Cascade Prodrug employs a platform technology that has lead to our lead compound, CPD100.  CPD100 is a proprietary N-oxide prodrug of vinblastine, an approved cytotoxic vinca-alkaloid that is used clinically to treat several hematologic malignancies. CPD100 is stable at normal tissue O2 levels but ‘switches’ to cytotoxic vinblastine under hypoxic conditions. By creating a novel on-off switch for vinblastine, we take advantage of tumor hypoxia and trigger drug conversion in the tumor where it’s needed, thus limiting the exposure of healthy tissue to a potent cytotoxic agent. Cascade Prodrug believes that this technology will significantly increase the maximum-tolerated-dose of chemotherapy, thereby improving outcomes in patients with solid tumors.

Our studies have demonstrated that tumor cells grown in tissue culture are 25-times more susceptible to killing by CPD100 when they are incubated under hypoxic conditions.

Trifecta Chemotherapy Solution

Cascade Prodrug’s Trifecta Chemotherapy™ Solution brings three key therapeutic enhancements that will provide patients with improved chemotherapy options for treating a variety of solid tumor types: efficacy, safety and enhanced tumor penetration. These therapeutic enhancements are made possible by our proprietary hypoxia-activated prodrug switch—CPD100. This novel vinblastine prodrug has potent anti-tumor activity when exposed to the tumor microenvironment; it effectively masks vinblastine toxicity until it reaches the tumor, so it is much safer for the patient; encapsulation into small liposomal particles enables extended circulation times and enhanced tumor penetration.

EFFICACY   |   SAFETY   |   PENETRATION

Potent Anti-Tumor Efficacy

Two liposomal formulations of CPD100 have been developed that exhibit potent anti-tumor efficacy in established preclinical xenograft models in which hypoxic tumors develop. Both CPD100 liposomal preparations (CPD100-Li & CPD100-PEGLi) inhibited tumor growth in the A549 non-small cell lung cancer model, significantly outperforming both cisplatin (treatment control) and unformulated CPD100. Similarly, CPD100-Li also proved highly effective in the Panc-1 orthotopic pancreatic cancer model, a fast-growing tumor model that is normally resistant to treatment.

Non-small cell lung cancer solid tumor xenograft
CPD100 dosed at 40 mg/kg (iv) in all on-treatment cohorts
Cisplatin dosed at 2.5 mg/kg
tumor volumes at start of treatment normalized to 100%

Highly aggressive; difficult to treat; extreme hypoxia
CPD100 dosed at 40 mg/kg (iv) in all on-treatment cohorts
Gemcitabine dosed at 100 mg/kg (ip)
tumor volumes at start of treatment normalized to 100%

Summary

  • Liposomal encapsulation significantly enhances activity of unformulated CPD100 in both models
  • Treatment with Lipo-CPD100 outperforms treatment controls by slowing or halting tumor growth in all models examined to date
  • Combination with gemcitabine results in tumor regression with the Panc-1 model

Improved Safety Profile

We believe that Cascade Prodrug’s Lipo-CPD100 formulations will offer patients a significantly improved safety profile relative to currently approved chemotherapy agents. Our liposomal formulations of CPD100 have the potential to significantly reduce the side effects that would accompany an equivalent amount of vinblastine. We believe that our technology will significantly increase the maximum-tolerated-dose of chemotherapy, thereby improving outcomes in patients with solid tumors.

  • Lipo-CPD100 formulations have been well tolerated in all in vivo studies conducted to date in mice
  • No acute toxicities observed to date (MTD = 40 mg/kg)
  • No weight loss in tumor-bearing mice on treatment
  • Modest elevations of liver enzymes and hematological markers
  • Unformulated CPD100 has >10X greater MTD than vinblastine

Enhanced Penetration of Solid Tumors

Cascade Prodrug has optimized the pharmacology profile of CPD100 for treating solid tumors by developing two liposomal formulations: CPD100-Li & CPD100-PEGLi. These Lipo-CPD100 formulations have been engineered to enhance tumor penetration. They have an average particle size of 170 nm, which allows tumor penetration through the aberrant vascular endothelium found in many tumor types. Liposomal formulation also extends the circulation half-life of CPD100 by more than 10-fold. In mouse PK studies, unformulated CPD100 is rapidly cleared with a t1/2 of 0.4 h. By contrast, the t1/2 clearance rates observed with CPD100-Li and CPD100-PEGLi were 5.5 h and 9.5 h respectively. The small particle size, combined with extended circulation time, optimize the potential for efficient tumor penetration.

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