Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Navidea Biopharmaceuticals Europe Ltd., Kilminion South, Ballinroad, Dungarvan, Co. Waterford, X35 WP70, Ireland
Pharmacotherapeutic group: diagnostic radiopharmaceutical, tumour detection
ATC Code: V09IA09
Lymphoseek is a receptor-targeted radiopharmaceutical that is designed to rapidly transit lymphatic vessels; it biotargets, accumulates, and is retained in primary, key predictive, draining lymph nodes (sentinel lymph nodes). The substance, tilmanocept, specifically binds to mannose binding receptor proteins (CD206) that reside on the surface of macrophages and dendritic cells. Macrophages are present in high concentrations in lymph nodes.
Tilmanocept is a macromolecule consisting of multiple units of diethylenetriaminepentaacetic acid (DTPA) and mannose, each synthetically attached to a 10 kDa dextran backbone. The mannose acts as a substrate for the receptor, and the DTPA serves as a chelating agent for labelling with technetium Tc 99m. The mean diameter of tilmanocept is 7 nm and this small molecular size permits enhanced transit into lymphatic channels resulting in rapid and consistent injection site clearance.
Following reconstitution and labelling, Lymphoseek is intended to be injected in close proximity to the tumour and used in preoperative gamma detection imaging in conjunction with a stationary gamma camera (scintigraphy), single photon emissioncomputed tomography (SPECT), or SPECT/computerized tomography SPECT/CT, and/or intraoperatively in conjunction with a gamma detection probe to localise sentinel lymph nodes in the lymphatic pathway draining the tumour.
In in vitro studies, technetium Tc 99m tilmanocept exhibited specific and tight binding to human CD206 receptors with a primary binding site affinity of Kd = 2.76 × 10-11 M. In Phase 1 clinical studies, approximately 0.5 to 1.8% of the dose is accumulated in draining lymph nodes through specific binding after 30 minutes. Technetium Tc 99m tilmanocept binding is independent of tumour type or severity.
In Phase 3 clinical studies, technetium Tc 99m tilmanocept was detectable in sentinel lymph nodes within 10 minutes. In external gamma imaging analysis, bound technetium Tc 99m tilmanocept has been shown to be retained in the same draining lymph nodes for up 30 hours. Preoperative lymphoscintigraphy was performed in 100% of melanoma patients, 100% of head and neck squamous cell carcinoma patients, and 82% of breast cancer patients. The overall rate of agreement between lymph node localisation (determined by radioactivity detection) on preoperative lymphoscintigraphy and intraoperative lymph node survey was 97.8% for all patients.
In Phase 3 clinical studies in breast cancer patients mapped with both technetium Tc 99m tilmanocept and vital blue dye, technetium Tc 99m tilmanocept localised in 99.91% of patients with a mean 2.08 localised sentinel lymph nodes per patient by fixed effects meta-analyses. These rates were significantly greater (p<0.0001) against a random effects meta-analysis of localisation rates from published literature for colloidal lymphatic mapping agents as used in European clinical practice. In a fixed effects meta-analysis of two Phase 3 studies, technetium Tc 99m tilmanocept localised in 99.99% of the excised lymph nodes stained blue by a vital blue dye (concordance). Alternatively, vital blue dye localised in 66.96% of the excised lymph nodes detected by technetium Tc 99m tilmanocept (reverse concordance).
In Phase 3 clinical studies in melanoma patients mapped with both technetium Tc 99m tilmanocept and vital blue dye, technetium Tc 99m tilmanocept localised in 99.89% of patients with a mean 2.30 localised sentinel lymph nodes per patient by fixed effects meta-analyses. These rates were significantly greater (p<0.0001) against a random effects meta-analysis of localisation rates from published literature for colloidal lymphatic mapping agents as used in European clinical practice. In a fixed effects meta-analysis of two Phase 3 studies, technetium Tc 99m tilmanocept localised in 99.99% of the excised lymph nodes stained blue by a vital blue dye (concordance). Alternatively, vital blue dye localised in 63.50% of the excised lymph nodes detected by technetium Tc 99m tilmanocept (reverse concordance).
In one Phase 3 clinical study in patients with intraoral or cutaneous squamous cell carcinoma, technetium Tc 99m tilmanocept localised sentinel lymph nodes in 97.59% of patients who underwent lymph node evaluation. Relative to the pathology status of lymph node collection from a complete lymph node dissection, technetium Tc 99m tilmanocept correctly localised in sentinel lymph nodes predictive of harbouring metastatic tumour in 38 of 39 patients, for a false negative rate of 2.56%. The overall accuracy of technetium Tc 99m tilmanocept for identification of true positive and true negative patients relative to pathology in the localised lymph nodes was 98.80%.
The European Medicines Agency has deferred the obligation to submit the results of studies with Lymphoseek in one or more subsets of the paediatric population for visualisation of lymphatic drainage of solid malignant tumours for diagnostic purposes (see section 4.2 for information on paediatric use).
Two Phase 1 clinical trials in breast cancer patients and one Phase 1 study in melanoma patients have been completed. The purpose of the studies included the radiopharmacokinetic evaluation of Lymphoseek.
In one Phase 1 study in breast cancer patients, Lymphoseek at all three doses tested (4, 20, and 100 micrograms) exhibited fast injection site clearance (elimination rate constants in the range of 0.222/h to 0.278/h). Uptake of technetium Tc 99m tilmanocept into the primary sentinel node increased dose-dependently (p=0.009): Lymphoseek injection at 4, 20, and 100 micrograms produced primary sentinel node levels (LSN) of 0.09 ± 0.20 pmol, 6.53 ± 2.52 pmol, and 10.58 ± 8.43 pmol of technetium Tc 99m tilmanocept, respectively. The percent-of-injected dose reaching the primary sentinel node (IDSN) was 0.05 ± 0.10%, 0.52% ± 0.38%, 0.21% ± 0.17% in the 4, 20, and 100 microgram Lymphoseek dose groups, respectively. The plasma ID per gram for two dose levels peaked at 4 hours; the mean values for the 4 and 100 microgram doses were 0.0090/g ± 0.0048%/g and 0.0039%/g ± 0.0046%/g, respectively. The 20 microgram dose peaked at 2.5 hours with a mean ID/g of 0.0023/g ± 0.0005%/g.
In the second Phase 1 study in breast cancer patients in which patients were injected with 20 micrograms Lymphoseek, the mean elimination rate constant of technetium Tc 99m tilmanocept was 0.299/h and the drug half-life at the injection site was 2.6 h. The IDSN was 1.68 ± 1.22% in the 3 hour injection-to-surgery group and 1.81% ± 2.19% in the Lymphoseek 16 hour injection-to-surgery group.
In the Phase 1 study in melanoma patients, Lymphoseek at all three doses tested (20, 100, and 200 micrograms) cleared the injection site with elimination rate constants in the range of 0.227/h to 0.396/h, resulting in drug half-life at the injection site of 1.75 to 3.05 h). Uptake of technetium Tc 99m tilmanocept into the primary sentinel node increased dose-dependently: Lymphoseek injection at 20, 100, and 200 micrograms produced LSN values of 5.01 ± 8.02 pmol, 17.5 ± 13.7 pmol, and 58.2 ± 41.2 pmol of technetium Tc 99m tilmanocept, respectively. The IDSN taken up into the primary lymph node was 0.50 for the 20 microgram dose, 0.35% for the 100 microgram dose, 0.58% for the 200 microgram dose of Lymphoseek. The plasma ID per gram for two dose levels peaked at 15 minutes; the mean values for the 20 and 200 microgram doses were 0.0104/g ± 0.0135%/g and 0.0065%/g ± 0.0082%/g, respectively. The 100 microgram dose peaked at 1 and 2 hours with a mean ID/g of 0.0018/g ± 0.001%/g at each timepoint.
Technetium Tc 99m tilmanocept is eliminated primarily through the kidneys. The metabolism of technetium Tc 99m tilmanocept has not been investigated experimentally. Tilmanocept may be metabolised in the liver to its component molecules, namely dextran (which is renally excreted and/or further metabolised to glucose), mannose (an endogenous sugar) and diethylenetriaminepentaacetic acid (which is renally excreted). As with all general metabolites, especially those in which the liver plays a measurable roll of elimination, some biliary elimination of technetium Tc 99m tilmanocept is also likely to occur.
The ID for liver, kidneys, and bladder as calculated from the whole body scans of breast cancer patients at 1, 2.5, and 12 hours after administration was below 2.6 at all times (all dose levels combined). The ID for liver, kidneys, and bladder as calculated from the whole body scans of melanoma patients at 1 and 12 hours after administration ranged from 1.1 to 3.1% at 1 hour, and all decreased to less than 1% by 12 hours.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, acute and repeated dose toxicity, and genotoxicity.
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