Don’t Bank on OncoGeneX Phase III Data

As much as RNAi Therapeutics is contributing to and benefiting from the fact that RNA Therapeutics as a whole is rapidly materializing as the 3^rd major drug discovery platform, this relationship could also backfire to some extent.  I am particularly thinking here about the upcoming OncoGeneX 2nd gen RNaseH-antisense (ASO) phase III results in prostate cancer (partnered with TEVA).

Obviously, a successful outcome of the SYNERGY trial which is analyzing the ASO compound custirsen (aka OGX-011) in combination with chemotherapy would be a big win for the field and represent the first more significant commercial success.  In February, the company announced that the pre-specified number of ‘events’ (i.e. deaths) had been reached in this ~1000-patient study, and depending on the robustness of the results (good or bad) we could be hearing any day now of the top-line results.

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.

Promising phase I PK-PD data at very high dose of 640mg

Consistent with the concern of unintended/undesirable immune stimulation, the apparent increase in overall survival observed in the phase II prostate cancer study of custirsen was seen at the dose of 640mg, a dose at the very upper limit of phosphorothioate chemistry (Chi et al. 2010).  This study in ~80 prostate cancer patients provided the rationale for investing in the ongoing phase III trial.

Unsurprisingly, immunostimulatory side effects in the form of chills and fevers were seen in the majority of subjects taking custirsen in combination with chemo, but not those on chemo alone (plus the liver and kidney tox you’d expect from such a high PS-ASO dose).  Moreover, the apparent clusterin knockdown, as assessed on the basis of the protein found in serum (not in cancer tissue directly), was a very modest ~30%.

This unsatisfactory degree of knockdown stands in stark contrast to a promising phase I PK-PD study which showed >90% knockdowns in prostate/tumor biopsies (Chi et al. 2005).  This was accompanied by mid- to high single-digit microgram of oligonucleotide concentrations per gram tumor tissue.  Such concentrations do not necessarily predict (normal) mRNA knockdown efficacy, but do not exclude such activity either. 

One explanation for the apparent discrepancy could be that the phosphorothioate oligo preferentially localizes to solid tumors and that solid tumors are not a significant source of serum clusterin. Possible, but...  

Under the radar for a reason

A sub $200M market cap for a company with imminent pivotal phase III data in prostate cancer and low trading volumes indicate that the market has not been paying all that much attention to Oncogenex. 

In this case, I would like to think for a good reason, and while I do not exclude ‘positive’ results (at the cost of considerable side effects and an uncertain mechanism of action), I hope that the public won’t read too much into them regarding the ongoing RNA Therapeutics revolution.  Every mechanism and chemistry has its place. PS-ASOs knockdown of (cytoplasmic) mRNA for cancer is not it. 

For cancer, RNAi and microRNA Therapeutics have the edge.