Grant: Proof of Principle Program - Phase I

Bladder cancer is the fourth most prevalent cancer in the US with an overall mortality rate of 20% and the highest lifetime treatment cost per patient of any cancer. Despite the drivers of cost, high mortality and morbidity, no new therapies have emerged in the past few decades with numerous clinical trials showing no improvement over mitomycin C and Bacillus Calmette-Guerin (BCG), the current standard of care. Microtubules are one of the most successful targets in cancer therapy and the recent phase I trial of intravesical docetaxel for the treatment of non-muscle-invasive bladder cancer, refractory to BCG, has shown this to be a promising IVC agent. However, conventional formulations are maintained in the bladder for only 2 hours and urothelial drug exposure rarely lasts beyond the first voiding of urine, resulting in low drug uptake into bladder tissues. As such, there is a clear unmet need for formulations that improve the residence time and penetration of IVC agents. We have developed a novel polymeric drug delivery platform for the intravesical delivery of docetaxel employing Hyperbranched Polyglycerol (HPG) drug delivery technology. It has demonstrated superior efficacy in proof of concept studies in mice over the commercial Taxotere® formulation and provides enhanced drug retention and tissue penetration characteristics in in vivo and ex vivo studies. Ongoing research is exploring the mechanism of action of amine-modified HPGs, in particular the polymer's ability to alter bladder wall permeability by stimulating exfoliation of the urothelium. To enable commercial development, the chemistry to produce HPG polymers with a specified amine content must be further developed into a scalable process; and a more robust toxicology data package must be produced in rats, along with toxicokinetic endpoints. This proposal will determine the optimal formulation with respect to safety, enabling a future iteration to evaluate the formulation in a second efficacy model.