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OGXI > Don’t Bank on OncoGeneX Phase III Data

http://rnaitherapeutics.blogspot.de/2014/03/dont-bank-on-oncogenex-phase-iii-data.html

Reasons to be skeptical

In evaluating the prospects of an Oligonucleotide Therapeutics compound, I first ask whether the delivery has been firmly established and how good the target is.

Usually, since Oligonucleotide Therapeutics enjoy the benefit of being able to pursue virtually any target, target risk should be minimal.

Unfortunately, in this case, there are considerable risks in both the delivery and the target.

Custirsen targets clusterin expression. Clusterin has chaperone activity and is thought to protect cancer cells from stress, including stress arising from cancer therapies such as radiation and chemo. Accordingly, limiting clusterin activity by knocking it down would be predicted to improve the effectiveness of conventional cancer therapies.

The most important validating preclinical study in that regard comes from a publication by Zellweger and colleagues…from the year 2001 (which got me wondering about the patent clock). While some of the predicted effects were seen such as increased sensitivity to chemotherapy agents, the effect sizes were rather modest and their correlation with ASO potencies poor.

In general, in reviewing even more recent ASO chemistries such as cET2.5 for cancer (e.g. STAT3 by ISIS/AstraZeneca), I was struck by the poor correlation often seen between knockdown potency and therapeutic effect (e.g. much more potent anti-cancer effects with an ASO that had 20% knockdown activity compared to one that had 60% knockdown activity) and sometimes also between mRNA and protein levels (mRNA e.g. reduced by 50%, protein essentially disappearing; patent application WO2012/135736).

This raises the prospect that some of the apparent anti-cancer activities were not due to on-target efficacy, but due to some unintended side effects such as immune stimulation.