Imlygic
talimogene laherparepvec
Species
RatMouseDog
Longest study
12 wk (derived)
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Mouse (BALB/c) for GLP tox; single-dose studies also in rats and dogs; no permissive/relevant species for human GM-CSF
“Exploratory and GLP-compliant repeat dose toxicity studies were conducted in Balb/c mice with up to 12 weekly doses.”
Why that species
Mouse used with mouse surrogate virus because human GM-CSF does not bind mouse receptor; human GM-CSF not bioactive in mice
“The expressed human GM-CSF is not bioactive in the mice, thus the findings are likely not related to exposure to this human protein.”
Surrogate molecule
Yes: mouse surrogate HSV-1 encoding murine GM-CSF (OncoVEXmGM-CSF) for pharmacology; clinical virus used in tox
“A mouse surrogate HSV-1 vector encoding the murine GM-CSF (OncoVEXmGM-CSF; JS1/34.5-/47-/mGM-CSF) was developed and used for the in vivo mouse studies because of the inability of human GM-CSF to bind to mouse GM-CSF receptor.”
Study lengthopen answer page →
Longest pivotal study
12 (derived from the dosing and observation schedule)
“Exploratory and GLP-compliant repeat dose toxicity studies were conducted in Balb/c mice with up to 12 weekly doses.”
Pivotal GLP studies
GLP SC repeat-dose studies in BALB/c mice, up to 12 weekly doses; GLP biodistribution and mouse embryo-fetal studies
“Pivotal repeat-dose toxicology, biodistribution, and embryo-foetal development studies were performed in accordance with Good Laboratory Practice (GLP) regulations.”
Route in tox
Subcutaneous (pivotal); intratumoural, IV also used
“single or repeated doses of talimogene laherparepvec administered by SC, IV, or intratumoural injection were well tolerated in immunocompetent mice, rats, and dogs.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“In accordance with ICH S6(R1) guideline, genotoxicity studies were not conducted.”
Carcinogenicity
Not conducted; literature review of HSV-1 epidemiology provided
“No carcinogenicity studies have been conducted (see non-clinical discussion).”
Reproductive & developmental
Mouse embryo-fetal study (IV, up to 4e8 PFU/kg) no effects; adult reproductive tissues unaffected; no fertility/PPND studies
“No effects on embryo-foetal development were observed when talimogene laherparepvec was administered during organogenesis to pregnant mice at doses up to 4 x 108 (400 million) PFU/kg”
Safety pharmacology
Not conducted (no specific safety pharmacology studies)
“The applicant did not submit specific safety pharmacology studies (see non-clinical discussion).”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
Single SC dose NOAEL 1e7 PFU/kg in mice (~1.7x max clinical dose); transient injection-site inflammation; HSV-1-related findings
“a no-observed-adverse-effect-level (NOAEL) of 107 PFU/kg was achieved, which is approximately 1.7-fold higher than the maximum clinical dose level”
Risksopen answer page →
Immune & cytokine safety
Lethal disseminated HSV infection in immunodeficient mice (up to 20% nude, 100% SCID); immunocompetent mice tolerated doses
“Lethal systemic viral infection was observed in up to 20% of nude mice (primarily deficient in T lymphocyte function) and 100% of SCID mice (devoid of both T and B lymphocytes).”
Biodistribution & persistence
Low-level viral DNA at injection site, blood and urine 24 h after 5th SC dose in mice; cleared by later timepoints
“Viral DNA was detected at low levels in the injection site, blood and urine at 24 hours following the administration of the 5th injection of the product.”
Modality-specific risk
HSV-1 replication-competent virus: neurotropism/latency, dissemination in immunodeficient hosts, transmission to unintended recipients
“even though ICP34.5 has been removed from the viral genome, the virus still has some affinity for nervous system tissue.”