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We believed we could also improve upon the poor drug-like properties of this class of molecules, such as low solubility and short half-life.
Fumagillin-class drugs, derived from a fungus, inhibit methionine aminopeptidase type 2 (MetAP2), an enzyme that is overexpressed in many tumor types as well as in endothelial cells during angiogenesis. This class of drugs has shown efficacy in human trials, including:
a complete response in metastatic cervical cancer along with significant tumor shrinkage in metastatic breast, colon, renal and lung (both small cell and non-small cell) cancers and
Significant metabolic improvements in morbidly obese type 2 diabetic patients
Despite their clinical potential, fumagillin-based small molecules have been reported to cross the blood-brain barrier, causing neurotoxicity. This side effect halted the otherwise promising clinical development of Takeda’s anti-cancer agent TNP-470, the first fumagillin-class drug to enter clinical trials.
SynDevRx sought to solve the problem of neurotoxicity through polymer-drug conjugation.
After the polymer-drug conjugate is administered in the body, the small molecule remains attached while in general circulation until enzymes present in the diseased tissue cleave it from the polymer. Only after the small molecule is released does it become active.
A key benefit of our approach is an improved safety profile. The high molecular weight of the polymer-drug conjugate dramatically reduces the amount of active small molecule crossing the blood-brain barrier, thus decreasing the risk of neurotoxicity.
Furthermore, the intrinsic properties of our polymer-drug conjugate change the bio-distribution and pharmacokinetic profile versus the active small molecule alone. SDX-7320 exhibits significantly lower maximal drug concentrations and has a much longer half-life (24+ hours) than small-molecule fumagillin derivatives such as TNP-470. The result: potent inhibition of MetAP2 at much lower doses and with reduced dosing frequency.