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Opko Health Says Intravitreal Dose of siRNA AMD Drug Reaches Target Tissues in Animals

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Researchers from Opko Health last week published preclinical data showing that the company’s siRNA-based treatment for wet age-related macular degeneration, when injected intravitreally, is distributed throughout the eye, including to key retinal pigment epithelium cells.
 
The drug, called bevasiranib, is currently in phase III testing.
 
These data indicate that following intravitreal injection, bevasiranib distributes to the ocular structures relevant to the … neovascularization associated with vision loss in wet AMD,” Samuel Reich, executive vice president of Opko’s ophthalmics division, said in a statement.
 
"It is noteworthy that bevasiranib was distributed to the RPE cells, since we believe that even a fraction of the tissue-associated bevasiranib entering the RPE cell is likely to be effective in specifically suppressing” production of the growth factor associated with the disease’s hallmark neovascularization, he added.
 
In an interview with RNAi News this week, Reich also confirmed that Opko continues to develop additional RNAi drugs, including ones that may address other aspects of AMD’s pathology beyond VEGF. However, he declined to provide a timeframe for when specific details about these programs might become available.
 
Currently, Opko is evaluating bevasiranib a phase III trial as a maintenance therapy for AMD in combination with Genentech’s Lucentis, an approved drug that also targets VEGF (see RNAi News, 6/28/2007). Top-line efficacy data from that study is expected to be available in the second half of 2009.
 
“One of the questions in the general scientific community … is, ‘What is the fate of an siRNA after it is injected into the vitreous?’” Reich said. “We thought [that] with our drug in phase III, it would be an appropriate time to share our findings … that, indeed, [bevasiranib] does make its way from the vitreous, through the retina, and get into the RPE cells intact in the form necessary to mediate RNA interference.”
 
The data, which appeared in the May 28 issue of Molecular Vision,also show that bevasiranib is present in the eye in concentrations sufficient to mediate a “complete knockdown” of vascular endothelial growth factor A, the angiogenic growth factor targeted by the drug, he added.
 
In the study, the Opko investigators delivered a single injection of .5 mg or 2 mg of radiolabeled bevasiranib into the vitreous of 32 rabbits. Reich noted that these doses are equivalent to those being tested in the phase III study.
 

“One of the questions in the general scientific community … is, ‘What is the fate of an siRNA after it is injected into the vitreous?’ We thought, with our drug in phase III, it would be an appropriate time to share our findings.”

The rabbit eyes were then dissected into different ocular tissues and analyzed for radioactive content, “which is a … standard way to follow a drug or material throughout a tissue or organism,” Reich explained. The analysis revealed that the drug was present in the vitreous, iris, retina, RPE, and sclera.
 
“As expected, the highest concentrations were found in the vitreous, and vitreous levels steadily decreased over time, while concentrations of radioactivity in the other ocular tissues increased to maximum values between 24 [hours] and 72 [hours] after dosing,” the researchers wrote in the paper.
 
This study was followed by an experiment in which 2 mg doses of non-radioactive bevasiranib were injected once into the vitreous of a new set of rabbits. One day after treatment, the rabbit eyes were dissected and analyzed for evidence of intact drug using a locked nucleic acid non-competitive hybridization-ligation enzyme-linked immunosorbent assay.
 
The assay confirmed the presence of intact bevasiranib in ocular tissues 24 hours after administration, “suggesting [the drug] is not only taken up by the tissues, but that some remains intact for an extended period of time,” the authors wrote.
 
“These and previously published data from our laboratory collectively provide strong evidence that after an intravitreal or subretinal injection, bevasiranib does distribute to the retina and RPE [cells] … and therefore should effect the RNA interference mechanism resulting in gene silencing to halt the production of VEGF-A in those tissues,” they concluded.
 
RNA Aye
 
Since it was established last March (see RNAi News, 3/29/2007), Opko has been building itself into an ophthalmics healthcare company with broad developmental interests, including small-molecules and instrumentation.
 
But the company has maintained a focus on RNAi and has several early-stage programs ongoing using the gene-silencing technology, Reich told RNAi News.
 
One of the firm’s most promising candidates involves siRNAs targeting a subunit of the transcription factor hypoxia-inducible factor 1 called HIF1-alpha.
 
HIF1-alpha is responsible for up-regulating numerous pro-angiogenic cytokines including VEGF, according to Reich. An RNAi drug suppressing this target could potentially “inhibit the entire pathologic angiogenic cascade, which includes VEGF [and] other factors,” while leaving behind the VEGF that may be required by the eye, he said.
 
Opko is also developing siRNAs against transforming growth factor beta receptor 2, which is associated with inflammation and fibrosis.
 
“With VEGF inhibitors [such as Lucentis] on the market and ours coming along, the angiogenic element of wet AMD is well-addressed,” Reich said. “But there are fibrotic components of the disease [for which] there currently is no drug.”
As a result, AMD patients frequently hit a therapeutic ceiling following treatment with VEGF suppressors, Reich said. “But there is still more vision to be gained.
 
“We believe we may be able to break through the ceiling by addressing the fibrotic component of the disease, [and an] siRNA might be a nice … component of the eventual treatment profile of a wet AMD patient,” he said.
 
Opko has yet to provide details on their status.
 
“Hopefully, in the not-too-distant future, we’ll be able to make more announcements … about our next siRNA program,” Reich added.

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