Biodistribution (within the body) and Viral Shedding (excretion/secretion)

IMLYGIC viral DNA levels in various tissues and secretions were determined using a quantitative polymerase chain reaction (qPCR) assay. Infectious IMLYGIC at the injection sites and at some potential herpetic lesions was also quantified using viral infectivity assays.

Nonclinical data

Following repeat intratumoral administration in mice, IMLYGIC DNA was primarily detected in the tumor, blood, spleen, lymph node, liver, heart, and kidney. IMLYGIC DNA was not detected in bone marrow, eyes, lachrymal glands, nasal mucosa, or feces. The highest level of IMLYGIC DNA was found in the injected tumor. IMLYGIC DNA was found in the injected tumor through 84 days and in blood samples through 14 days after the last administration of IMLYGIC.

Clinical data

The biodistribution and shedding of intralesionally administered IMLYGIC were investigated in a clinical study that measured IMLYGIC DNA in blood, urine, injection site, occlusive dressings, oral mucosa, anogenital area, and suspected herpetic lesions. Occlusive dressings samples were collected during treatment. Blood and urine samples were collected during treatment and for up to 30 days after the end of treatment. Injection site, oral mucosa, and anogenital area samples were collected during treatment and for up to 60 days after the end of treatment. Suspected herpetic lesion samples were collected any time a patient experienced lesions of suspected herpetic origin. If the qPCR testing for IMLYGIC DNA was positive, then a TCID50 assay was performed to measure viral infectivity. In the 60 patients with melanoma who received IMLYGIC intralesional injection at a dose and schedule same as the clinical study [see Clinical Studies (14)], data indicate that IMLYGIC DNA was present in all sites during the study (see Table 5).

The proportion of samples and subjects with IMLYGIC DNA was highest during cycle 2 of treatment for the blood, urine, injection site, and occlusive dressings; highest in cycle 1 of treatment for the oral mucosa; and highest in cycles 1 and 2 for the anogenital area. Among patients with detectable IMLYGIC DNA in the blood, urine, oral mucosa and anogenital area, no samples had detectable IMLYGIC DNA 30 days after the end of treatment. For patients with detectable DNA in injected lesions, no samples had detectable IMLYGIC DNA 60 days after the end of treatment.

Overall 3 of 19 patients with lesions of suspected herpetic origin had IMLYGIC DNA present at any time during the study. Of the three subjects who had lesions of suspected herpetic origin that had IMLYGIC DNA detected during the study, none of the suspected lesions were injected with IMLYGIC. None of the subjects with the lesions of the suspected herpetic origin with IMLYGIC DNA had disseminated lesions or received antiviral therapy and these events were non-serious, lasting from 16 days to 4 months. The data suggest that IMLYGIC may cause herpetic lesions in treated patients. 

In addition to the presence of IMLYGIC DNA, viral activity was measured in samples that were positive for IMLYGIC DNA from the injection site, occlusive dressings, oral mucosa, anogenital area, and suspected herpetic lesions. No viral activity was detected in samples of the occlusive dressings, oral mucosa, anogenital area, and suspected herpetic lesions. Infectious IMLYGIC virus was detected at the site of injection in 7 (11%) patients at multiple time points in the study; no samples were positive for viral infectivity after cycle 2 or after the end of treatment.