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Early Phase I Data for Sirna s AMD Drug Positive; Phase II Planned for Mid-2006

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FORT LAUDERDALE, Fla. — Sirna Therapeutics released this week the first ever clinical data for an RNAi-based drug, announcing interim results from an ongoing phase I study of the company's age-related macular degeneration treatment Sirna-027.

The preliminary data were presented by Wilmer Eye Institute researcher and trial investigator Edward Quinlan at this year's Association for Research in Vision and Ophthalmology annual meeting, held here this week, and included results collected from 14 patients. The open-label study is set to enroll 30 patients. Data so far indicate that Sirna's drug is both safe and well-tolerated. The drug also appears to improve patients' disease in a dose-dependent manner, according to Sirna President and CEO Howard Robin.

"At this point in time … a single vitreal injection of Sirna-027 up to 800 micrograms appears to be safe and well-tolerated; no dose-limiting toxicity has been observed," Quinlan said at the meeting. "The visual acuity has remained stable in all patients, and we are awaiting the analysis of the [optical coherence tomography] and fluorescein angiography data."

Begun late last year, that phase I study is being conducted at the Wilmer Ophthalmologic Institute at Johns Hopkins University; the Cole Eye Institute; the Joint Clinical Research Center, which was developed by Harvard Medical School, the Massachusetts Eye and Ear Infirmary, and the Schepens Eye Research Institute; and the Jules Stein Eye Institute at the University of California, Los Angeles. It is evaluating a single, intravitreal injection of Sirna-027 administered in a dose-escalating manner. According to the study's protocols, cohorts of between three and six patients are to receive either a 100, 200, 400, 800, 1,200, or 1,600 microgram dose of Sirna-027, and then be evaluated for adverse events and improvement in visual acuity. Biological effects of the drug are evaluated by OCT and FA.

According to Quinlan, inclusion criteria for the trial include being over 50 years of age with active subfoveal choroidal neovascularization. Exclusion criteria include having received other AMD treatments or surgery within three months of enrollment in the study. Thus far, the phase I study has enrolled 14 patients, roughly half female and half male, with a median age of 80, he said at the ARVO meeting. Doses ranging from 100 micrograms to 800 micrograms have already been administered, and to date there have been no serious adverse events or dose-limiting toxicities in any of the patients.

"We have safety data up to 157 days [for the 100 microgram dose cohort, and] there have been no signs of retinal or choroidal toxicities," he said. "Adverse events that have occurred have been mild and reversible," and appear to be unrelated to Sirna-027. Examples of adverse events, which mostly occurred in patients receiving lower doses of the drug, include diarrhea and upper respiratory infection, Quinlan noted.

Additionally, visual acuity in the first three cohorts — which comprised four, three, and three patients, respectively — remains stable to date.

While the stability of visual acuity is encouraging, Robin told RNAi News on the sidelines of the ARVO conference that Sirna-027 also appears to improve a number of the patients' vision.

Johns Hopkins "investigators aren't allowed to draw conclusions in the middle of a trial," Robin said. "That's why [Quinlan's] conclusion was … that patients' disease hasn't progressed, [that] they've remained stable." But in about 50 percent of the patients who have received treatment — seven or eight out of 14 — visual acuity has improved in a dose-dependent manner, he said.

"If you look at [the] charts, at the 100 microgram [dose] you saw … no improvement," Robin said. "At 200 micrograms it went up, and at 400 micrograms it went up on an even steeper slope. So not only do you have a trend towards visual acuity improvement, you also have a clear dose-dependent trend."

Although the number of patients showing improvement is too small to draw conclusions about statistical significance, Robin pointed out that this was "the first time anyone has shown any kind of effect of an siRNA in humans, and I think that's a major event."

Should the dose-dependent benefit prove real, Robin said he expects that the higher doses of Sirna-027 that have yet to be evaluated will yield even greater improvements in vision.

"If … there is a dose-dependent improvement in visual acuity … then I would expect [the higher doses] show some robust effects," he said. "The other thing you have to realize is that some of the data you saw from [other AMD drug studies involved] … multiple monthly dosing. What you saw here was data on a single, low-dose administration — one injection, that was it. Now we have to see what higher dose, single-administration looks like and move into phase II."

The study's investigators are currently finishing administering the drug to the 800-microgram cohort, Robin noted, and dosing with 1,200 micrograms is expected to begin shortly. Barring any unforeseen circumstances, Sirna expects to complete the phase I study around September, about six months ahead of schedule, and begin a phase II trial by "the middle of next year at the latest," he added.

Ultimately, Robin said he would hope Sirna-027 would not only be more effective than existing AMD drug therapies such as Eyetech's and Pfizer's Macugen, but also have a better dosing schedule. Macugen is administered once every six weeks.

Noting that Genentech's investigational AMD drug Lucentis "is planned to be dosed once a month," he said, "I'd like to see an siRNA dose less frequently than that."

Robin certainly isn't alone in that regard. Currently, Acuity Pharmaceuticals, Quark Biotech, and Alnylam Pharmaceuticals are all in the process of trying to develop a better AMD therapy using RNAi.

Acuity announced this week that interim top-line safety data on its siRNA-based therapy for AMD Cand5, which entered the clinic just before Sirna-027, indicates the drug is "positive with no drug-related adverse events." The company did not provide any efficacy data, but said that additional results from the trial would be released later this year.

As for Quark, CEO Daniel Zurr told RNAi News in March that his company plans to file an investigational new drug application to begin phase I testing of an siRNA targeting the gene RTP801 for AMD by the end of the year (see RNAi News, 3/18/2005). Meanwhile, Alnylam has not publicly provided any guidance on when it anticipates advancing its preclinical AMD therapy into human trials.

— DM

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