Skip to main content
Premium Trial:

Request an Annual Quote

Spain's Sylentis Looks to Move siRNA-Based Glaucoma Drug into Phase I This Year


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.

[ pagebreak ]

But Wright this week said that Sylentis plans to advance the glaucoma program at least through phase I on its own.

As a unit of Spanish pharmaceuticals firm Zeltia, Syletnis does not need partnership funding to carry its programs into the clinic, she said. As such, "the general policy we have … is usually to finish phase I independently. Sometimes we even advance to phase II" before seeking partners, she added.

That is not to say the company isn't open to alliance discussions, however.

"We have conversations with other companies in the field … [and] if a partnership came up, it would be duly evaluated," Wright said. "But we don't actually search for [a deal] until after phase I."

As its glaucoma program moves forward, Sylentis is also continuing work on other programs, including ones in Crohn's disease and dry eye/ocular pain.

Wright said that both programs are at a very early stage, but that the company expects to advance the dry eye/ocular pain work into preclinical toxicology studies later this year.

At last year's ARVO meeting, Sylentis investigators reported data indicating that siRNAs targeting transient receptor potential cation channel-1 could be used to decrease the behavioral response of guinea pigs to ocular surface irritation.

Specifically, the team administered capsaicin, the pungent ingredient in chili peppers, into the right eyes of the animals, while saline was administered into the left eyes as a control. The number of scratching and wiping movements, as well as tearing and conjunctival hyperemia, were used as measures of eye irritation.

According to the abstract of the ARVO data, capsaicin administration resulted in a significant increase in irritation parameters compared with saline, and topical administration of TRPV1 siRNA twice a day for three days resulted in reduced scratching and wiping movements for up to nine days in the treated eyes.

No differences in tearing or hyperemia values were observed between the treated and control eyes.

"Capsaicin activates the corneal polymodal nerve terminals expressing TRPV1," the abstract stated. "These nerve fibers are involved in signaling irritation and pain. It is conceivable that a reduced activation of polymodal nociceptor fibers secondary to a lower expression of TRPV1 receptors is the reason [for] the attenuated behavioral response to corneal irritation," it concludes.

The work in Crohn's disease, meanwhile, is largely focused on overcoming the delivery hurdle that faces almost all RNAi drugs.

According to Wright, Sylentis had generated "good" proof-of-concept data in animal experiments, but found delivery to the human intestines "a bit trickier." The company has been considering a suppository-based delivery approach for the program, but is now weighing the possibility of oral administration, she said.

Sylentis is hoping that it can develop a method to deliver an siRNA payload to specific areas of the intestine since Crohn's disease affects different parts of the gastrointestinal tract in different patients, Wright said.

However, she stressed that this delivery approach is still in the conceptual stage.

The Scan

Suicidal Ideation-Linked Loci Identified Using Million Veteran Program Data

Researchers in PLOS Genetics identify risk variants within and across ancestry groups with a genome-wide association study involving veterans with or without a history of suicidal ideation.

Algorithm Teases Out Genetic Ancestry in Individuals at Biobank Scale

Researchers develop an algorithm known as Rye to tease apart ancestry fractions in admixed individuals at a biobank-scale, applying it to 488,221 UK Biobank participants in Nucleic Acids Research.

Multi-Ancestry Analysis Highlights Comparable Common Variants at Complex Trait-Linked Loci

Researchers in Nature Genetics examine common variants implicated in more than three dozen conditions, estimating genetic effect similarities across ancestry tracts in admixed individuals.

Sick Newborns Selected for WGS With Automated Pipeline

Researchers successfully prioritized infants with potential Mendelian conditions for whole-genome sequencing or rapid whole-genome sequencing, as they report in Genome Medicine.