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Fumagillin is a naturally occurring metabolite from the fungus Aspergillus Fumagatus fresenius with potent anti-angiogenic and anti-metabolic effects. In a classic story of an experiment gone wrong, Dr. Ingber discovered the potent anti-angiogenic activity when his experiment was contaminated by fumagillin. Multiple small molecule drugs from this class have be in clinical trials for cancer and obesity, where anti-tumor and anti-metabolic effects were seen. However, small molecule fumagillin-derived MetAP2 inhibitors are generally poorly soluble and tend to cross the blood-brain barrier causing central neurotoxicity.
Fumagillin-class drugs inhibit methionine aminopeptidase type 2 (MetAP2), an enzyme that is over-expressed 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 when combined with traditional chemotherapy 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 the clear clinical benefits, 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 central neurotoxicity through polymer-drug conjugation. What we made had properties we didn’t expect.
After the polymer-drug conjugate is administered in the body via subcutaneous injection, the small molecule remains attached while in general circulation until specific 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. In a Phase 1 study of SDX-7320 in late-stage cancer patients, the Cmax of the released small molecule SDX-7539 was generally < 1ng/ml. Furthermore, the intrinsic properties of our polymer-drug conjugate change the bio-distribution and pharmacokinetic profile as compared to 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 (once every 2 weeks).