AAO/SOE 2008: Antisense IRS-1 Eye Drops Show Efficacy in Corneal Neovascularization

Emma P Hitt, PhD

November 11, 2008

November 11, 2008 (Atlanta, Georgia) — GS-101 eye-drop therapy results in a significant regression of corneal neovascularization, whereas treatment with placebo shows an increase in new vessels in all patients, according to the findings of a new phase 2 study.

Claus Cursiefen, MD, from the Department of Ophthalmology at the Friedrich Alexander University, in Erlangen, Germany, presented the findings in an oral session here at the 2008 Joint Meeting of the American Academy of Ophthalmology and the European Society of Ophthalmology.

"There are no agents approved so far for inhibition of corneal angiogenesis," Dr. Cursiefen told Medscape Ophthalmology. "The only option is off-label use of bevacizumab, which inhibits only VEGF [vascular endothelial growth factor], while topical steroids do not specifically target angiogenesis. By contrast, GS-101 targets more angiogenic signaling pathways, including interleukin-1-mediated pathways," he said.

GS-101 is an antisense oligonucleotide against insulin-receptor substrate (IRS)-1 that is being evaluated for the treatment of neovascularization as a preconditioning to corneal-graft replacement.

"Pathologic corneal neovascularization, both prior to and after keratoplasty, constitutes one of the strongest risk factors for subsequent immune rejections," noted Dr. Cursiefen during the meeting.

In an interim analysis of a multicenter double-blind randomized phase 2 study, researchers assessed corneal neovascularization in 40 patients with progressive corneal neovascularization due to different underlying diseases, including herpetic or bacterial keratitis, chemical burn, and contact-lens-induced keratitis.

Patients were divided into 4 groups: GS-101 twice a day at a total dose of 43, 86, or 172 µg/day, or placebo. The groups were followed for 3 months.

A dose of 86 µg/day produced significant regression of corneal neovascularization. In patients receiving this dose (n = 7), 6 patients (85.7%) demonstrated regression, compared with 0 patients in the placebo group (n = 6; P = .0047). No additional benefit was observed with the higher dose of GS-101, however; only 3 patients in the group receiving GS-101 172 µg/day (n = 8) demonstrated regression.

GS-101 appeared to be safe. A total of 57 adverse reactions occurred in 21 patients, of which 94.7% were deemed unrelated or unlikely to be related to treatment. All severe adverse reactions were considered unrelated to the study treatment. Three patients reported ocular surface discomfort.

"Based on data from the phase 1 and 2 studies, the compound seems to be very safe," he said. According to Dr. Cursiefen, epithelial and stromal wound-healing problems, including neurotrophic keratopathy, and altered corneal immune responses have all been reported with off-label intravitreal bevacizumab.

If approved, GS-101 would be the first specific inhibitor of angiogenesis available for use in the anterior segment of the eye. "Based on these encouraging interim results, the European Medicines Agency has recommended a phase 3 trial, which will start end of 2008," he said.

"We are all excited about the potential application of these new anti-VEGF agents for the treatment of new corneal neovascularization," said session moderator Terry Kim, MD, associate professor of ophthalmology at Duke University Eye Center, in Durham, North Carolina. "The current medications that we are using now are for off-label use, so it will be a benefit to have something specifically with an ophthalmic indication," he told Medscape Ophthalmology.

"This was a very heterogeneous population," Dr. Kim added, with more than "15 underlying causes of neovascularization. One of the reasons that a higher dose may not have been as effective is [because of] a difference among the dosinggroups — it would be interesting to see if there is some pattern linked to their original diagnosis."

The study was sponsored by Gene Signal, the manufacturer of GS-101. Dr. Cursiefen has disclosed that he is an advisor for Gene Signal.

2008 Joint Meeting of the American Academy of Ophthalmology (AAO) and the European Society of Ophthalmology (SOE): Scientific Session PO069. Presented November 10, 2008.

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