As much as RNAi Therapeutics is contributing to and
benefiting from the fact that RNA Therapeutics as a whole is rapidly materializing as the 3rd 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.
