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After Acquiring Opko Assets, RXi Aims to Resurrect Former Phase III AMD Drug

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This story has been updated to include comment from RXi's management.

Roughly four years after being pulled from phase III testing amid poor indications of efficacy, the wet age-related macular degeneration treatment bevasiranib — the first siRNA drug to enter human testing — may be getting a second chance.

RXi Pharmaceuticals, which recently acquired bevasiranib, is in the process of testing whether its proprietary self-delivering technology, which eliminates the need for a delivery vehicle, can be used to enhance the compound’s ability to penetrate cells in the eye, RXi President and CEO Geert Cauwenbergh said last week at the Jefferies Global Healthcare Conference.

During a webcast presentation at the event, Cauwenbergh also provided some details on RXi’s other ocular disease programs.

Bevasiranib was originally developed by Acuity Pharmaceuticals, and comprised unformulated, unmodified siRNAs designed to inhibit vascular endothelial growth factor, or VEGF, as a way to suppress the ocular vascularization associated with AMD.

By 2006, bevasiranib had advanced through phase II testing, with clinical data showing that intravitreal injections of the drug were safe and could produce dose-dependent decreases in AMD-associated lesions.

Less than a year later, Acuity merged with two other companies to become Opko Health (GSN 3/29/2007). In the hands of the new company, bevasiranib’s development continued and, in mid-2007, it moved into phase III testing — an achievement that has yet to be reproduced with any other RNAi drug.

However, in early 2009, Opko disclosed that it had halted that study, which was evaluating bevasiranib in combination with the approved AMD treatment Lucentis, after a data-monitoring committee deemed it “unlikely” to meet its primary endpoint despite indications of drug activity (GSN 3/12/2009).

Opko said at the time that it intended to continue working on bevasiranib and in the RNAi space, but has made little mention of such efforts in the years since stopping the phase III trial . Then, in March this year, it announced that it had sold off its RNAi assets, including bevasiranib, to RXi in exchange for about $7 million in stock (GSN 3/7/2013).

RXi did not provide specific details about its plans for the Opko assets at the time, but at the Jefferies conference last week Cauwenbergh disclosed that it has been seeing whether it can resurrect bevasiranib.

Noting that the drug has already been proven safe in humans and capable of downregulating its target, he said that RXi plans to keep bevasiranib’s patented sequence but change its guide strand to incorporate the chemical and structural modifications that comprise the company’s self-delivery technology.

This, along with the addition of hydrophobic conjugation to the passenger strand to enhance cellular penetration, is expected to help the drug overcome the limitations that led to its failure in the clinic, he said.

Cauwenbergh did not provide any timeframe for when the new bevasiranib might be ready to make another try in the clinic, but cautioned that work with the molecule is “early-stage.” This week, he told Gene Silencing News that despite bevasiranib's previous testing in humans, a reworked molecule would "look quite different" than what Opko brought forth and that he expects RXi will have to conduct the "full gamut" of clinical studies.

If RXi should find success applying its delivery technology to the molecule, he added, the company may seek licensing arrangements with other companies that developed siRNAs that effectively silenced their targets but failed due to delivery issues.

Elsewhere in the Pipeline

RXi’s flagship drug candidate is the anti-scarring agent RXI-109, which comprises self-delivering siRNAs targeting connective tissue growth factor, or CTGF, a protein linked to wound healing and other fibrotic processes. Last week, the company announced data from a phase I trial showing the drug to be safe and well-tolerated, and it remains on track to advance the compound into a phase II trial for scar remodeling later this year (GSN 6/6/2013).

Behind RXI-109 are four other research and development efforts, all in ophthalmology. Aside from bevasiranib, RXi is developing RXI-209 for proliferative vitreal retinopathy, a condition caused by the buildup of scar tissue on the retina, often following surgery to correct a detached retina.

Like RXI-109, RXI-209 targets CTGF, and during his Jefferies presentation Cauwenbergh said that the drug has been shown to silence its target in normal rat retinas up to 48 hours following a single intravitreal injection.

Meanwhile, in a rat model of retinal detachment, the drug was found to penetrate all retinal layers 24 hours after injection and remain present up to 14 days later. Specifically, the drug was detected in Muller cells and photoreceptors, which are the “relevant reactive cells in retinal scarring,” Cauwenbergh noted.

RXi is also working on a combination therapy for diseases associated with ocular neovascularization and/or fibrosis such as AMD and diabetic retinopathy.

In preclinical testing, RXi has achieved dose-dependent mRNA silencing of up to 90 percent with a duration of action through 14 days in the rat retina with a VEGF-targeting compound. Cauwenbergh said that the company is examining whether this molecule can be combined with an RNAi agent against CTGF in order to provide a competitive advantage over existing VEGF inhibitors such as Lucentis.

Notably, he said that RXi may not have to develop this dual-targeting drug as a combination therapy, which could lower regulatory hurdles.

Finally, RXi is working on a treatment for retinoblastoma, a rare pediatric malignancy that develops in retinal cells, in collaboration with teams at Memorial Sloan-Kettering Cancer Center and Children’s Hospital Los Angeles.

Cauwenbergh said that in mouse models, RXi’s self-delivering siRNAs have been found to localize within retinoblastoma cells in the subretinal space and the vitreous, as well as the retina, following ocular injection. The molecules have also been shown to trigger dose-dependent mRNA silencing in retinoblastoma cell lines, according to his presentation.

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