Sylentis Aims to Begin Phase I Study of Glaucoma Drug in September

By Doug Macron

Spanish RNAi drug shop Sylentis expects to dose the first patient in a phase I study of its glaucoma-associated ocular hypertension drug SYL040012 in Spain around the end of September, a company official confirmed to RNAi News this week.

The disclosure comes about a month after the company announced that it had received clearance from Spanish regulators to begin the trial, in line with its previously disclosed guidance (see RNAi News, 2/19/2009).

SYL040012 is an siRNA targeted against adrenergic receptor beta-2 and has demonstrated the ability to both reduce intraocular pressure and prevent glaucoma in animal models, according to the company. The trial will examine the drug’s safety and tolerability in healthy volunteers.

Background:

Spain's Sylentis Looks to Move siRNA-Based Glaucoma Drug into Phase I This Year
February 19, 2009
By Doug Macron

Spanish RNAi drugs shop Sylentis has completed non-human primate studies of a topical siRNA-based treatment for glaucoma and aims to begin testing the drug in humans before the end of the year, RNAi News has learned.

The company will perform initial clinical testing on its own in Spain, though it expects to later test the drug in other countries, including the US, Natalia Wright, Sylentis' head of intellectual property, told RNAi News this week.

Since the planned phase I trial would be Sylentis' first attempt at testing a drug in humans, the company wanted to ensure it has an active role in how it is run, which includes having the ability to easily visit the clinical sites, she said.

"It's just a case where, logistically, it's simpler" to run the trial in Spain, she noted.

Wright declined to provide specific details about the glaucoma drug or its target. However, at last year's Association for Research in Vision and Ophthalmology's annual meeting Sylentis presented in vivo data on a topically administered open-angle glaucoma drug candidate called SYL04003.

According to the abstract from that presentation, SYL04003 is an unformulated siRNA targeting carbonic anhydrase IV, a member of a family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide. Another carbonic anhydrase inhibitor, Merck's Trusopt, is already on the market as a treatment for elevated intraocular pressure associated with ocular hypertension and open-angle glaucoma.

SYL04003 was administered as eyedrops in saline solution to New Zealand rabbits to evaluate its effect on intraocular pressure levels, the abstract stated. Treatment resulted in a reduction in intraocular pressure of 14.47 percent, plus or minus 5 percent, for 72 hours, it notes.

As a comparison, treatment with Pfizer's approved eye pressure-lowering drug Xalatan cut intraocular pressure levels in the rabbits by 23.4 percent, plus or minus 2.36 percent, for five to six hours, the abstract states.

"The IOP decreases obtained by instillation of [SYL04003] in rabbits were maintained during one month of treatment with a daily dose with no rebound effect" and no side effects during or after the one-month treatment, the Sylentis researchers reported.

An in vivo analysis of target gene expression revealed "a clear reduction of mRNA levels in the ciliary body of treated animals," the abstract adds. "On the other hand, the preliminary toxicology experiments performed in rabbit and mouse showed no toxicological effects after [the drug's] administration."

In the end, these data "postulate SYL04003 as a new therapeutic candidate to treat ocular hypertension and open-angle glaucoma," the abstract concludes. "The IOP decrease obtained with [the drug] is similar to that produced by commercial drugs, but siRNA treatment shows a generalized long-lasting effect" compared with existing therapies.

Although its glaucoma program has long been Sylentis' most-advanced drug program, the company has made a slight change in course with its strategy for developing the candidate.

In early 2007, Sylentis Vice President Catherine Moukheibir told RNAi News that Sylentis expected to find an industry partner for the program before moving it into human trials (see RNAi News, 3/29/2007).

"I think we would prefer to work with a partner because … you are talking about a significant capital investment and you are talking about a knowledge [of clinical development] that we, today, do not have," Moukheibir, who is no longer with Sylentis, said at the time.

Read more: http://www.genomeweb.com/rnai/spains-sylentis-looks-move-sirna-based-glaucoma-drug-phase-i-year