Tuesday, November 4, 2014

Ocular Applications Back in the Focus of Oligonucleotide Therapeutics

Following yesterday's disclosure that yet another one of GSK’s target picks for clinical development under their antisense options agreement with ISIS Pharmaceuticals is an ocular one, I thought it worth highlighting that ocular applications are regaining traction in oligonucleotide therapeutics in general.  This follows a temporary lull in the area due to setbacks with older generations of the technologies and funding issues for the industry.

Aptamers still in the lead

It may surprise you, but the eye is the one area in oligonucleotide therapeutics where aptamers, nucleic acids binding protein targets based on their shape not sequence (similar to antibodies), are most advanced.  Despite of the fact that the first approved aptamer, Macugen, is considered a great disappointment as it lost out to the monoclonal antibody competition in the VEGF market for wet AMD and DME, there are at least two new development candidates that are poised to become blockbusters in the same market: Fovista by Ophthotech targeting PDGF which has shown unprecedented activity in a phase II study in combination with anti-VEGF antibody Lucentis, and an earlier-stage, but potentially superior VEGF/PDGF bispecific aptamer approach by privately held SomaLogic.

It is now thought that the Macugen failure was due to it not targeting the relevant VEGF isoforms.  In other words, it was a failure of target selection/biological insight, not a failure of the technology.  Aptamers should work well for trapping extracellular proteins for ocular applications, because unlike their often rapid elimination following systemic administration, they can be maintained at elevated concentrations in the eye for sustained periods of time.  Their limitation, however, is in the number of targets available to them, similar to monoclonal antibodies.  Nevertheless, it should be kept in mind that with even just 2 or 3 commercial successes in a therapeutic area, a platform technology can be considered tremendously valuable there.

Gene-regulatory oligos catching up

Although ocular drug development has also been popular in both the antisense and especially RNAi fields, previous technology generations were inadequate to effect robust gene modulation, especially target gene knockdown.  This holds true for 1st (à Vitravene) and 2nd generation (cRaf inhibitor by iCo Therapeutics) antisense and the ‘naked’ RNAi trigger folly of the early days of RNAi Therapeutics (à Acuity Pharmaceuticals, Sylentis, Quark, and Sirna/Allergan to name just some of the worst offenders of sound science).

The reason why antisense and RNAi are both staging a comeback in ophthalmology is due to the use of higher affinity chemistries (e.g. cET by ISIS) and self-delivering RNAi triggers, both in the form of (partially) double-stranded (e.g. sd-rxRNAs by RXi Pharmaceuticals) and single-stranded RNAi triggers (à ISIS Pharmaceuticals).  The increased stability and lipophilicity combined with small molecular size should allow such an RNAi approach to efficiently penetrate the vitreous of the eye following needle injection and reach deep into the retina and other ocular structures.  Similarly, what used to be a mediocre 40% knockdown for ASOs could now be a genetically much more useful 70-80% knockdown with gen2.5 RNaseH.

It is too early to tell whether RNaseH gen2.5, ssRNAi, or sdrxRNAs will win out in the end.  At least in terms of timing, it will be as much a matter of investing in the technologies as it is about their potential.  In particular, I am disappointed by the failure of RXi Pharmaceuticals to recognize the need to further develop their sd-rxRNA chemistry.

So keep your eyes peeled as clinical results from the new wave of gene-modulating Oligo Therapeutics will start to emerge in 2016 and beyond.  It is possible that QPI-1007 by Quark Pharma for ocular neuroprotection for NAION may be earlier than that, although the chemical nature of this ‘2nd generation’ non-AtuRNAi trigger remains unclear to me and therefore might be, or might not be a 'self-delivering' RNAi trigger.  If not this one, the upcoming clinical development of CTGF-targeting RXI-109 for retinal scarring by RXi Pharmaceuticals should be an interesting one to follow.


Terry Chrisomalis said...

I think RXII has an opportunity to capitalize on the eye indications as their technology penetrates the cells immediately as they are injected into the eye. More importantly specifically for macular degeneration Rxi Pharmaceuticals has developed a more potent anti-VEGF compound even greater than Bevasirnib. If they decide to combine that potent anti-VEGF compound with RXI-109 successfully they can make for a superior product on the market. This is because the VEGF component would handle the underlying blindness of macular degeneration while RXI-109 will handle the underlying tissue damage associated with the disease.

As for RXI-109 in scarring we have seen some efficacy from the 3 month pictures but the full 3-month photos will come Q1 2015. I think though that the company can do well with liver fibrosis or pulmonary fibrosis if RXI-109 succeeds in scarring in the upcoming results. Time will tell but RXII is well positioned in the RNAi space.

Anonymous said...

"As for RXI-109 in scarring we have seen some efficacy from the 3 month pictures but the full 3-month photos will come Q1 2015"

rxii is dead money until then. could be a grand slam long term but I don't like the risk. I've done well with with alny and rgls. Ebola scare gave me the gift of getting out of tkmr at a nice profit. rxii feels technically very weak right now and there's no institutional support.

Anonymous said...

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By Dirk Haussecker. All rights reserved.

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