ATI-1123
Azaya Therapeutic’s lead product candidate, ATI-1123, is the PSN™ formulation of Aventis’ Taxotere (docetaxel). Docetaxel is a poorly water-soluble semi-synthetic taxane analog commonly used in the treatment of non-small cell lung, prostate, and breast cancer. Because of it is poor water-solubility Taxotere (docetaxel) is formulated with a toxic carrier Tween 80 to account for its poor solubility. This is done in order to achieve higher dose levels, contributing to numerous unwanted treatment-related adverse events such as hypersensitivity reactions; nausea, fatigue and anemia. The surfactant Tween 80 is toxic to healthy cells but improves the drug’s solubility and enables intravenous delivery. In short, current taxane formulations often complicate drug delivery and can alter both pharmacokinetics and toxicity profiles. Azaya Therapeutics, Inc. has encapsulated docetaxel (ATI-1123) utilizing a novel proprietary nanotechnology-based platform call Protein Stabilized Nanoparticle (PSN™) technology that avoids these major formulation issues, potentially resulting in a safer and more efficacious drug delivery system.
Pre-clinical Studies:
Azaya Therapeutics has completed pre-clinical studies with ATI-1123 validating the PSN technology, while significantly improving activity and pharmacokinetics compared with Taxotere.
Single agent efficacy studies were carried out in several human tumor xenograft models representing prostate (PC-3), pancreatic (PANC-1), and non-small cell lung (H460) malignancies. Standard docetaxel was tested intravenously (IV) at its maximum tolerated dos (MTD) and ½ MTD once every other day for three treatments (Q2Dx3) while ATI-1123 was administered IV at 12.5 and 25 mg/kg on an identical schedule. Significant endpoints for these studies included tumor growth inhibition (TGI), partial or complete tumor regression, and agent toxicity as measured by weight loss and deaths. In these studies, standard docetaxel produced dose-dependant tumor growth inhibition and statistically significant (p<0.05) activity at MTD. Comparable TGI results were reported in groups dosed with ATI-1123 at 12.5 mg/kg, suggesting liposomal encapsulation had no negative effect on drug activity. Treatment with ATI-1123 at 25 mg/kg resulted in statistically significant (p<0.05) tumor growth inhibition and partial tumor regressions in 90% (PC-3) and 70% (PANC-1) animals, which was not seen in groups dosed with standard docetaxel; weight loss measured was comparable with standard docetaxel at MTD compared to 25 mg/kg ATI-1123.
Pharmacokinetic (PK) studies were conducted using Azaya Therapeutics ATI-1123 (PSN formulation of docetaxel) compared with standard Taxotere. Animals were dosed at several concentration of standard docetaxel (Taxotere) or ATI-1123. Plasma samples for PK analysis were obtained at multiple time points ranging from time zero to 72 h. Total plasma docetaxel concentrations were analyzed and PK parameters were calculated by non-compartmental methods.
Plasma elimination of docetaxel following ATI-1123 and standard docetaxel was initially rapid, followed by a slower elimination rate out to 72 hours. Overall, the docetaxel AUC values for ATI-1123 were 4-fold or greater than the area under the curve (AUC) observed following treatment with standard docetaxel for all doses. The concentration max (Cmax) values were 3-fold or higher for ATI-1123 versus Taxotere over all 3 dose levels. As the dose increased, both AUC and Cmax increased dose proportionally. Overall, these differences in systemic exposure corresponded to a >5 fold clearance of standard docetaxel compared to ATI-1123 lipsomal formulation, independent of the dose level tested.
Total systemic docetaxel exposures were substantially enhanced following PSN-formulated docetaxel (ATI-1123) compared to standard docetaxel (Taxotere). Differences between the two formulations were consistent across the doses explored in the study. These data would suggest that the increased exposure of doxetaxel in ATI-1123 correlates to the improved activity and toxicities observed in the efficacy models.
