IT-141: A Novel Top1 Inhibitor

Intezyne Technologies Initiates First-In-Human Trials for Topoisomerase 1 Inhibitor IT-141 (NCT03096340)

IT-141 is a formulation of SN-38 encapsulated using Intezyne’s nanoparticle drug delivery platform, and is the lead formulation for clinical development incorporating the IVECT polymer micelle technology.

As the active pharmaceutical ingredient in IT-141, SN-38 binds DNA within cells and blocks the ability for the DNA to replicate. This inhibits the cells ability to proliferate, and ultimately leads to cell death. SN-38 is the most potent compound in a family known as camptothecins, which have been used to treat cancer for over 30 years. However, SN-38 has not been able to successfully be administered in humans because it is not soluble in water and cannot be given by intravenous injection or infusion. Irinotecan was developed as an alternative way to administer SN-38 by altering the chemical structure so that it can be administered intravenously. This approach requires irinotecan to be metabolized in the body once administered in order to change the compound back to SN-38. Studies have shown that this activation process in the body is highly inefficient, thus irinotecan is approximately 1000-times less potent than the active compound SN-38. IT-141 is the first formulation to actively deliver SN-38 without any chemical modifications. In addition, the encapsulation of SN-38 protects the body against the drug while circulating in the blood while the nanoparticles accumulate in the tumor environment. This allows for a safer, more effective way to utilize SN-38 for cancer therapy.


Technical Overview

IT-141 is a formulation of topoisomerase I inhibitor, SN-38 (7-ethyl-10-hydroxy camptothecin), encapsulated in a stabilized polymer micelle. The triblock copolymer that forms the micelle is composed of an amphiphilic poly(ethylene) glycol (PEG) block that renders solubility in aqueous solvents, and provides stealth properties to evade detection from immune surveillance. The stabilizing middle block of the copolymer incorporates hydroxamic acid moieties such that iron molecules can form dative bonds between polymer strands, leading to improved stability upon dilution and exposure to biological components such as blood. The encapsulation block is composed of a mixture of hydrophobic amino acids that sequesters the SN-38 into the core without the need for chemical conjugation or modification, and allows for self-assembly into a micellar morphology. The resulting drug product is a lyophilized powder for reconstitution in saline for intravenous infusion. The physiochemical properties of IT-141 include an average particle diameter of approximately 100 nm, a neutral zeta potential, and formulation efficiency greater than 85%. IT-141 facilitates prolonged circulation of SN-38 in the plasma compartment compared to SN-38 from irinotecan administration, and demonstrates potent antitumor efficacy in multiple human tumor xenograft models (Carie et al.). In an HT-29 colon cancer xenograft model IT-141 delivers 9 times more SN-38 to the tumor compartment compared to NKTR-102 (liposomal irinotecan, Nektar Pharmaceuticals), and 50 times more SN-38 to the tumor than NK-012 (polymer conjugated SN-38, Nippon Pharmaceuticals) (Figure). In addition, the geometrical arrangement of iron molecules around the core of the micelle imparts superparamagnetic properties that allow for theragnostic monitoring by magnetic resonance imaging (Sill et al.). Thus, clinicians can monitor the accumulation of intact nanoparticles in the patient tumor environment and determine potential response early in the treatment regimen. IT-141 is currently under active IND status, and a phase 1 clinical trial has been initiated.