Oligonucleotide
Therapeutics investors keen on playing binary events such as
clinical trial read-outs should have the phase II iDEAL study of RNaseH
antisense compound iCo-007 in diabetic macular edema (DME) on their radars. This 2nd generation compound
targeting c-Raf had been discovered by ISIS Pharmaceuticals and was then licensed
to iCo Therapeutics.
The outcome
of that trial will also serve as a proxy for the utility of RNaseH
antisense for ocular indications, although higher-affinity chemistries might be expected to achieve superior results. In January, Roche gave their nod of approval to
this approach in signing a partnership with Danish LNA company Santaris.
In trying to
predict the outcome of the iDEAL study, I focused on the dose regimen in the trial in
light of the preclinical data. Once
again, given that Oligonucleotide Therapeutics enjoy virtually unlimited target
space, I typically give the target the benefit of the doubt. To be successful, however, you need both a
good target and sufficient targeting.
Preclinical studies
Similar to
OGX-011 discussed recently, the history of iCo-007 goes back to the time when
ISIS transitioned to second-generation 2’MOE gapmer chemistry. Following failure in clinical studies for cancer indications with first-generation chemistry, the antisense compound was converted
into 2nd generation chemistry with the same sequence and
re-positioned for ocular indications.
In a seminal
study by Danis et al. from 2003, a pig-specific anti-c-Raf sequence (ISIS
107189) was tested in pigs for c-Raf knockdown and a retinal vein occlusion
model of neovascularization (c-Raf is thought to play a role in the neovascularization
aspect of DME, e.g. downstream of VEGF signaling).
Disappointingly,
regardless of whether 34ug or 180ug of antisense were injected into the pig
eyes, there mere 40% target gene knockdowns were observed.
Of course,
it would have been more insightful if the human sequence, i.e. iCo-007,
had been evaluated in an animal efficacy model. Although I looked in vain for
such data, a 2009 analyst note by Versant noted that in a mouse model this had
indeed been done. Unfortunately, the
knockdown, again, was merely 40%:
iCo-007 preclinical data was
encouraging and was generated by partner Isis prior
to out-licensing the drug to
iCo. In mice experiencing new ocular blood vessel
growth, Isis administered
iCo-007 (then called ISIS 13650) to one eye and saline
to the other in two separate
injections, one administered seven days before
blood vessel growth
commenced, and then at onset of growth. Three days after
antisense dosing, c-raf
kinase mRNA levels in the eye were reduced by 40% but
were unaffected in the
saline-treated eye, and after seven days, c-raf kinase
mRNA levels were still reduced from baseline by 30%.
Question marks over phase II study design
The phase II
DME study is testing 350ug and 700ug iCo-007 either as monotherapy or in
combination with anti-VEGF antibody Lucentis or laser photocoagulation.
Although
350ug and 700ug in humans appear to be higher relative doses than 34ug and
180ug in pigs, given that there was no dose response in pigs I am not sure why
we should expect much increased c-Raf knockdown potencies in the phase II
study.
Another
cause for concern is the fact that the 208 subject study appears to lack a
control group according to the clinicaltrials.gov entry. So be prepared for positive headlines and fanciful comparisons to historical controls, similar to the ‘positive’ results from the
uncontrolled phase I study.
Altogether,
given the weak preclinical data and the questionable phase II trial design, I
remain highly skeptical that truly medically positive results, barring
non-specific anti-angiogenic effects due to immunostimulation of the
antisense molecule, will be forthcoming.
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