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Acuity Reports Positive Phase II Data for AMD Drug; Eyes Phase III in Mid-'07, NDA in Mid-'09

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Acuity Pharmaceuticals this week released additional results from an uncontrolled phase II trial of its siRNA-based therapy for wet age-related macular degeneration, reporting that its drug was safe and produced dose-dependent decreases of the lesions that characterize the condition.
 
The company said that the results support advancing the drug bevasiranib, formerly known as Cand5, into phase III testing by mid-2007 with the goal of filing the drug for approval as a maintenance therapy two years later.
 
"The [phase II] data provides us with confidence to proceed into phase III pivotal trials, a clear path to eventual product approval, and strong evidence that bevasiranib has the fundamental attributes needed for competitive positioning in the large and growing ophthalmic marketplace,” Acuity President and CEO Dale Pfost said in a statement.
 
The data were presented at the 24th annual meeting of the American Society of Retina Specialists in Cannes, France.
 
Bevasiranib is an unmodified siRNA designed to inhibit the expression of vascular endothelial growth factor. According to Acuity, the phase II trial — called CARE, or Cand5 Anti-VEGF RNAi Evaluation — enrolled 129 patients with classic or active minimally classic AMD, including ones who had failed previous therapy.
 
Trial participants were randomized to receive one of three different dose levels of bevasiranib — either 2 mg, 1.5 mg, or 3 mg per eye. They received two intravitreal injections of the drug, one at the outset of the trial and one at week six. Patients were evaluated every three weeks over an 18-week period.
 
Acuity said that all doses of bevasiranib were well tolerated, and that most adverse events were mild and associated with the administration of the drug. Additionally, no systemic adverse events were observed, bolstering phase I data suggesting that bevasiranib does not enter the bloodstream.
”The importance of this finding is highlighted by US Food and Drug Administration language required in the labels of newly approved VEGF antagonist drugs warning of the possible risks of systemic exposure to VEGF inhibitors,” Acuity said. The company added that the new labeling states that “there is a theoretical risk of arterial thromboembolic events following intravitreal use of inhibitors of VEGF.”
 
As for bevasiranib’s efficacy, Acuity said that independently assessed flouroscein angiography scans confirmed dose-dependent decreases in the growth and size of choroidal neovascularization lesions, which “is an important confirmation that bevasiranib is working as expected to combat the primary anatomic feature causing vision loss in wet AMD.”
 
Furthermore, in the 1.5 mg and 3 mg dose groups CMV growth was essentially halted for at least 12 weeks following the last administration of bevasiranib.
 
“We think this was a very profound demonstration of the biologic effect of an siRNA, and really the first true clinical proof of concept of an siRNA,” Sam Reich, Acuity co-founder and vice president of research and development, told RNAi News this week.
 
The finding was also a “demonstration of the longer duration of effect of an RNAi-based drug compared to, perhaps, an antibody-based drug,” he said, which is a key characteristic for AMD therapies that are delivered via injection into the eye — a major hurdle to patient compliance.
 
Given this, Reich said, Acuity expects that “the frequency of administration [of bevasiranib] will be between 8 and 12 weeks, initially when the drug is first approved. We also believe that certain patient populations that may have less VEGF-driven disease or less aggressive disease would be fine on even fewer injections,” he added.
 
By comparison, Eyetech's and Pfizer's AMD drug Macugen is administered every six weeks, while Novartis’ Lucentis was recently approved with a once-a-month dosing schedule.
 
Acuity noted that although the CARE study did not include a placebo arm, researchers referenced placebo cohorts in comparable AMD trials to compare measurements of visual acuity in study patients with the likely natural course of disease progression without treatment.
 
This comparison indicated that patients receiving bevasiranib “demonstrated stronger measures of visual acuity than predicted by the comparative placebo analysis.”
 
Further, while the visual acuity of patients in the CARE trial declined during the first months of the study, acuity on average stabilized while more than one-third of patients — mostly in the higher-dose cohorts — ultimately experienced some improvement in visual acuity.
 
Acuity added that while no dose response was seen in measures of visual acuity, there was a dose response trend in the measure of CMV growth.
 
Acuity also restated the time-to-rescue findings from the study that Reich had presented at the American Society of Gene Therapy annual meeting in Baltimore this summer (see RNAi News, 6/8/2006). 
 

“We think this was a very profound demonstration of the biologic effect of an siRNA, and really the first true clinical proof of concept of an siRNA.”

The CARE study’s protocols included a provision allowing physicians to rescue patients with progressing disease by putting them on an FDA-approval AMD treatment.
 
“The median time to rescue in the lowest-dose group was established at 154 days, or about 14 weeks after the last injection of bevasiranib,” Acuity said. “For the two higher dose groups, no median time to rescue had yet been established as a result of the fact that most of these patients, who had been in the study for up to six months following their last bevasiranib injection, did not yet require drug rescue as determined by their physicians.”
 
Eyeing the Path to Approval
 
Reich noted that the FDA typically requires “two independent, definitive studies” supporting a drug’s safety and efficacy to receive approval. With the first of these beginning sometime around the middle of next year, he said that Acuity expects to file a new drug application for bevasiranib in mid-2009.
 
He added that this NDA would likely be seeking approval of bevasiranib as a maintenance therapy to be used in conjunction with an acute VEGF protein-blocking agent that would be administered at the start of treatment to drive down a patient’s VEGF levels.
 
“It’s important to note that wet AMD is a disease that can last for many years, and patients can live for 10 or 15 years after they are diagnosed,” Reich noted. “So there could be years where … patients are receiving bevasiranib alone.”
 
He said that Acuity also presented at the ASRS meeting data from a phase II trial of bevasiranib in diabetic macular edema.
 
“We showed clinical proof of concept in that trial, which confirms what we saw in the CARE study,” Reich said. “Now, in two different ocular indications with two different endpoints, we have clear evidence of the biologic effect of VEGF inhibition.”
 
He said that the outcome of the DME study was “positive” and that Acuity plans to begin phase III testing in the indication, adding that the timing of this clinical work will hinge on the availability of resources.
 
An Acuity spokeswoman said the company would release further information on the DME trial results in the next couple of weeks.

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