LTP Technology™

LTP TECHNOLOGY™ is the second-generation liver-targeting prodrug technology and can be used to deliver a clinically validated or novel nucleotide molecule to the liver cells in efficiency and selectivity superior to the other technologies such as ProTide and HepDirect technologies. The high selectivity to the liver is achieved in prodrug activation in the liver cells by conversion of the inactive prodrugs to the active form initiated by a key activation enzyme, cytochrome P450 subtype 3A4 (CYP3A4), that is primarily expressed in the liver with much lower levels of expression in other tissues. The tissue-specific expression of CYP3A4 leads to high levels of active drug in the liver with much lower levels in systemic circulation. In contrast, PtoTide prodrugs are cleaved by several enzymes including histidine triad nucleotide-binding protein 1 (HINT-1) which have broader tissue distributions.

An example of LTP Technology superiority in improving prodrug delivery efficiency of tenofovir (TFV) is summarized below by a published literature (EASL 2018 SAT-345 poster by Nucorion Pharmaceuticals). Tenofovir is a known antiviral agent, a nucleotide analog reverse-transcriptase inhibitor (NtRTI), to treat HBV and HIV, mainly in two types of prodrugs, tenofovir disoproxil fumarate (TDF) and the more efficient tenofovir alafenamide (TAF). To assess the prodrug efficiency and selectivity in vivo, three types of tenofovir prodrugs were orally administered to Sprague-Dawley rats (3/group) at the same doses: ProTide prodrug (tenofovir alafenamide (TAF-base,)), HepDirect prodrug (NCO-8429), and LTP prodrug (NCO-8548). Blood was collected and tissues were harvested and snap-frozen in liquid nitrogen.  Tenofovir diphosphate in the liver (TDPliver) and TFV in blood (TFVblood) concentrations were measured by LC-MS/MS to compare systemic exposure and liver-targeting efficiency. The slide below summarizes the measured results. LTP-tenofovir compound, NCO-8548, delivered TDP levels in the liver much higher than that of ProTide-tenofovir compound, TAF-base, and HepDirect-tenofovir compound, NCO-8429 despite the administration of equivalent oral doses of 5 mg/kg. And NCO-8548 showed liver-targeting efficiency superior to the HepDirect-tenofovir and ProTide-tenofovir compounds, which demonstrates that LTP-based prodrugs have superior liver-targeting properties. LTP Technology can be an effective method to increase the therapeutic index of nucleos(t)ide prodrugs.