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.”
Species: general tox
Mouse (BALB/c, up to 12 weeks); additional single-dose studies in rats and dogs
“The nonclinical toxicology studies consisted of general toxicity studies up to 12 weeks in mice and an embryo-foetal development study in mice. Additional single dose studies were also conducted in rats and dogs.”
Species: DART
Mouse (embryo-fetal development only)
“The potential for reproductive or developmental toxicity of talimogene laherparepvec was evaluated in an embryo-foetal toxicity study conducted in the mouse.”
Species: carcinogenicity
Not conducted (ICH S9)
“In accordance with the ICH S9 guideline, no carcinogenicity studies have been conducted.”
Surrogate used in
Yes: mouse surrogate HSV-1 encoding murine GM-CSF (OncoVEXmGM-CSF) for in vivo mouse studies
“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).”
Genotox: Ames
Not conducted (ICH S6(R1)); HSV-1 forms episomes and does not integrate into host DNA
“In accordance with ICH S6(R1) guideline, genotoxicity studies were not conducted. Talimogene laherparepvec is a genetically-modified HSV-1 virus, which is an enveloped, double-stranded DNA virus that forms stable, circular episomes and does not integrate with host DNA.”
Genotox: in vitro mammalian
Not conducted (ICH S6(R1)); HSV-1 forms episomes and does not integrate into host DNA
“In accordance with ICH S6(R1) guideline, genotoxicity studies were not conducted. Talimogene laherparepvec is a genetically-modified HSV-1 virus, which is an enveloped, double-stranded DNA virus that forms stable, circular episomes and does not integrate with host DNA.”
Genotox: in vivo
Not conducted (ICH S6(R1)); HSV-1 forms episomes and does not integrate into host DNA
“In accordance with ICH S6(R1) guideline, genotoxicity studies were not conducted. Talimogene laherparepvec is a genetically-modified HSV-1 virus, which is an enveloped, double-stranded DNA virus that forms stable, circular episomes and does not integrate with host DNA.”
Carcinogenicity model
Not conducted; carcinogenic potential assessed by review of HSV-1 epidemiological data
“The carcinogenic potential for an HSV-1-based therapy was evaluated by review of the available epidemiological data.”
Carcinogenicity timing
Not conducted: not required per ICH S9; carcinogenic potential assessed from HSV-1 epidemiological data
“In accordance with the ICH S9 guideline, no carcinogenicity studies have been conducted. The carcinogenic potential for an HSV-1-based therapy was evaluated by review of the available epidemiological data.”
hERG / QT
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
Why it's blank
The public FDA and EMA reviews of Imlygic 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: Single SC dose NOAEL 1e7 PFU/kg in mice (~1.7x max clinical dose); transient injection-site inflammation; HSV-1-related findings (FDA pharmacology/toxicology review, p. 99)
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.”
Anti-drug antibodies: animals
Significant serum anti-HSV antibodies in treated tumour-bearing mice by day 27, similar with or without the GM-CSF gene
“Significant levels of serum HSV antibodies were seen in treated animals on day 27. Antibody levels were similar in the talimogene laherparepvec and hGM-CSF deficient talimogene laherparepvec treated groups.”
Anti-drug antibodies: patients
Anti-GM-CSF antibody response not reported in clinical trials; listed as theoretical important potential risk
“Talimogene Laherparepvec-mediated anti-GM-CSF Antibody Response is therefore considered an important potential risk in the RMP based on theoretical concerns as this event has not been reported in clinical trials.”
Label warnings
- Accidental Exposure to IMLYGIC
- Herpetic Infection
- Injection Site Complications
- Immune-Mediated Events
- Plasmacytoma at the Injection Site
- Obstructive Airway Disorder
- Hepatic Hemorrhage from Transcutaneous Intrahepatic Route of Administration
InfectionsHypersensitivity & infusion reactionsImmune-mediated reactionsHepatotoxicityBleedingSkin 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 Imlygic 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: Single SC dose NOAEL 1e7 PFU/kg in mice (~1.7x max clinical dose); transient injection-site inflammation; HSV-1-related findings (FDA pharmacology/toxicology review, p. 99)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
Mouse subcutaneous study, once weekly for 12 weeks, with 12-week recovery
“Groups 1 to 4 (Toxicity phase) were injected once weekly for 12 weeks and were sacrificed at 24 hours and 4 and 12 weeks post-last injection.”
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.”
DART package
Species: DART
Mouse (embryo-fetal development only)
“The potential for reproductive or developmental toxicity of talimogene laherparepvec was evaluated in an embryo-foetal toxicity study conducted in the mouse.”
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”
PPND / ePPND: when
Not conducted: no pre- and postnatal development study submitted (mouse embryo-fetal study only)
“The applicant did not submit prenatal and postnatal development studies or in juvenile animals (see non-clinical discussion).”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S9)
“In accordance with the ICH S9 guideline, no carcinogenicity studies have been conducted.”
Carcinogenicity model
Not conducted; carcinogenic potential assessed by review of HSV-1 epidemiological data
“The carcinogenic potential for an HSV-1-based therapy was evaluated by review of the available epidemiological data.”
Carcinogenicity timing
Not conducted: not required per ICH S9; carcinogenic potential assessed from HSV-1 epidemiological data
“In accordance with the ICH S9 guideline, no carcinogenicity studies have been conducted. The carcinogenic potential for an HSV-1-based therapy was evaluated by review of the available epidemiological data.”
Safety marginopen answer page →
Safety margin at NOAEL
Mouse repeat-dose SC NOAEL ~70x the recommended maximum dose (PFU/kg basis)
“A dose level of 1x107 PFU/mouse/injection was 88-fold higher than the maximum human dose level (on a PFU/kg basis) administered in the first-in-human clinical trial (Document No. 4648-00028), and 70-fold higher than the recommended maximum dose level (on a PFU/kg basis) listed in the label for T-VEC.”
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”
Efficacy evidenceopen answer page →
Efficacy evidence
Syngeneic mouse melanoma (B16F10-muNectin1) with clinical virus: significant anti-tumour effect after one or three intratumoral doses
“Intratumoral administration of a single dose and 3 doses of talimogene laherparepvec produced statistically significant (p<0.0001) anti-tumour effect in the mouse syngeneic melanoma model (Figure 4).”
Why that model
Human GM-CSF does not bind the mouse GM-CSF receptor, so a murine GM-CSF surrogate virus was used in mice
“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.”
Reviewer's view of the efficacy data
FDA: T-VEC shows anti-tumour activity in mice even though encoded human GM-CSF is not biologically active there
“Although human GM-CSF transcript levels were detected in mice, the protein is not biologically active in this species. However, T-VEC displays anti-tumor activity in mice.”
Flexibilityopen answer page →
Flexibility accepted
GenotoxicityAccepted
No genotoxicity studies; non-integrating HSV-1 episome
Why: ICH S6(R1); HSV-1 forms episomes and does not integrate into host DNA · Within the guideline · Low-risk modality
“In accordance with ICH S6(R1) guideline, genotoxicity studies were not conducted. Talimogene laherparepvec is a genetically-modified HSV-1 virus, which is an enveloped, double-stranded DNA virus that forms stable, circular episomes and does not integrate with host DNA.”
“Because wild-type HSV-1 does not integrate into the host genome, the risk of insertional mutagenesis with talimogene laherparepvec is negligible (SmPC section 5.3).”
CarcinogenicityAccepted
No carcinogenicity studies; carcinogenic potential assessed from HSV-1 epidemiology literature
Why: ICH S9; extensive human HSV-1 exposure and mechanism of action make tumour induction highly unlikely · Within the guideline · Human data · Weight of evidence
“In accordance with the ICH S9 guideline, no carcinogenicity studies have been conducted. The carcinogenic potential for an HSV-1-based therapy was evaluated by review of the available epidemiological data.”
“Given the extensive human exposure to HSV-1, and in view of the mechanism of action of talimogene laherparepvec, it is considered highly unlikely that talimogene laherparepvec will induce tumour development or proliferation.”
DARTVerdict not stated
No pre- and postnatal development or juvenile animal studies; mouse embryo-fetal study only
“The applicant did not submit prenatal and postnatal development studies or in juvenile animals (see non-clinical discussion).”
Safety pharmacologyVerdict not stated
No dedicated safety pharmacology studies
“The applicant did not submit specific safety pharmacology studies (see non-clinical discussion).”
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