FAQ FOR HEALTHCARE PROFESSIONAL

Unlike other commercialized paclitaxel in the market which is produced from semi-synthetic process, PAXUS PM is produced with a novel technology resulting high purity and better toxicity profile of paclitaxel. This technology allows the production of paclitaxel from 1 cell derived from bark or leaf of Taxus Chinensis tree. There are 3 main steps of its process: fermentation, extraction/production and purification.

*(Data on file Samyang Corp)

The currently commercialized paclitaxel are using cremophor EL in Ethanol as vehicle to enhance drug solubility. Paclitaxel with Polymeric Micelle technology (PAXUS PM or Genexol PM- brand of Samyang) in lyophilized formulation utilizes the polymeric degradation system that replacing cremophor to minimize the toxicity effects of the vehicle solvent. This technology is developed by Samyang Corp Korea.

*(Kim TY, Clin Cancer Res 2004;10:3078-3716)

PM stands for Polymeric Micelle is a low molecular weight, biodegradable amphiphilic diblock copolymer, mPEG-DPLLA ( methoxy-Poly Ethylene Glycol - Poly (D,L-Lactide) with Lactose anhydrous ) which has 2 segments, hydrophilic and hydrophobic. The Hydrophobic segment of PM assemble with the active ingredient, paclitaxel performing a core structure, while its hydrophilic segment acts as the biodegradable shell which make the PM complex soluble in physiological solution.

* (Kim TY, Clin Cancer Res 2004;10:3078-3716)

Copolymer is a polymer derived from two (or more) monomeric species, as opposed to a homopolymer where only one monomer is used.

A polymer is a large molecule (macromolecule) composed of repeating structural units typically connected by covalent chemical bonds.

A covalent bond is a form of chemical bonding that is characterized by the sharing of pairs of electrons between atoms, or between atoms and other covalent bonds. In short, attraction-to-repulsion stability that forms between atoms when they share electrons is known as covalent bonding.

A micelle is an aggregate of surfactant molecules dispersed in a liquid colloid. A typical micelle in aqueous solution forms an aggregate with the hydrophilic "head" regions in contact with surrounding solvent.

*( J. M. Seddon, R. H. Templer. Polymorphism of Lipid-Water Systems, from the Handbook of Biological Physics, Vol. 1, ed. R. Lipowsky, and E. Sackmann. (c) 1995)

Because of paclitaxel's poor water solubility, systemic administration of this drug relies upon concomitant use of Cremophor EL (polyoxyl 35 castor oil, USP/NF) to produce an adequately soluble formulation.

Unfortunately, Cremophor EL use is also associated with patient toxicity as it is not well tolerated and leads to hypersensitivity reactions in some individuals.

To overcome these difficulties, clinicians have attempted to prolong infusion schedules or use corticosteroids and anti-histamines as a part of a pre-medication regimen. and the administration of paclitaxel would be less than 300 mg/m2. By replacing cremophor with PM, the higher dose is possible to use.

*(Data on file Samyang Corp)

PAXUS PM formulation consists of spherical, polymeric micelles, which do not aggregate or are taken-up by Reticulo-Endothelial System (RES) and thus freely circulate throughout the vasculature. The need for using a cosolvent to solubilize a compound is eliminated, thereby reducing the overall toxicity of the formulation.

Reducing overall toxicity potentially enables higher dose administration, which could improve therapeutic response. Eliminating the use of a cosolvent also eliminates any risk that the compound will precipitate in situ upon contact with blood, which again improves the safety profile for this drug. Some cosolvents require special administration sets to eliminate the risk of leaching plasticizer during infusion.

*(Data on file Samyang Corp)

Since cremophor had been replaced with PM, it is also removing all toxicities related to it. From result of clinical trial conducted by Samyang Corp – Korea when PAXUS PM administered in metastatic breast cancer as monotherapy setting, the premedication was not necessarily required prior to the treatment even though it was given in 300 mg/m2 or higher 1.7 times of conventional paclitaxel.

However depends on doctor decision to prescribe such premedication as there is still a chance to the development of hypersensitivity reaction due to paclitaxel itself.

*(Data on file. Samyang Corp)

Preparation of solution for infusion is simple. PAXUS PM should be reconstituted by injecting 5 ml or 16.5 ml of 0.9% NaCl or 5% Dextrose to each vial of 30 mg or 100 mg with aseptic syringe and needle and swirling gently to dissolve .

The next phase is to take that reconstituted solution (Pre-Mix Solution) and diluted with 0.9% NaCl or 5% Dextrose solution for infusion to a final concentration of 0.6 -3.0 mg/ml and swirled gently for complete mixing, and it should be visually inspected prior to administration. The solution of infusion should be administered over 3 hours.

*(Data on file. PAXUS PM product information)

As PAXUS PM is cremophor-free paclitaxel, so it is not necessary to use a non-PVC infusion set + bottle glass or any special set unlike other commercialized paclitaxel in the market.

Because there is neither the leaching of plasticizer from polyvinyl chloride (PVC) equipment nor the precipitation of paclitaxel crystal, it can be safely administered using conventional PVC infusion set without in-line filtration.

*(Data on file. PAXUS PM product information)

Study in patients with metastatic breast cancer (2006, Korea) use paclitaxel polymeric micelle as a single, first-line chemotherapy in 41 women with histologically confirmed metastatic breast cancer (MBC). The study showed the response rate-ITT was 58.5% (95% CI, 43.5;72.3), survival rate 21.7 months with main side effects were neutropenia (17.1%), neuropathy (41.5%) and hypersensitivity (19.5%).

The authors concluded that paclitaxel polymeric micelle at 300 mg/m2 appears to be a promising agent with high response rate for anthracycline sensitive MBC.

*(Breast Cancer: Lee KS, Chung HC, Im SA, et al. Multicenter phase II study of a cremophor-free polymeric micelle-formulated paclitaxel in patients (pts) with metastatic breast cancer (MBC). J Clin Oncol 2006 )

A combination clinical trial of paclitaxel polymeric micelle and cisplastin was performed in patients with non-small cell lung cancer (2007, Korea). Sixty-nine subjects with locally advanced, metastatic, recurrent NSCLC and no prior chemotherapy were given paclitaxel polymeric micelle 230 mg/m2 and cisplastin 60 mg/m2. This study showed the objective response rate-ITT was 37.7% (95% CI 26.3-49.1), median follow-up was 9.6 months. Main side effect was neutropenia (grade 3 / 4 neutropenia 46.4%) and neuropathy (grade 3 neuropathy 13%), a little higher than the conventional paclitaxel/cisplastin regimen (4% - 9%).

The authors concluded that this agent are promising, and further studies with different dosing schedules, in combination with other drugs or comparison with standard regimens are warranted. *(NSCLC : Kim DW, Kim SY, Kim HK, Kim SW, Shin SW, Kim JS et al. Multicenter Phase II Trial of Genexol-PM, a Novel Cremophor-free, Polymeric Micelle Formulation of Paclitaxel, with Cisplastin in Patients with Advanced Non-Small-Cell Lung Cancer. Am Oncol 2007. 18(12):2009-2014)

Final abstract no. 269 ASCO 2008, Podoltsev NA, et al presented from phase II clinical trial of paclitaxel PM in patients with advanced pancreatic cancer (APC) with total number of 56 patients and used 300 mg/m2 every 21 days over 3 hours infusion without pre-medication given.

This study showed the disease control rate was 60% with median overall survival 6.2 months. The authors concluded that in this advanced pancreatic cancer, paclitaxel PM was generally well tolerated and it is promising for further studies.*(Abst. No 269. Multicenter Phase II trial of Genexol-PM, a novel Cremophor-free, polymeric micelle formulation of paclitaxel in patients with advanced pancreatic cancer (APC): Final results)

Brand Name: PAXUS™ PM (South East Asia), GENEXOL® PM (Korea & other territories)