Imlygic

Uses

Imlygic is a genetically modified virus used to treat recurrent melanoma, or metastatic melanoma.

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 . 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 .

Imlygic is also used to associated treatment for these conditions: Unresectable Skin Lesion

How Imlygic works

Imlygic is an oncolytic immunotherapy that is derived from Herpes Simplex Virus type-1 (HSV-1) . 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) . The medication causes the death of tumor cells and the release of tumor-derived antigens . It is believed that together with GM-CSF, talimogene laherparepvec can promote a systemic anti-tumor immune response and an effector T-cell response . Mice subjects involved in talimogene laherparepvec treatment studies that had complete regression of their primary tumors following therapy were resistant to subsequent tumor rechallenge .

The genetic modifications to talimogene laherparepvec from HSV-1 include deletion of the ICP34.5 and ICP47 genes . 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 . 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 .

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 .

Toxicity

There is no clinical experience with overdose with talimogene laherparepvec . 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 . The maximum dose of talimogene laherparepvec that can be safely administered has not been determined .

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 .

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 . 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 .

Food Interaction

Volume of Distribution

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

Elimination Route

Cellular uptake of talimogene laherparepvec occurs through HSV-1 receptors on both tumor and non-tumor cells following local injection into physical tumors . 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 .

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 and the half-lives of antibody-based therapeutics are often times generally long, on the order of days versus hours with small molecule drugs .

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 . 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 . 17% of samples from the exterior occlusive dressing tested positive for talimogene laherparepvec DNA but none tested positive for the presence of infective virus . 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 .

Elimination Route

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 .

Innovators Monograph

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