the product characteristics and safety profile.”
Carcinogenicity model
Not conducted (not warranted based on product characteristics and safety profile)
“Studies to evaluate the safety pharmacology, genotoxicity, and carcinogenicity of TUDRIQEV were not conducted. These studies are not warranted based on the product characteristics and safety profile.”
Carcinogenicity timing
Not required (not warranted based on product characteristics and safety profile)
“Studies to evaluate the safety pharmacology, genotoxicity, and carcinogenicity of TUDRIQEV were not conducted. 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
NOAEL = highest dose tested of mRP1 in rats, 1x10^7 PFU/animal/injection; no adverse findings
“was 1x107 plaque-forming units (PFU)/animal/injection, which was the determined no-observed-adverse-effect level for all studies.”
Efficacy evidenceopen answer page →
Efficacy evidence
Human tumor cell lines in vitro; murine surrogate mRP1 in syngeneic lymphoma, colorectal and melanoma tumor-bearing mice
“In vivo pharmacology studies were conducted with a murine surrogate product, mRP1 (identical to TUDRIQEV, except that human GM-CSF is replaced by murine GM-CSF) using syngeneic murine lymphoma, colorectal and melanoma tumor-bearing immunocompetent BALB/c or C57BL/6 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
Nonclinical data support accelerated approval in combination with nivolumab
“The nonclinical data provided in this BLA submission support the accelerated approval of TUDRIQEV in combination with nivolumab for the treatment of adult patients with unresectable advanced cutaneous melanoma”
Flexibilityopen answer page →
Flexibility accepted
OtherVerdict not stated
Rat toxicology, biodistribution and DART studies used the murine surrogate mRP1 (murine GM-CSF); clinical product tested only in tumor-bearing mice
“Toxicology studies evaluating TUDRIQEV and mRP1 were conducted in tumor-bearing immunocompetent mice and healthy rats, respectively.”
Safety pharmacologyAcceptedBeyond the letter
No safety pharmacology, genotoxicity or carcinogenicity studies
Why: Not warranted based on product characteristics and safety profile · Low-risk modality
“Studies to evaluate the safety pharmacology, genotoxicity, and carcinogenicity of TUDRIQEV were not conducted. These studies are not warranted based on the product characteristics and safety profile.”
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