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Zomer E.,Galectin Therapeutics Inc. | Klyosov A.A.,Galectin Therapeutics Inc. | Platt D.,Pro Pharmaceuticals
ACS Symposium Series | Year: 2012

The GMP process has been developed for manufacturing of GM-CT-01 (DAVANAT®), a modified galactomannan from Cyamopsis tetragonoloba, or guar gum. The material was structurally identified and characterized by standard analytical techniques, as well as by 13C Nuclear Magnetic Resonance (13C-NMR), Size Exclusion Chromatography with Multi Angle Laser Light Scattering (SEC-MALLS) for the molecular weight determination, and by Anion Exchange Liquid Chromatography with Pulsed Amperometric Detection (AELC-PAD) for carbohydrate composition and to establish the uniformity and purity of the final products. Both in the manufacturing of the bulk material and the final drug product, precautions were taken to control degradation by either thermal or microbial/enzymatic activity. As a parental i.v., the slow dissolving polymer was formulated as a sterile solution to make it easy to handling in a hospital. The shelf life of the polymer solution has been estimated to be at least nine years at room temperature. Pre-clinical studies with 5-fluorouracil, doxorubicin, irinotecan and cisplatin have shown no detectable toxicity along with a noticeable efficacy enhancement in both colon and breast cancer models in nude mice. Phase I and II clinical studies have been conducted, and the Drug Master File was submitted to the FDA in 2009. © 2012 American Chemical Society. Source

Klyosov A.,Galectin Therapeutics Inc. | Zomer E.,Galectin Therapeutics Inc. | Platt D.,Pro Pharmaceuticals
ACS Symposium Series | Year: 2012

DAVANAT® (trade name) or GM-CT-01 (operational name) is the galactomannan isolated from seeds of Cyamopsis tetragonoloba, or Guar gum, and subjected to a controlled partial chemical degradation. A backbone of the galactomannan is composed of (1→4)-linked β-D-mannopyranosyl units, to which single α-D-galactopyranosyl is attached by (1→6)-linkage. Chemical names of the galactomannan are 1,4-β-D-Galactomannan, or [(1→6)-α-D-galacto-(1→4)-β-Dmannan]. The average repeating unit of GM-CT-01 consists of seventeen β-D-Man residues and ten α-D-Gal residues (Man/Gal ratio is 1.7), and an average polymeric molecule contains approximately 12 of such repeating units (for the average molecular weight of 51,000 Da, though the specification permits it to be within 42 to 60 thousand Dalton). GM-CT-01 has been tested alone and in combination with a chemotherapy drug 5-Fluorouracil (5-FU) in pre-clinical studies, and in Phase I and Phase II of the clinical studies, as well as in the pre-clinical studies in combination with some other chemotherapy drugs such as Camptosar®, or irinotecan (IRI); Adriamycin®, or doxorubicin (DOX), Platinol® or cisplatin (CIS), and Eloxatin® or oxaliplatin (OXA). The pre-clinical studies employed nude mice at conventional-chemotherapy drug's tolerated doses, calculated to give approximately 50% inhibition of tumor growth. GM-CT-01 alone and a drug alone were given intravenously once every four days for a total of four injections (q4d x 4). GM-CT-01 was used at 30 and 120 mg/kg/dose, or co-administered as one injection on the same treatment schedule. Three tumors - colon tumors COLO 205 and HT-29, and mammary tumor ZR-75-1 - were used. The selected doses were well below LD50, and weight loss was insignificant. The average experiment in the preclinical studies lasted 35 to 60 days. Fourteen studies with three tumor models have resulted in the average overall improvement of tumor growth inhibition of 26 percent, with average improvement of 27 percent, 28 percent, 25 percent, 22 percent, and 14 percent for 5-FU, irinotecan, cisplatin, oxaliplatin, and doxorubicin, respectively. In the clinical studies (Phase I) GM-CT-01 was tested at doses of 30 to 280 mg/m2/day (0.74 to 6.9 mg/kg/day) co-administered with 500 mg/m 2/day of 5-FU, and after the non-toxicity of DAVANAT® was established as the principal result of Phase I, GM-CT-01 was tested in Phase II at the highest dose established as 280 mg/m2/day being co-administered with 5-FU at 500 mg/m2/day dose, according to the approved clinical regimen. All preceding treatments with approved therapies failed in their cases. In the Phase II study all (100%) patients had a primary diagnosis of colorectal cancer, and all (100%) patients had received prior therapy for their cancer, as indicated above. As reported in the "Final Clinical Study Report, Phase II Study, IND Number 64,034 of January 31, 2008", "no patient died on study". It was shown that: (a) DAVANAT® was non-toxic, and a DLT (dose limiting toxicity) was not reached, (b) 70% of the patients were stabilized at highest DAVANAT® dose level (280 mg/m2/day) level, (c) a 46% increase in longevity of the patients (based on the Median Overall Survival) was achieved compared with the Best Standard of Care, and (d) a 41% reduction of SAE (Serious Adverse Effects) was achieved compared to the Best Standard of Care. Phase II clinical studies was successfully complete, and objections for Galectin Therapeutics to move into a Phase III clinical trial was not expressed by the FDA. © 2012 American Chemical Society. Source

Ben-Josef A.M.,Pro Pharmaceuticals | Platt D.,Pro Pharmaceuticals | Zomer E.,Pro Pharmaceuticals
ACS Symposium Series | Year: 2012

A heat stable complex polysaccharide (molecular weight of 4300 Da) purified from the cell wall of the fungus Mucor rouxii (CPM) and a cationic polysaccharide from crab chitin (CPP) are potent antifungal agents both in vitro and in vivo. These compounds possess several highly desirable characteristics for the next generation of antifungal agents. First, being novel compounds, unrelated to the existing antifungal drugs, there is no cross resistance between the compounds and the currently used antifungal agents. Second is the importance of the rapidity of action, low MIC (Minimum Inhibitory Concentration) values and the lethal effect of these compounds against a wide spectrum of pathogenic yeasts. This will help reduce treatment duration and the development of untoward effects. Third, these compounds are heat and light-stable, making them promising to use for topical applications as was proven by the in vivo experiments with CPP. Fourth, being a large molecule with highly charged residues, these compounds are acting on external targets of the cell membrane. Thus, it is unlikely to develop resistance to CPM by the efflux mechanism that is a major cause of drug resistance in microorganisms including fungi. © 2012 American Chemical Society. Source

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