Senesco reports encouraging results from pre-clinical studies of myeloma drug

SNS-01 is a nano-encapsulated combination therapy of Factor5A and an siRNA against Factor 5A. These studies, undertaken to determine the efficacy, maximum tolerated dose and the feasibility of long-term intravenous administration of SNS-01, were performed at the University of Waterloo, Ontario, Canada.

The company’s anti-myeloma efficacy study in severe combined immune-deficient mice with human multiple myeloma subcutaneous tumors tested SNS-01 dosages ranging from 0.15mg/kg to 1.5mg/kg. In these studies, mice treated with a dose of either 0.75mg/kg or 1.5mg/kg both showed a 91% reduction in tumor volume and a decrease in tumor weight of 87% and 95%, respectively. For mice that received smaller doses of either 0.38mg/kg or 0.15mg/kg, there was also a reduction in tumor volume (73% and 61%, respectively) and weight (74% and 36%, respectively). All of the treated mice, regardless of dose, survived, the company said.

This therapeutic dose range provided the basis for an eight-day maximum tolerated dose study in which normal mice received two intravenous doses of increasing amounts of SNS-01 (from 2.2mg/kg to 3.7mg/kg). Body weight, organ weight and serum levels of liver enzymes were used as clinical indices to assess toxicity. A dose between 2.2mg/kg and 2.9mg/kg was well tolerated with respect to these clinical indices, and the survival rate at 2.9mg/kg was 80%.

Those mice receiving above 2.9mg/kg of SNS-01 showed evidence of morbidity and up to 80% mortality. The 2.9mg/kg threshold, twice the upper end of the therapeutic dose range, was therefore determined to be the maximum tolerated dose in mice.

The final study, a nine-week repeated dose study in normal mice, was designed to assess toxicity following long-term administration of twice-weekly therapeutic doses (1.5 mg/kg) of SNS-01. This study also included a group of mice that were dosed with a mouse-specific eIF5A siRNA to determine whether there were any toxic effects of suppressing eIF5A in mouse tissues. The change in mean body weight of the treated and untreated mice was exactly the same over the course of the study.

According to the company, it is Senesco’s goal to file an investigational new drug application for SNS-01 before the end of calendar year 2009. The company will need to conduct longitudinal toxicology studies and meet with the FDA during this process.

Richard Dondero, Senesco’s vice president of R&D, said: These mouse efficacy studies allowed us to determine a proposed therapeutic dose range for SNS-01. The results of our pre-clinical toxicology and dose-ranging studies indicate a maximum tolerated dose 2-4 times higher than those producing anti-tumor effects in mice.