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At UBS, Opko Outlines RNAi Programs Showing Commitment to the Technology

Officials from Opko Health this week presented the investment community with an overview of the newly formed company at the UBS 2007 Global Life Sciences conference in New York, detailing both its broad interest in ocular pharmaceuticals and instrumentation and its growing portfolio of siRNA-based drug candidates.
Opko was created early this year when Acuity Pharmaceuticals merged with private ophthalmic drug firm Froptix and the public shell company eXegenics (see RNAi News, 3/29/2007). Although the new company promotes itself as one focused on ophthalmics — much like Acuity did — statements by management at the UBS conference indicate that it remains committed to RNAi.
Opko is “proud and excited about its siRNA portfolio,” Sam Reich, an Acuity co-founder and now executive vice president of Opko’s ophthalmologics division, told RNAi News this week. “We maintain the high priority of it and all of the senior management of Opko realizes the tremendous value in it.”
During his presentation at the conference, which was webcast, Reich highlighted bevasiranib, an siRNA developed at Acuity that targets vascular endothelial growth factor and which recently entered phase III testing for wet age-related macular degeneration. As first reported by RNAi News, Opko is evaluating the drug as a maintenance therapy for the disease in combination with Genentech’s Lucentis (see RNAi News, 6/28/2007).
Bevasiranib has also been tested in phase II trials for diabetic macular edema.
Reich also provided a glimpse at some of the other siRNA drugs making their way through Opko’s development pipeline along with a number of non-RNAi-based compounds.
The company’s most advanced siRNA candidate behind bevasiranib, Reich said, is one that targets a subunit of the transcription factor hypoxia-inducible factor 1 called HIF1-alpha.
According to Reich, HIF1-alpha is responsible for the up-regulation of numerous pro-angiogenic cytokines including VEGF. As such, a drug targeting HIF1-alpha could take the form of a next-generation wet AMD treatment “or some kind of adjunct therapy for aggressive ocular neo-vascular disorders,” he told RNAi News.
Opko has already identified a lead siRNA candidate for this program and has generated “solid preclinical proof-of-concept and pharmacology data in vivo,” Reich said. “We’re now exploring entering the development stage.”
At the UBS meeting, Reich also touched on Opko’s Syk kinase program, which Acuity acquired from ZaBeCor last year (see RNAi News, 5/4/2006).
Syk kinase is a cell-signaling molecule shown to play a central role in initiating critical elements of inflammation. Reich told RNAi News that there are a number of ocular conditions currently treated with steroids that would make promising targets for an siRNA drug against Syk kinase, including diabetic macular edema and posterior uveitis.
“Currently, steroids are used widely in the eye and they have significant side effects such as causing cataract and intraocular pressure,” he explained. “So we would hope that [a syk kinase targeting drug] would provide the same therapeutic benefit as steroids … without the side effects.”
The last siRNA program Reich discussed at the conference is one focused on transforming growth factor beta receptor 2, or TGF beta receptor 2, which is associated with inflammation and fibrosis.

Opko is “proud and excited about its siRNA portfolio. We maintain the high priority of it and all of the senior management of Opko realizes the tremendous value in it.”

He told RNAi News that a drug silencing TGF beta receptor 2 could prove useful in treating the fibrosis associated with wet AMD.
“VEGF therapies [such as Lucentis and bevasiranib] really only deal with the angiogenic component of the disease,” he said. “We think there may be a place … for an anti-fibrotic agent.”
Opko is also developing siRNA drug candidates against Intracellular adhesion molecule-1, or ICAM-1, and Angiopoietin-2, or Ang-2. However, because of the preliminary nature of these programs, they were not discussed at the UBS meeting, Reich told RNAi News.
“Those [drug candidates] could have a variety of uses … but they’re earlier in the development stage so we’re not discussing them as much,” he said, adding that active research on these compounds is ongoing, however.
ICAM-1 “is involved in inflammation and has been studied for different inflammatory conditions,” he explained. “It’s thought to be importantly involved in diabetic retinopathy … [but] could have applications beyond ophthalmology.”
Ang-2, meanwhile, “is one of the pro-angiogenic cytokines that is heavily implicated in ocular neo-vascular diseases. It’s up-regulated by the Hif1 alpha pathway … and it has been shown to interact with VEGF — like a feedback loop, it causes [increased] VEGF up-regulation,” Reich said.
In light of a growing body of preclinical evidence showing that VEGF and angiopoietin-2 likely work together in the angiogenesis pathway, “an Ang-2 therapy could be synergistic with a VEGF therapy,” he added.
Reich declined to offer any kind of timeline for Opko’s preclinical siRNA programs, noting that “we’ll be announcing … milestones … as we hit them. In the future, we hope to be able to give guidance on [the timing of] these programs.”

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