About Us: Background
Prior to founding Topo Medtech, Zhisong was principally responsible for the drug development program at the Christus Stehlin Foundation for Cancer Research. During his tenure they tested hundreds of compounds, both experimental and FDA approved drugs, on human tumors grown in the nude mouse model. This testing had never resulted in a complete regression of a human tumor. That is before they started testing CPT derivatives synthesized in the lab. With several of these derivatives, for the first time, complete regression was obtained in multiple tumors of several different tumor types. These results left little doubt of the enormous potential of these drugs.
The next step was to study these drugs in humans. Several clinical trials were performed with CPT based drugs. The first trial was with plain CPT (the natural extract). Fifty patients were treated with one complete response (CR) in a Stage 4 lymphoma patient. In the laboratory several new derivatives were designed which demonstrated improved efficacy and lower toxicity. One of these compounds was 9-NitroCamptothecin (9NC). This derivative was then studied in a Phase I trial and there was activity seen in pancreatic cancer. From these results a Phase II trial was initiated treating patients with pancreatic cancer. Even with the best medical care available the average survival is just 6 months.
106 patients with advanced pancreatic cancer were treated with survival as an endpoint. Of the evaluable patients approximately one third had no difference in survival, one third lived past 12 months and another third lived past 18 months, with 11 of these surviving 24 months with 2 long term cures. As good as these results were there was a tremendous disconnect between the near cure in the nude mouse model and these clinical results.
From basic laboratory research, it was determined that the last ring in the CPT drug must remain closed in the lactone form to be active. When the ring opens forming the carboxylate the compound loses over 90% of its activity. It was determined that the reason for the disparity between the mouse data and the pancreatic trial outcome was an albumin species difference between mouse and man. Albumin is a natural protein component of the blood and accounts for over 50% of blood protein. In the mouse blood there is a high concentration of active drug for several hours. Unfortunately Human Serum Albumin (HSA) has an avid affinity to bind to the inactive form of the drug (carboxylate) and causes rapid conversion of the active form of the drug to the inactive form. In humans in just one hour there is less than 10% active drug circulating in the blood. The encouraging news was that the positive outcomes in the Phase II pancreatic study were obtained with just this small fraction of active drug.
Topo Medtech's lead drug candidate has been synthesized to circumvent this binding to HSA, yet retain a high degree of anti-cancer activity. In vitro studies show that when this drug is incubated with Human Serum Albumin (HSA), there is more than a tenfold increase in active drug compared to 9NC. This increase in drug availability should translate into an even higher degree of efficacy. Clinical trials of this new drug are scheduled to begin in 2016.