AEG35156
Targeted Therapeutic for Cancer


Cancer cells acquire multiple mutations that disable their normal response to apoptotic triggers. AEG35156, a 2nd generation antisense which targets XIAP, is designed to lower the apoptotic threshold of cancer cells, enhancing their sensitivity to intrinsic death and chemotherapy, without harming healthy cells. Aegera's published data with AEG35156, both in vitro and in vivo, strongly supports this hypothesis, and validates XIAP as a novel drug target for the development of anti-cancer therapeutics. AEG35156 has demonstrated strong efficacy in models of lung, breast, ovarian, colorectal and prostate cancers.

AEG35156 began Phase I clinical trials for cancer using a 7-day continuous infusion dosing regimen at two sites in UK in March 2004. This first monotherapy study has shown preliminary evidence of XIAP mRNA knockdown and suggestive evidence of anti-tumor activity. This monotherapy trial was amended to a 3-day continuous infusion (completed) and we have also initiated an additional trial using a 2-hour continuous infusion dosing regimen (ongoing). Two additional Phase 1b/2a clinical trials using AEG35156 in combination with Taxotere® in solid tumors and in combination with idarubicin/araC for the treatment of AML are currently ongoing in the US and Canada.

Background on XIAP


Although apoptotic pathways in cells are complex, most appear to converge on a single family of proteases, the caspases, that dismantle the cell in an orderly, non-inflammatory fashion. The mammalian gene family known as Inhibitors-of-Apoptosis (IAPs), first discovered by Aegera Founders, Drs. A. MacKenzie and R. Korneluk, are the only known cellular inhibitors of caspases. IAPs inhibit caspases which are responsible for the intrinsic mitochondrial death pathway triggered by chemotherapy and radiotherapy. In addition, they also effectively block the extrinsic, death receptor-mediated cell death pathway. Leading scientific opinion strongly believes that the X-linked Inhibitor-of-Apoptosis (XIAP) is the most potent member of the IAP family for in vitro caspase inhibition, and that XIAP provides the strongest protection in cells and animals from apoptotic events.