Talimogene laherparepvec

Identification

Name
Talimogene laherparepvec
Accession Number
DB13896
Description

Talimogene laherparepvec is an oncolytic treatment used in local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with recurrent melanoma. It is a genetically administered herpes simplex virus 1 (HSV-1) that expresses human cytokine granulocyte-macrophage colony stimulating factor (GM-CSF) with antitumor and immune-stimulating activities. It specifically replicates within tumor cells and causes lysis. It was approved by the FDA in 2015 under the market name Imlygic.

In general, talimogene laherparepvec has been modified so that it can infect and multiply inside melanoma cells 4. The drug subsequently uses the melanoma cells' own machinery to multiply, eventually overwhelming the melanoma cells and killing them 4. Alternatively, although talimogene laherparepvec also enters healthy cells, it is not designed to multiply inside them 4.

Type
Biotech
Groups
Approved, Experimental, Investigational
Biologic Classification
Protein Based Therapies
Other protein based therapies
Protein Structure
Db13896
Protein Chemical Formula
Not Available
Protein Average Weight
Not Available
Sequences
Not Available
Synonyms
  • T-Vec

Pharmacology

Indication

This medication is a genetically modified oncolytic viral therapy indicated for the local treatment of unresectable, cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery Label. Elsewhere, the EMA notes that the agent is indicated for the treatment of adults with unresectable melanoma that is regionally or distantly metastatic (Stage IIIB, IIIC, and IVM1a) with no bone, brain, lung, or other visceral diseases 2.

Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Talimogene laherparepvec has been genetically modified to replicate within tumors and to produce the immune stimulatory protein GM-CSF (granulocyte macrophage colony stimulating factor) Label. The medication causes lysis of tumors, followed by the release of tumor-derived antigens, which together with virally derived GM-CSF may promote an anti-tumor immune response in the body Label.

Mechanism of action

Talimogene laherparepvec is an oncolytic immunotherapy that is derived from Herpes Simplex Virus type-1 (HSV-1) 3. It has been modified to replicate within tumor cells and to produce the immune response stimulatory protein, human GM-CSF (granulocyte macrophage colony stimulating factor) 3. The medication causes the death of tumor cells and the release of tumor-derived antigens 3. It is believed that together with GM-CSF, talimogene laherparepvec can promote a systemic anti-tumor immune response and an effector T-cell response 3. Mice subjects involved in talimogene laherparepvec treatment studies that had complete regression of their primary tumors following therapy were resistant to subsequent tumor rechallenge 3.

The genetic modifications to talimogene laherparepvec from HSV-1 include deletion of the ICP34.5 and ICP47 genes 3. Whereas anti-viral immune responses defend normal cells following infection by talimogene laherparepvec, tumors have been shown to be susceptible to injury and cell death from ICP34.5-deficient HSV-1 derived viruses, including talimogene laherparepvec 3. Moreover, deletion of ICP47 prevents the down-regulation of antigen presentation molecules in the targeted tumor cells and increases the expression of the HSV US11 gene, thereby enhancing the talimogene laherparepvec viral replication in tumor cells and increases chances of tumor cell injury and death 3.

Although the talimogene laherparepvec virus is specifically modified to infect and multiply inside melanoma cells and uses melanoma cells' own machinery to multiply, the medication is not designed to multiply inside healthy cells, which it is also capable of entering 4.

TargetActionsOrganism
AHeparan sulfateNot AvailableHumans
ADNA polymerase catalytic subunit
activator
HHV-1
ADNA polymerase catalytic subunit
activator
HHV-3
Absorption

Cellular uptake of talimogene laherparepvec occurs through HSV-1 receptors on both tumor and non-tumor cells following local injection into physical tumors 3. After injection, the talimogene laherparepvec subsequently replicates intratumorally, where bioavailability and systemic concentration of the agent are not largely predictive of drug substance activity and therefore such data has not been evaluated to any particular degree 3.

Volume of distribution

Talimogene laherparepvec is a genetically modified and replication-competent HSV-1 virus 3. Therefore, its pharmacokinetics and biodistribution are driven by the specific site of intralesional injection, tumor-selective replication, and release from tumor tissue 3. As a result, the specific pharmacokinetics of the agent, including distribution may vary depending on particular parameters of each unique administration.

Protein binding

Talimogene laherparepvec is a genetically modified and replication-competent HSV-1 virus 3. Therefore, its pharmacokinetics and biodistribution are driven by the specific site of intralesional injection, tumor-selective replication, and release from tumor tissue 3. As a result, the specific pharmacokinetics of the agent, including any kind of protein binding may vary depending on particular parameters of each unique administration.

Metabolism

Talimogene laherparepvec is cleared through general host defense mechanisms like autophagy and adaptive immune responses 3. The agent is ultimately degraded by common endogenous protein and DNA catabolic pathways 3. As with other wild-type HSV-1 (herpes simplex virus type-1) infections, a latent pool of talimogene laherparepvec DNA may persist in neuronal cell bodies innervating the injection sites 3. Consequently, the occurrence of latent infection with talimogene laherparepvec cannot be excluded 3.

Route of elimination

In an ongoing melanoma study, interim results from 30 patients show that talimogene laherparepvec DNA was detected at transient and low concentrations in blood in 90% of patients and in urine in 20% of patients in the study, which suggests that perhaps at least some portion of the drug is eliminated in the urine Label,2,3,4.

Half-life

Readily accessible data regarding the half-life of talimogene laherparepvec is not available, although talimogene laherparepvec DNA has been found in patient subjects' injected tumor through 84 days Label and the half-lives of antibody-based therapeutics are often times generally long, on the order of days versus hours with small molecule drugs 1.

Clearance

Although readily accessible data regarding the clearance of talimogene laherparepvec is not available, in an ongoing melanoma study, it was determined that the proportion of patients with detectable talimogene laherparepvec DNA in blood and urine was highest during the second cycle of therapy 3. Additionally, even though talimogene laherparepvec DNA was detected in samples from injected lesions in about 90% of patients, only 14% of patients tested positive for infective virus by 50% Tissue Culture Infectious Dose (TCID50) assay, all within 8 days of treatment administration 3. 17% of samples from the exterior occlusive dressing tested positive for talimogene laherparepvec DNA but none tested positive for the presence of infective virus 3. Moreover, only 1 sample had detectable talimogene laherparepvec DNA located on the oral mucosa - but the sample did not test positive for the presence of infective virus 3.

Adverse Effects
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Toxicity

There is no clinical experience with overdose with talimogene laherparepvec Label,2. Doses up to 4 mL at a concentration of 10^8 PFU/mL every 2 weeks have been administered in clinical trials with no evidence of dose-limiting toxicity Label,2. The maximum dose of talimogene laherparepvec that can be safely administered has not been determined Label,2.

Nevertheless, some adverse reactions that are possible from taking talimogene laherparepvec range from fatigue, chills, pyrexia, nausea, influenza-like illness, injection site pain, to even injection site complications (including cellulitis, systemic bacterial infection, and others), herpetic infection, or plasmacytoma at or near the injection site Label,2.

As a result, healthcare providers and caregivers must observe the necessary safety precautions when administering talimogene laherparepvec to patients as accidental exposure to the agent can lead to exposure to and transmission of talimogene laherparepvec and herpetic infection in individuals who do not need the medication or in whom the medication is not indicated Label,2. Moreover, in the event of a suspected overdose or inadvertent intravenous administration, the patient should be treated symptomatically, ie. with acyclovir or other anti-viral agents and supportive measures instituted as needed Label,2.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
Darbepoetin alfaThe risk or severity of Thrombosis can be increased when Darbepoetin alfa is combined with Talimogene laherparepvec.
ErythropoietinThe risk or severity of Thrombosis can be increased when Erythropoietin is combined with Talimogene laherparepvec.
Methoxy polyethylene glycol-epoetin betaThe risk or severity of Thrombosis can be increased when Methoxy polyethylene glycol-epoetin beta is combined with Talimogene laherparepvec.
PeginesatideThe risk or severity of Thrombosis can be increased when Peginesatide is combined with Talimogene laherparepvec.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

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Food Interactions
Not Available

Products

Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ImlygicInjection, suspension1000000 [PFU]/1mLIntralesionalAMGEN INC2015-11-02Not applicableUs
ImlygicInjection, suspension100000000 [PFU]/1mLIntralesionalAMGEN INC2015-11-02Not applicableUs
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

ATC Codes
L01XX51 — Talimogene laherparepvec
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available

Chemical Identifiers

UNII
07730V90L6
CAS number
1187560-31-1

References

General References
  1. Sandip Pravin Patel, Razelle Kurzrock (2017). Early Phase Cancer Immunotherapy: Current Cancer Research. Springer. [ISBN:3319637576]
  2. EMA: Imylgic (talimogene laherparepvec) prescribing information [Link]
  3. Electronic Medicines Compendium: Imlygic (talimogene laherparepvec) monograph [Link]
  4. European Medicines Agency: Imlygic (talimogene laherparepvec) [Link]
KEGG Drug
D09966
PubChem Substance
347911465
RxNav
1721264
Wikipedia
Talimogene_laherparepvec
FDA label
Download (400 KB)
MSDS
Download (33.5 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentMelanoma1
3CompletedTreatmentMelanoma2
3No Longer AvailableNot AvailableUnresected Stage IIIb to IVM1c Melanoma1
3TerminatedTreatmentCutaneous Melanoma / Recurrent Melanoma1
3TerminatedTreatmentHead and Neck Carcinoma / Squamous Cell Carcinoma (SCC)1
2Active Not RecruitingTreatmentAngiosarcoma of Skin1
2Active Not RecruitingTreatmentCompletely Resectable Stage IIIB, IIIC, or IVM1a Melanoma1
2Active Not RecruitingTreatmentMalignant Chest Wall Neoplasm / Recurrent Breast Carcinoma / Recurrent Inflammatory Breast Carcinoma / Stage IV Breast Cancer AJCC v6 and v7 / Stage IV Inflammatory Breast Carcinoma1
2Active Not RecruitingTreatmentUnresected Stage IIIb to IVM1c Melanoma1
2CompletedTreatmentMelanoma3

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, suspensionIntralesional1000000 [PFU]/1mL
Injection, suspensionIntralesional100000000 [PFU]/1mL
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
Not Available

Targets

1. Heparan sulfate
Kind
Small molecule
Organism
Humans
Pharmacological action
Yes
References
  1. Spear PG: Herpes simplex virus: receptors and ligands for cell entry. Cell Microbiol. 2004 May;6(5):401-10. doi: 10.1111/j.1462-5822.2004.00389.x. [PubMed:15056211]
Kind
Protein
Organism
HHV-1
Pharmacological action
Yes
Actions
Activator
General Function
Rna-dna hybrid ribonuclease activity
Specific Function
Replicates viral genomic DNA. The replication complex is composed of six viral proteins: the DNA polymerase, processivity factor, primase, primase-associated factor, helicase, and ssDNA-binding pro...
Gene Name
Not Available
Uniprot ID
P04293
Uniprot Name
DNA polymerase catalytic subunit
Molecular Weight
136419.66 Da
Kind
Protein
Organism
HHV-3
Pharmacological action
Yes
Actions
Activator
General Function
Rna-dna hybrid ribonuclease activity
Specific Function
Replicates viral genomic DNA. The replication complex is composed of six viral proteins: the DNA polymerase, processivity factor, primase, primase-associated factor, helicase, and ssDNA-binding pro...
Gene Name
Not Available
Uniprot ID
P09252
Uniprot Name
DNA polymerase catalytic subunit
Molecular Weight
134046.615 Da

Drug created on September 08, 2017 14:22 / Updated on June 12, 2020 10:53

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