IT-147 is a formulation of epothilone D encapsulated using IVECT polymer micelle nanoparticle technology, and is currently transitioning from preclinical to clinical development.

Epothilone D is a naturally occurring chemical that was originally isolated from microbes in soil. It was found to have potent cytotoxic effects against cancer cells by binding to microtubules that form during cell division. This stabilizes the tubules, locking them in place, and halting cell proliferation. Other drugs on the market, such as Taxol, share this mechanism of action for cancer therapy. However, patients can become resistant to Taxol treatment allowing cells to bypass the cytotoxic effects. Epothilone D has shown the ability to overcome multi-drug resistance in cancer cells, which can be a significant advantage in the clinic. Development of epothilone D was halted after phase II clinical trials due to the toxicity profile of the drug at the therapeutic dose. Toxicities included neurotoxicity such as cognitive impairment and peripheral neuropathy, and studies have shown that a significant portion of the drug crosses the blood-brain barrier. The IT-147 formulation sequesters the epothilone D inside the core of a stabilized nanoparticle which keeps the body protected from the drug as it circulates in the blood, limits the amount of drug that accumulates in the brain, and targets the release of the drug to the tumor environment. IT-147 development has been partially funded by Small Business Innovative Research (SBIR) phase I and II contracts from the National Cancer Institute and National Institute of Health.

Technical Overview

IT-147 is a formulation of microtubule inhibitor, epothilone D, encapsulated in a stabilized polymer micelle. The drug product is a lyophilized powder for reconstitution in saline for intravenous infusion. The average nanoparticle diameter for IT-147 is 70 nm, and has a neutral zeta potential. Encapsulation of epothilone D using IVECT triblock copolymer results in greater than 90% formulation efficiency, and has been manufactured on a 200 gram scale to facilitate dose range-finding studies for IND-enabling animal toxicity studies. Preclinical studies demonstrated a 4-fold increase in maximum tolerated dose for IT-147 compared to epothilone D free drug. Plasma pharmacokinetics for epothilone D from IT-147 showed a 2-fold increase in CMax, a 4-fold increase in AUC, and greater than 10-fold increase in terminal half-life compared to epothilone D free drug. Biodistribution studies resulted in a 9-fold decrease in exposure (AUC) of epothilone D to the brain from IT-147 compared to free drug. Delivery efficiency to the tumor for IT-147 was 7.1%, which is the highest delivery efficiency reported in the literature and 10-fold higher than the average drug delivery efficiency for nanoparticles as reported by Wilhelm et al (Nature Reviews Materials, 2016). In addition to increasing the therapeutic window for epothilone D, IT-147 has inherent theragnostic properties based on the arrangement of iron molecules bound to the stabilizing blocks of the polymer chains. This will allow clinicians to monitor accumulation of the intact nanoparticles in the tumor microenvironment by magnetic resonance imaging.