Tuesday, March 18, 2014

Preclinical Data Do Not Instill Confidence in iCo Therapeutics Trial Outcome

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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By Dirk Haussecker. All rights reserved.

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