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.”
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.”
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.”