All dose groups of siRNA show positive change in visual acuity

Baltimore-Intravitreal injection of a small interfering RNA molecule (Sirna-027, Sirna Therapeutics Inc.) appears to be safe and well tolerated by patients for treatment of choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD), according to Edward J. Quinlan, MD, who reported the preliminary data from the phase I clinical trial.

"It has been shown that when double-stranded RNA enters a cell, an enzyme known as DICER cleaves it into smaller fragments that can combine with proteins to form a complex called RISC, or the RNA-induced silencing complex," he said.

"This silences the expression of the gene. The short RNA fragments have become known as siRNAs," said Dr. Quinlan, assistant professor of ophthalmology, Johns Hopkins University School of Medicine, Wilmer Eye Institute, Baltimore.

The siRNAs are highly versatile and can be designed to target any gene. In this case, Sirna-027 is designed to target vascular endothelial growth factor receptor 1 (VEGFR1) mRNA. Dr. Quinlan explained that Sirna-027 has been "chemically optimized" to enhance its stability, which is in contrast to most siRNAs, which have a short half life.

Mouse model

"Preclinical data have demonstrated the efficacy of Sirna-027 in a mouse model of laser-induced CNV," Dr. Quinlan reported.

In this study, after a laser was used to disrupt Bruch's membrane, the mice received either an intravitreal injection of Sirna-027 or a control substance. Fourteen days after treatment, the mice were perfused with fluorescein-labeled dextran and flat mounts of choroidal tissue were viewed by fluorescence microscopy.

"There was a marked reduction of target in the eyes treated with Sirna-027 compared with the control eyes," he said.

The investigators further quantified their findings by image analysis to measure the area of CNV in the mice. The investigators found a 66% reduction in the area of CNV in the eyes treated with Sirna-027 compared with the control eyes.

Phase I clinical trial

Based on these encouraging results, a phase I clinical trial has been started to assess the safety, efficacy, and dose-limiting toxicity of Sirna-027.

"This is the first trial in humans of a chemically optimized siRNA," he pointed out.

The study is an open-label trial of a single intravitreal injection of Sirna-027 in a dose-escalation manner. Visual acuity, optical coherence tomography (OCT), and fluorescein angiography are assessed throughout the study. Data will be collected and evaluated in order to determine what doses will be used in a phase II trial.

To participate in the study, patients had to be older than 50 years with active subfoveal CNV secondary to AMD. Lesions must be less than 12 MPS disc areas with blood and scarring occupying less than 50% of the lesion. The ETDRS visual acuity should be between 20/100 and 20/800 in the study eye.

Dr. Quinlan reported on 23 patients who have been treated thus far with 100-, 200-, 400-, 800-, and 1,200-μg doses of Sirna-027.

"There have been no serious adverse events or dose-limiting toxicities observed. There have been no signs of retinal or choroidal toxicity and no evidence of intraocular inflammation in any of the patients. All adverse events that have occurred have been mild and reversible and have been judged by the investigators to be unrelated to the study drug," Dr. Quinlan reported.