PHILADELPHIA and CANNES, France, Sept. 11 /PRNewswire/ -- Acuity Pharmaceuticals, a clinical stage ophthalmic pharmaceutical company, today announced positive results from its Phase II C.A.R.E(TM) trial for bevasiranib sodium (formerly Cand5), Acuity's lead compound for the treatment of wet age-related macular degeneration (wet AMD). Bevasiranib is a first-in-class small interfering RNA (siRNA) therapeutic designed to silence the genes that produce vascular endothelial growth factor (VEGF), believed to be largely responsible for this leading cause of adult blindness. The findings were presented yesterday at the 24th Annual Meeting of the American Society of Retina Specialists in Cannes, France.
The Acuity Cand5 Anti-VEGF RNAi Evaluation, or C.A.R.E. study, was a randomized, double-masked trial that included three dose levels of bevasiranib tested in 129 patients with wet AMD at 28 sites nationwide. The study focused on patients with serious disease, classic or active minimally classic AMD, including those patients who had failed previous treatments.
The drug was shown to be very safe in the study, with all doses well tolerated and most adverse events mild and related to the administration procedure. There were no systemic adverse events observed -- in two separate bevasiranib clinical trials, pharmacokinetic studies have now confirmed that there was no systemic bevasiranib exposure in patients, an important consideration in an agent targeting VEGF. The importance of this finding is highlighted by U.S. 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. It notes, "there is a theoretical risk of arterial thromboembolic events following intravitreal use of inhibitors of VEGF." The safety results and pharmacokinetic studies reported in this new study and in the Phase I data reported earlier provide strong evidence that bevasiranib does not enter the circulation, avoiding the potential for these serious systemic adverse events.
"Bevasiranib is a promising new agent that has now demonstrated encouraging potential in this first large-scale study in wet AMD patients with aggressive disease," said Lawrence Singerman M.D., founder and executive secretary of the Macula Society, clinical professor of ophthalmology at Case University and a principle investigator for the study at its Cleveland site. "Bevasiranib's excellent safety profile, its demonstrated ability to inhibit the growth of choroidal neovascular lesions and its potential for prolonged duration of effect warrant proceeding to Phase III trials. Bevasiranib's potential to complement VEGF antagonist drugs in combination or as a maintenance therapy could provide an important benefit to patients, and I look forward to helping to assess its utility in future trials."
Unlike VEGF antagonists, which neutralize VEGF that has already been produced in the eye, bevasiranib works by shutting down the genes that produce future VEGF. As a result, there is residual VEGF remaining in the eye during the first weeks of administration of bevasiranib, which stops production of new VEGF but does not neutralize the residual VEGF that naturally dissipates over time. Accordingly, the impact of the drug's anti-VEGF activity becomes evident only after several weeks of therapy, after the existing VEGF dissipates. This results in a lag between starting bevasiranib therapy and observing a therapeutic effect.
This expected lag was seen in the C.A.R.E. study, where the results of bevasiranib's activity were most clearly demonstrated after several weeks of treatment. At that point, independently assessed flouroscein angiography scans confirmed that bevasiranib produced dose-dependent decreases in the growth and the size of the CNV lesions that are the primary characteristic of the disease. This key finding is an important confirmation that bevasiranib is working as expected to combat the primary anatomic feature causing vision loss in wet AMD.
The duration of activity is a critical measure for wet AMD therapies, since these agents are administered by intravitreal injection, which can be burdensome if too frequent injections are required. Bevasiranib showed encouraging signs that it has a good duration of effect, evidenced by the fact that at the two higher doses CNV growth was on average essentially halted for at least 12 weeks following the last administration of bevasiranib.
The "time to rescue" measure also demonstrated the durability of response. The study investigators had the option to "rescue" any patients with progressing disease using a then-FDA approved wet AMD therapy. According to the study protocol, patients received bevasiranib injections at baseline and week six and then were scheduled to be followed for two years with no additional study therapy. 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. 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.
Despite the absence of a placebo arm in this trial, researchers were able to compare measures of visual acuity in study patients with what would have been expected from the natural course of disease progression as determined by reference to the most comparable placebo cohorts in other trials. In this analysis, bevasiranib study patients demonstrated stronger measures of visual acuity than predicted by the comparative placebo analysis. Visual acuity declined somewhat in the first months of the study, most likely from the on- going activity of the residual VEGF in the eye. On average, it then stabilized, with some visual acuity improvement in more than one-third of the patients, especially among those in the higher dose cohorts. Although no dose response was observed in measures of visual acuity in the bevasiranib study, there was a dose response trend observed in the important anatomic measure of CNV growth.
"As pioneers in the clinical development of siRNA therapeutics, we are delighted with the encouraging results from this first large scale trial of bevasiranib in wet AMD," said Dale Pfost, Ph.D., president and CEO of Acuity. "The 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. We believe that bevasiranib has the potential to play an important role in the treatment of wet AMD as a result of its ability to work in a complementary fashion with other therapies to improve the efficacy, safety, practicality and compliance of regimens incorporating new anti-VEGF agents."
Bevasiranib uses RNA interference (RNAi) to silence genes that promote the overgrowth of blood vessels that lead to vision loss in wet AMD. This shuts down the production of VEGF, which has been shown to be the central stimulus in the development of wet AMD. Bevasiranib is administered directly into the eye and does not affect the patient systemically, an important safety consideration. The Phase III clinical trial will further examine efficacy parameters, as well as dosing and dose scheduling regimens.
About Wet AMD
Wet age-related macular degeneration (wet AMD) is the number one cause of irreversible vision loss in the developed world, and its incidence is growing rapidly. Advanced age is the main risk factor for wet AMD, and it is expected to become an increasingly common condition as the population grows older. An estimated 1.65 million Americans have wet AMD today and an estimated 11 million people worldwide will have AMD by 2013. Existing treatments for wet AMD are of limited efficacy and fail to halt disease progression in many patients. In the search for more effective treatments, researchers are targeting VEGF, which has been shown to be a key cause of the excess growth of blood vessels that results in loss of vision.
About Acuity Pharmaceuticals
Founded in 2002, Acuity Pharmaceuticals is an ophthalmic pharmaceutical company applying proprietary technologies to the treatment and prevention of ophthalmic diseases. Acuity's lead clinical compound, bevasiranib, a small-interfering RNA (siRNA) therapeutic targeting VEGF, is in clinical trials for two of the leading causes of adult vision loss. Acuity recently completed a Phase II trial of bevasiranib in age-related macular degeneration and is conducting a Phase II trial in diabetic macular edema. Acuity is applying its drug development expertise to a growing pipeline of novel agents for ophthalmic conditions. In support of these programs, Acuity is also developing proprietary technologies for ocular drug delivery. For more information, see http://www.acuitypharma.com
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Source: Acuity Pharmaceuticals