Sep 26 2015
Celator Pharmaceuticals, Inc., a biopharmaceutical company that is transforming the science of combination therapy and developing products to improve patient outcomes in cancer, announced their successful R&D efforts to apply the CombiPlex® technology platform to optimize the efficacy of anticancer drug combinations incorporating molecularly targeted agents (MTAs).
CombiPlex is Celator's proprietary technology that aims to address several of the fundamental shortcomings of conventional combination regimens, as well as the inherent challenges in combination drug development. Celator is applying this technology to create new drug combinations that target pathways associated with tumor cell growth and/or resistance to treatment. Such MTAs are being widely pursued with an increasing focus on combining agents that target multiple cellular pathways in order to improve therapeutic responses.
"While there have been promising signs of activity for certain molecularly targeted agents, it is clear that combinations will be required for optimal efficacy," said Dr. Joseph Bertino, chief scientific officer at Rutgers Cancer Institute of New Jersey and chairman of Celator's Scientific Advisory Board. "In addition, many combinations will require simultaneous exposure and attempts to accomplish this to date have often led to toxicity problems."
CombiPlex is well positioned to address the challenges with the development of combination drug candidates. Nano-scale delivery systems coordinate the pharmacokinetics (PK) of drug combinations after administration so that the optimal ratio of the two drugs is exposed to tumor cells for prolonged times while reducing drug exposure and toxicity to normal tissues.
Recent results from preclinical studies conducted by Celator suggest the technology may significantly improve the therapeutic index of combinations containing MTAs. Celator's efforts have focused on two combinations: the heat shock protein 90 inhibitor AUY922 combined with docetaxel and the MEK inhibitor selumetinib combined with the Akt inhibitor ipatasertib. In both cases, the drug combinations were stably co-formulated in Celator's proprietary hydrophobic prodrug nanoparticle delivery systems which provided well-coordinated plasma concentrations over 24 hours that were orders of magnitude higher than observed for the free drug combinations. Free drug combinations refer to the drugs as they are currently administered; individual drugs administered in combination without regard to their ratio dependent interaction. In addition, whereas combined treatment with the free drugs required marked dose reductions due to toxicity, the nanoparticle formulations could be administered at higher doses.
For both combinations, the CombiPlex formulations provided significant improvements in efficacy over the free drugs in human xenograft tumor models including breast, colorectal and ovarian. Furthermore, there was evidence of strong drug ratio-dependent efficacy and in vivo synergy.
Another benefit observed during this research was the versatility and modular nature of the nanoparticle technology. Once formulation conditions were optimized for the two initial combinations, the drug components could be "mixed and matched," rapidly generating additional CombiPlex products with coordinated PK. This versatility was then taken one step further by generating a 3-drug combination, co-formulating selumetinib, AUY922 and docetaxel into a single hydrophobic prodrug nanoparticle.
The data have been accepted for presentation at the 2015 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics being held in Boston, MA November 5-9.
"We are very pleased with the data packages generated on the CombiPlex formulations containing molecularly targeted agents," said Dr. Lawrence Mayer, president and chief scientific officer at Celator. "CombiPlex appears to address difficulties associated with the free drugs, resulting in important efficacy improvements. We achieved this milestone on time, and believe these data may help Celator establish collaborative R&D programs with pharma partners where CombiPlex can provide a strategic advantage for their agents."