Trodusquemine (MSI-1436)
Approximately 113 million Americans are considered to be obese, and although only 4 million are being treated for weight loss, nearly 12 million are treated for co-morbidities (dyslipidemia and type 2 diabetes) that are associated with obesity. Experts in obesity and metabolic diseases suggest that up to 70% of the risk for developing type 2 diabetes is attributable to obesity. Approximately 46% of type 2 diabetic patients are obese, and it is estimated that their life expectancy is shortened by up to 2-5 years. Whereas exercise and diet control have proven beneficial to limit the health concerns of these syndromes, compliance issues and side effects limit their effectiveness.
MSI-1436 is a potent appetite suppressant discovered at Genaera that has been found to cause weight loss without metabolic rebound and normalize both fasting blood glucose, blood cholesterol and triglyceride levels in obese animals. We have confirmed these results in a number of strains of obese mice (including the diet-induced obese (DIO) male AKR/J mouse, Ob/Ob, Db/Db and Agouti mouse strains). This preclinical activity of MSI-1436 reduces food intake by appetite suppression.
In addition, MSI-1436 simultaneously enhances insulin sensitivity through inhibition of PTP-1B. With this molecule, we have overcome selectivity hurdles and have the only drug candidate which inhibits PTP-1B both centrally and peripherally.
We therefore believe MSI-1436 is a first-in-class molecule with a unique mechanism of action that is acting upon a scientifically validated target, and has the potential for use in treating two multi-billion dollar market opportunities, obesity and diabetes, characterized by unmet medical needs, huge costs to society, and epidemic growth rates. This drug candidate provides multiple investment opportunities by redefining the treatment paradigm.
Genaera began Phase 1 clinical studies with MSI-1436 in 2Q07.
Supportive Publications
Apparent receptor-mediated activation of Ca2+-dependent conductive Cl- transport by shark-derived polyaminosterols. Chernova MN, Vandorpe DH, Clark JS, Williams JI, Zasloff MA, Jiang L, Alper SL. Am J Physiol Regul Integr Comp Physiol. 2005;289(6): R1644-58.
A novel aminosterol reverses diabetes and fatty liver disease in obese mice. Takahashi, N, Qi Y, Patel HR, Ahima RS. J. Hepetology 2004; 41(3): 391-398.
Appetite suppression and weight reduction by a centrally active aminosterol. Ahima RS, Patel HR, Takahashi N, Qi Y, Hileman SM, Zasloff MA. Diabetes 2002; 51(7): 2099-2104
A spermine-coupled cholesterol metabolite from the shark with potent appetite suppressant and antidiabetic properties. Zasloff M, Williams JI, Chen Q, Anderson M, Maeder T, Holroyd K, Jones S, Kinney W, Cheshire K, McLane M. International Journal of Obesity and related Metabolic Disorders, 2000; 25(5): 689-697 [pdf]
Protein tyrosine phosphatase 1B deficiency or inhibition delays ErbB2-induced mammary tumorigenesis and protects from lung metastasis.
Julien SG, Dube N, Read M, Penney J, Paquet M, Han Y, Kennedy BP, Muller WJ, Tremblay ML.
Improvement of Peripheral Endothelial Dysfunction by Protein Tyrosine Phosphatase Inhibitors in Heart Failure. Vercauteren M, Remy E, Devaux C, Dautreaux B, Henry JP, Bauer F, Mulder P, Hooft van Huijsduijnen R, Bombrun A, Thuillez C, Richard V. Circulation 2006;114;2498-2507
Increased Insulin Sensitivity and Obesity Resistance in Mice Lacking the Protein Tyrosine Phosphatase-1B Gene. Mounib Elchebly, et al. Science 283, 1544 (1999)
Increased Energy Expenditure, Decreased Adiposity, and Tissue-Specific Insulin Sensitivity in Protein-Tyrosine Phosphatase 1B-Deficient Mice. Klaman LD, Boss O, Peroni OD, Kim JK, Martino JL, Zabolotny JM, Moghal N, Lubkin M, Kim YB, Sharpe AH, Stricker-Krongrad A, Shulman GI, Neel BG, Kahn BB. Molecular And Cellular Biology, Aug. 2000, p. 5479?5489.
Neuronal PTP1B regulates body weight, adiposity and leptin action Bence KK, Delibegovic M, Xue B, Gorgun CZ, Hotamisligil GS, Neel BG, Kahn BB. Nature Medicine 12, 917-924 (2006).