Papzimeos
zopapogene imadenovec
Species
MonkeyMouse
Longest study
3 wk
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
Mouse only (wild-type C57BL/6); no NHP studies
“The following toxicology study was conducted to evaluate the safety of PRGN-2012 following SC administration in WT mice.”
Why that species
Mouse used for immunogenicity/safety; reviewer notes murine antigen processing likely differs from human T-cell recognition
“The dose level assessed in this non-GLP toxicology study provides a 5-fold safety factor for the clinical dose level with the caveat that the processing and binding sequences in wildtype mice is likely different than the peptides recognized by human T cells .”
Surrogate molecule
No surrogate; nonclinical lot PRGN-2012 of clinical vector, differing only in scale and standardized manufacturing
“The differences made between PRGN-2012 nonclinical lot and PAPZIMEOS are scaling and the use of standardized manufacturing for PAPZIMEOS.”
Species: general tox
Wild-type mouse only
“The following toxicology study was conducted to evaluate the safety of PRGN-2012 following SC administration in WT mice.”
Species: DART
Not conducted (not warranted given product characteristics and nonclinical safety profile)
“No biodistribution (BD), genotoxicity, carcinogenicity, reproductive and developmental toxicity, juvenile, nor dedicated local tolerance studies of PRGN-2012 were conducted. These studies are not warranted based on the product characteristics and nonclinical safety profile of PRGN-2012.”
Species: carcinogenicity
Not conducted
“No biodistribution (BD), genotoxicity, carcinogenicity, reproductive and developmental toxicity, juvenile, nor dedicated local tolerance studies of PRGN-2012 were conducted.”
Surrogate used in
No surrogate used; research-grade PRGN-2012 identical in adenovirus and fusion protein to clinical product
“There are no differences between the adenovirus and fusion protein in PRGN-2012 compared to the clinical product, PAPZIMEOS.”
Study lengthopen answer page →
Longest pivotal study
3 weeks
“Dosing Regimen Once weekly for three weeks, a total of three administrations on Days 0,7, and 14 for all groups.”
Pivotal GLP studies
Single non-GLP repeat-dose SC mouse study (1x10^10 VP weekly x3, Days 0/7/14, sacrifice Day 21)
“GLP Status No”
Route in tox
Subcutaneous (clinical route)
“Route of Administration SC”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (non-integrating, replication-incompetent adenovector; no insertional mutagenesis)
“PRGN-2012 does not rely on host cell genome integration for expression of the transgene, thus, it has a reduced genotoxic risk and will not result in insertional mutagenesis or position-effect variation.”
Carcinogenicity
Not conducted (non-integrating adenovector; no significant human tumorigenicity history)
“Per the applicant, studies were not conducted to evaluate carcinogenicity as adenovectors are non-integrating. Therefore, the risk for insertional mutagenesis is not a major concern.”
Reproductive & developmental
Not conducted (predictable local adenovector biodistribution, species C-like vector); reviewer agreed
“This reviewer agrees with the rationale provided by the applicant for not conducting developmental and reproductive toxicology studies.”
Safety pharmacology
Not conducted
“Safety Pharmacology studies were not conducted.”
Genotox: Ames
Not conducted (not warranted given product characteristics)
“No biodistribution (BD), genotoxicity, carcinogenicity, reproductive and developmental toxicity, juvenile, nor dedicated local tolerance studies of PRGN-2012 were conducted. These studies are not warranted based on the product characteristics and nonclinical safety profile of PRGN-2012.”
Genotox: in vitro mammalian
Not conducted (not warranted given product characteristics)
“No biodistribution (BD), genotoxicity, carcinogenicity, reproductive and developmental toxicity, juvenile, nor dedicated local tolerance studies of PRGN-2012 were conducted. These studies are not warranted based on the product characteristics and nonclinical safety profile of PRGN-2012.”
Genotox: in vivo
Not conducted (not warranted given product characteristics)
“No biodistribution (BD), genotoxicity, carcinogenicity, reproductive and developmental toxicity, juvenile, nor dedicated local tolerance studies of PRGN-2012 were conducted. These studies are not warranted based on the product characteristics and nonclinical safety profile of PRGN-2012.”
Carcinogenicity model
Not conducted (adenovectors non-integrating; insertional mutagenesis not a major concern)
“Per the applicant, studies were not conducted to evaluate carcinogenicity as adenovectors are non-integrating. Therefore, the risk for insertional mutagenesis is not a major concern.”
Carcinogenicity timing
Not required; reviewer agreed with rationale for not conducting
“This reviewer agrees with the rationale provided by the applicant for not conducting carcinogenicity/tumorigenicity studies.”
hERG / QT
Not conducted; no safety pharmacology studies
“Safety Pharmacology studies were not conducted.”
First doseopen answer page →
First-in-human starting dose
Not explicitly stated; mouse repeat-dose 1x10^10 VP gives ~5-fold safety factor over clinical 5x10^11 PU dose
“Repeat administration of a dose level approximately 5-fold higher than the intended clinical dose, assuming a 60-kilogram adult of 5x1011 PU (1x1010 VP/mouse/dose) of PRGN-2012 once weekly on Days 0, 7, and 14 was well tolerated in WT C57BL/6 mice with no safety findings reported at termination after 21 Days.”
NOAEL / key findings
No test article-related findings at 1x10^10 VP/dose (~5x clinical); no local or systemic toxicity
“There were no test article-related findings reported.”
Risksopen answer page →
Immune & cytokine safety
Intended HPV-specific CD8+ T-cell IFN-gamma/TNF-alpha responses; in silico screen shows low off-target human protein reactivity
“The only protein sequences with alignment to the PRGN-2012 fusion antigen were proteins expressed by HPV, indicating there is a low potential for off-target human protein reactivity.”
Biodistribution & persistence
No biodistribution/shedding studies; mice unreliable for adenoviral shedding; clinical shedding study as postmarketing commitment
“Shedding analyses were not required for nonclinical studies for this product as mice are generally an unreliable species for adenoviral shedding studies to compare to human shedding.”
Modality-specific risk
Adenoviral vector shedding/transmission and off-target antigen immunity; low integration risk; minimal nonclinical package accepted
“The potential risk of viral shedding following PAPZIMEOS administration is considered very low due to the replication-defective nature of the vector and the subcutaneous route of administration.”
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
- Injection-Site Reactions
- Thrombotic Events
Hypersensitivity & infusion reactionsThrombosis & embolism
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 explicitly stated; mouse repeat-dose 1x10^10 VP gives ~5-fold safety factor over clinical 5x10^11 PU dose
“Repeat administration of a dose level approximately 5-fold higher than the intended clinical dose, assuming a 60-kilogram adult of 5x1011 PU (1x1010 VP/mouse/dose) of PRGN-2012 once weekly on Days 0, 7, and 14 was well tolerated in WT C57BL/6 mice with no safety findings reported at termination after 21 Days.”
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
3-week mouse (C57BL/6) SC study, once weekly; non-GLP; recovery phase not stated
“Local tolerance and systemic toxicity were assessed as part of the repeat dose toxicity study of PRGN-2012 in wild type (WT) C57BL/6 mice. PRGN-2012 or GC46.empty vector was administered once weekly for three weeks at 1×1010 VP/administration.”
Pivotal GLP studies
Single non-GLP repeat-dose SC mouse study (1x10^10 VP weekly x3, Days 0/7/14, sacrifice Day 21)
“GLP Status No”
DART package
Species: DART
Not conducted (not warranted given product characteristics and nonclinical safety profile)
“No biodistribution (BD), genotoxicity, carcinogenicity, reproductive and developmental toxicity, juvenile, nor dedicated local tolerance studies of PRGN-2012 were conducted. These studies are not warranted based on the product characteristics and nonclinical safety profile of PRGN-2012.”
Reproductive & developmental
Not conducted (predictable local adenovector biodistribution, species C-like vector); reviewer agreed
“This reviewer agrees with the rationale provided by the applicant for not conducting developmental and reproductive toxicology studies.”
PPND / ePPND: when
Not conducted; reviewer agreed with the applicant's rationale
“This reviewer agrees with the rationale provided by the applicant for not conducting developmental and reproductive toxicology studies.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“No biodistribution (BD), genotoxicity, carcinogenicity, reproductive and developmental toxicity, juvenile, nor dedicated local tolerance studies of PRGN-2012 were conducted.”
Carcinogenicity model
Not conducted (adenovectors non-integrating; insertional mutagenesis not a major concern)
“Per the applicant, studies were not conducted to evaluate carcinogenicity as adenovectors are non-integrating. Therefore, the risk for insertional mutagenesis is not a major concern.”
Carcinogenicity timing
Not required; reviewer agreed with rationale for not conducting
“This reviewer agrees with the rationale provided by the applicant for not conducting carcinogenicity/tumorigenicity studies.”
Safety marginopen answer page →
Safety margin at NOAEL
Mouse repeat-dose level without findings gives ~5-fold safety factor over the clinical dose
“The dose level assessed in this non-GLP toxicology study provides a 5-fold safety factor for the clinical dose level with the caveat that the processing and binding sequences in wildtype mice is likely different than the peptides recognized by human T cells .”
NOAEL / key findings
No test article-related findings at 1x10^10 VP/dose (~5x clinical); no local or systemic toxicity
“There were no test article-related findings reported.”
Efficacy evidenceopen answer page →
Efficacy evidence
HPV antigen-specific T-cell responses in immunized healthy wild-type C57BL/6 mice; no disease model
“In a second study of healthy wildtype animals (C57BL/6 mice), T cells were isolated on Day 14 and 21 from mice immunized via SC injection with either PRGN-2012, GC46.empty vector, or FFB on Day 0.”
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
Supportive of mechanism: HPV6/11 antigen-specific CD8+ T-cell cytokine and chemokine responses in vivo
“These data provide evidence that PRGN-2012 immunization leads to an HPV6 and HPV11 antigen specific response, CD8+ T cell production of cytokines, and production of effector T cell recruiting chemokines in vivo. These data are supportive of the proposed mechanism of action of PRGN-2012.”
Flexibilityopen answer page →
Flexibility accepted
GLPCriticised but acceptedBeyond the letter
Definitive repeat-dose toxicology study non-GLP, in wild-type mice only; murine antigen processing likely differs from human
Why: No safety findings at about 5-fold the clinical dose · Other reason
“The dose level assessed in this non-GLP toxicology study provides a 5-fold safety factor for the clinical dose level with the caveat that the processing and binding sequences in wildtype mice is likely different than the peptides recognized by human T cells .”
“The lack of safety findings in this definitive repeat administration safety study conducted in mice provide limited support for the safety of the clinical route of administration and clinical dose level.”
BiodistributionAcceptedBeyond the letter
No biodistribution or shedding studies
Why: Product characteristics and nonclinical safety profile · Low-risk modality
“No biodistribution (BD), genotoxicity, carcinogenicity, reproductive and developmental toxicity, juvenile, nor dedicated local tolerance studies of PRGN-2012 were conducted. These studies are not warranted based on the product characteristics and nonclinical safety profile of PRGN-2012.”
DARTAcceptedBeyond the letter
No developmental and reproductive toxicity studies
Why: Locally administered adenovectors have a well-defined, predictable biodistribution profile · Class precedent
“Locally administered adenovectors (SC or intramuscular) have a well-defined and predictable BD profile that is consistent despite differences in vector serotypes, transduction methods, payload, and manufacturing processes; thus, PRGN-2012 is expected to behave similarly to human .”
“This reviewer agrees with the rationale provided by the applicant for not conducting developmental and reproductive toxicology studies.”
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity or tumorigenicity studies
Why: Adenovectors are non-integrating; adenovirus has not shown significant tumorigenicity risk in humans · Low-risk modality · Class precedent
“Per the applicant, studies were not conducted to evaluate carcinogenicity as adenovectors are non-integrating. Therefore, the risk for insertional mutagenesis is not a major concern. In addition, previous data indicates adenovirus has not demonstrated a significant risk for tumorigenicity in humans.”
“This reviewer agrees with the rationale provided by the applicant for not conducting carcinogenicity/tumorigenicity studies.”
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