AEG35156, a XIAP antisense oligonucleotide, suppresses XIAP levels in targeted tissues isolated from pre-clinical models and from patients

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X-linked inhibitor of apoptosis (XIAP) is a potent anti-apoptotic protein whose over expression and dysfunction is associated with resistance to chemotherapy and radiotherapy. AEG35156 is a synthetic 19-mer, 2^nd generation, mixed backbone antisense oligonucleotide to human XIAP. Inhibition of XIAP expression by AEG35156 enhances cancer cell apoptosis both in vitro and in vivo, either as a single agent or in combination with chemotherapeutic agents. In animal models, AEG35156 reduced XIAP-mRNA and protein levels in representative tissues at therapeutically feasible doses. In a H460 human lung carcinoma xenograft study in mice, AEG35156, effectively suppressed XIAP protein levels in tumors at doses that achieved dramatic reductions in the rate of tumor growth, particularly when combined with suboptimal doses of docetaxel. A murine-specific variant of AEG35156 attenuated XIAP protein in circulating PBMCs and bone marrow when administered s.c. to mice at < 10mg/kg. A continuous IV infusion study in cynomolgus monkeys revealed that AEG35156 reduced XIAP protein levels in liver and kidney in a dose-dependent manner. XIAP liver protein levels fell 60% and 80% in animals infused with 2.5 mg/kg and 10 mg/kg AEG56156, which achieved steady state plasma levels of 0.250 and 1.25uM, respectively. A Phase 1, 7-day continuous IV infusion evaluation of AEG35156, as a single agent, conducted in collaboration with the Cancer Research-UK has demonstrated steady-state plasma levels ranging from 0.2uM to 0.6uM. Evidence of XIAP-mRNA knockdown and suggestive evidence of antitumor activity have been observed. One patient with refractory low grade NHL experienced repeated marked reductions in circulating lymphoma cells during AEG35156 infusion, concurrent with XIAP-RNA knockdown of >80%. Flow cytometric analysis of the patient’s circulating blasts indicated a loss of XIAP protein, and elevated levels of activated caspase 3 and PARP cleavage during AEG35156 infusion. XIAP antisense also caused a dose-dependent reduction in XIAP-mRNA in PBMCs in most patients, suggesting that these cells could serve as a surrogate to target effects in solid tumor tissue. Other trials with AEG35156 are currently underway: a Phase 1 trial in combination with docetaxel in Canada (sponsored by National Cancer Institute of Canada), and an AML trial, in combination with idarubicin and ara-C, in the US and Canada. ( )