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Choosing Skin and Eye Disorders, RXi Will Face Well-Worn R&D Paths

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By Doug Macron

By selecting skin and eye disorders as its two areas of initial focus, RXi Pharmaceuticals will not only be taking aim at indications amenable to local routes of drug administration and have lower delivery hurdles, but it will also be treading a path well-worn by other players in the space.

Last week, the company announced it had chosen as its lead pipeline programs dermal anti-scarring and retinal diseases, including wet age-related macular degeneration and diabetic macular edema (related story, this issue).

During a presentation at an investor conference, RXi President and CEO Noah Beerman called the market opportunities for RNAi-based drugs in these indications "tremendous" and "significant." And based on the general activity in those areas, he is not alone in thinking so.

On the dermal side, Sirnaomics is developing an siRNA-based drug for wound healing dubbed STP-705 in collaboration with General Research Laboratory. The agent comprises siRNAs against two undisclosed targets delivered in a proprietary nanoparticle formulation.

Sirnaomics said that in in vivo testing, STP-705 has been shown to promote scarless wound healing and rapid wound closure. It expects to file an investigational new drug application for the product in the fourth quarter.

Already in the clinic with a skin disease treatment is TransDerm, which was founded to develop an RNAi-based treatment for a rare condition called pachyonychia congenita. Last year, the company reported that its lead drug candidate, TD101, was safe in a one-patient phase I study (GSN 4/23/2009).

That trial examined TD101 when administered via intradermal injections, and follow-on studies are expected to involve a topical, cream-based delivery vehicle.

When it comes to ocular diseases, it is Quark Pharmaceuticals that leads the pack with PF-4523655. The drug, formerly called RTP-801i, is an siRNA designed to silence the proprietary gene target RTP-801, which the company says plays a role in angiogenesis, vascular permeability, and retinal neuron death.

In late 2006, Pfizer acquired the rights to the drug (GSN 9/28/2006), which is now in two phase II studies: the first in diabetic macular edema and another in wet age-related macular degeneration.

Quark also recently initiated a phase I study an ocular neuroprotectant being evaluated for non-arteritic anterior ischemic optic neuropathy. That drug, QPI-1007, is expected to ultimately be developed as a glaucoma treatment (GSN 3/4/2010).

Meanwhile, Spain's Sylentis recently completed the first portion of a phase I/II trial of its own siRNA-based glaucoma drug, SYL040012, which targets adrenergic receptor beta-2 and is delivered topically rather than intravitreally (GSN 4/1/2010).

Sylentis expects to begin the second part of the study this summer.

Skin Deep, Opting Out

Perhaps as notable as the companies who have ongoing programs in dermatology and ocular disorders are those that bowed out of the fields after running into technological barriers.

The first RNAi player to throw its hat into the dermatology ring was Sirna Therapeutics, now a subsidiary of Merck. In late 2004, while still on its own, the company announced the establishment of Sirna Dermatology. Created through the acquisition of privately held Skinetics Biosciences, the firm predicted it could have a compound for permanent hair removal in fewer than two years (GSN 12/10/2004).

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Sirna never achieved this goal, and after it was acquired in 2007 by Merck the drug giant quietly shut down the dermatology division. While dermatology is not one of Merck's core focus areas, Joseph Carroll, a Skinetics co-founder who headed up Sirna Dermatology, in 2008 put the blame on difficulties facing transdermal delivery of siRNAs (GSN 1/24/2008).

Sirna became another ocular has-been with its wet AMD drug, Sirna-027, an siRNA targeting vascular endothelial growth factor receptor-1. In 2005, Allergan licensed the drug when it was still in phase I testing (GSN 10/7/2005), but disclosed two years later that it failed to meet the primary endpoint of a phase II trial.

The rights to the drug, which had been renamed AGN-745, were handed back to Sirna, which said it has no plans to further develop it (GSN 5/28/2009).

Another wet AMD drug program to fail in human trials was Opko Health's VEGF-targeting siRNA bevasiranib. Originally developed by Acuity Pharmaceuticals, which was acquired by Opko in early 2007 (GSN 3/29/2007), bevasiranib showed early potential.

But questions about its mechanism of action began to surface, most notably with a 2008 Nature study showing that the drug's anti-angiogenic effect was the result of toll-like receptor 3 activation rather than an RNAi effect (GSN 3/27/2008).

Bevasiranib managed to reach phase III testing, but Opko halted its development last year after preliminary data indicated the drug was "unlikely" to meet its primary endpoint (GSN 3/12/2009).

Flaming out even before it reached human testing was Alnylam Pharmaceuticals' wet AMD drug ALN-VEG01, another VEGF-targeting siRNA.

Once the company's lead program, the AMD effort was put on hold in 2005 in light of strong clinical data on more advanced AMD treatments being developed by other drug makers, including long-time Alnylam partner Novartis, which developed the gold-standard AMD drug Lucentis in collaboration with Genentech (GSN 9/23/2005).

At the time, Alnylam said that it would continue to pursue other ocular diseases as part of a collaboration with Merck, but that relationship ended in 2007, in part due to Merck's purchase of Alnylam rival Sirna (GSN 9/20/2007).

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