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Sylentis Sees Phase III Trial for Glaucoma Drug by 2015

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With positive phase II data on its siRNA-based glaucoma treatment in hand, Spanish RNAi drug developer Sylentis is preparing to move into phase IIb study next year, with a pivotal trial possible by 2015, according to a company official.

Meanwhile, Sylentis is on track to complete enrollment for a phase I/II study of a treatment for pain associated with dry eye syndrome by year-end and release data shortly thereafter.

Sylentis was founded in 2006 as a spinoff of biotech firm Zeltia to develop topical RNAi therapeutics (GSN 3/29/2007). Although it began with an eye to both ophthalmological and gastrointestinal disorders, the company later sharpened its focus primarily onto eye diseases.

Since then, the firm has moved two drug candidates into human testing. The first, called SYL040012 is an unmodified 21-mer designed to silence adrenergic receptor beta-2 as a way to treat the ocular hypertension and elevated intraocular pressure associated with open-angle glaucoma. Given ADRB2's role in the synthesis of aqueous humour, a number of small-molecule glaucoma drugs against the target exist.

Administered as eye drops, SYL040012 has been examined in three clinical studies thus far. In the first, 30 healthy volunteers were given either a single 600 microgram dose of the drug or either a 600- or 900-microgram dose once a day for seven days.

Last month, Sylentis published the results of this study in Molecular Therapy, reporting that treatment was well tolerated with no local or systemic adverse events associated with the single dose and six mild adverse events in patients receiving repeated dosing.

Although all study participants had normal intraocular pressure levels, administration of the drug over seven days reduced intraocular pressure levels in 15 of the 24 patients who received this regimen, regardless of the dose used.

Notably, the drug was not detected in plasma of any of the study's volunteers, and a newly developed assay, which is designed to detect the presence of an SYL040012 metabolite that is produced only when the compound is inside of cells, indicated that the drug was only active in cells within the eye.

According to Paloma Tato, Sylentis' head of intellectual property, this finding is key to the company's efforts to differentiate its agent from small molecule ADRB2 antagonists, which are absorbed through the conjunctiva and naso-lacrymal duct, thereby entering the systemic circulation where they can trigger side effects that limit the dose that can be used.

In 2010, SYL040012 completed a follow-up study in volunteers with slightly elevated intraocular pressure but who were not receiving treatment, putting the drug on track for a phase IIa trial in glaucoma patients or individuals with elevated intraocular pressure.

A total of 80 patients were enrolled in that study and randomized to receive either one of three daily doses of the drug for 14 consecutive days or placebo. Data from this study have just recently become available, Tato told Gene Silencing News, and indicate that a 300 microgram-per-day dose led to a statistically significant reduction in intraocular pressure compared with placebo

"Further analyses of the results of this trial are currently ongoing," Tato added in an email. Assuming that the data are positive, Sylentis anticipates launching a phase IIb trial of SYL040012 next year, with phase III testing possible for 2015.

Sylentis' second drug candidate is SYL1001, a 19-nucleotide unmodified siRNA that targets transient receptor potential cation channel subfamily V member 1, which plays a role in pain sensitivity, for dry eye syndrome.

"Up to now, systemic and local wide-range analgesics are used for this condition without achieving significant pain reduction that is usually accompanied with undesired side effects," the spokesperson wrote.

Following animal studies that showed the compound could be administered topically and lessen ocular pain, the drug entered phase I testing in healthy volunteers in 2011. The next year, Sylentis kicked off a phase I/II placebo-controlled study in up to 60 dry eye patients to evaluate the drug's effect on ocular pain, as well as its safety and tolerability.

Sylentis aims to complete enrollment in this trial by the end of this year, with data ready in the first quarter of 2014.

Beyond the eye

In the years immediately after its creation, Sylentis had included programs in Crohn's disease and ulcerative colitis in its pipeline, which were centered on a proprietary oral delivery technology (GSN 4/1/2010).

The firm was also exploring central nervous system indications such as dementia and cerebral ischemia with a nasal delivery system, although these were much earlier stage than its other efforts.

By 2012, however, the company had pulled back on these initiatives in order to stay more streamlined, the company's then-head of IP had told Gene Silencing News.

This month, Tato indicated that Sylentis is continuing on this course, maintaining programs digestive and CNS diseases but dedicating the bulk of its resources to ocular diseases and its two clinical compounds.

The company is currently on the lookout for "new ocular pathologies" to add to its pipeline, she added, with more details likely to be available in the second half of next year.

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