Blind World

Macular Degeneration.
Study in Retina Demonstrates Acuity's siRNA Drug Inhibits Both Blood Vessel Overgrowth and Leakage in Primate Model of Macular Degeneration.

February 18, 2004.

Press Release.
Source: Acuity Pharmaceuticals.

In a study published today in the journal Retina, Acuity Pharmaceuticals reported that in a primate disease model, its lead product, Cand5, significantly inhibits both the blood vessel overgrowth (neovascularization) and vascular leakage that lead to vision loss in age-related macular degeneration (wet AMD), the leading cause of adult blindness in the developed world. Cand5 is a small interfering RNA (siRNA) that shuts down the genes that produce vascular endothelial growth factor (VEGF), which stimulates blood vessel overgrowth and regulates blood vessel permeability. The study data demonstrate that a single dose of Cand5 safely and significantly reduced both neovascularization and vessel leakage, in a dose-dependent manner for more than five weeks. These two factors represent key measures of disease progression and severity used by retinal specialists in clinical practice to assess wet AMD patients. Specifically, at the highest dose used in the study Cand5 reduced the incidence of clinically significant vascular leakage to zero by week three and for the duration of the study, and at day 35 neovascularization was inhibited by greater than 65 percent in the high dose group. No adverse effects were observed. The study, "Intravitreal injection of VEGF siRNA Inhibits growth and leakage in a non-human primate laser induced model of CNV," by Tolentino, et al., appears in the February, 2004 issue of the journal Retina, the Journal of Retinal and Vitreous Diseases.

"The positive data reported in this study suggest that its novel RNAi mechanism which blocks production of VEGF may enable Cand5 to achieve greater efficacy with fewer side effects and a prolonged interval between administrations than other treatments for wet AMD," said study co-author Michael Tolentino, M.D. "These impressive results also reflect the potency of Cand5 -- compared molecule to molecule, it may be 100 to 1000 times more potent than antagonist approaches that neutralize VEGF after it is produced. It is also noteworthy that a compound that is so pharmacologically active is completely safe at all dose levels tested." Dr. Tolentino is co-founder and medical affairs advisor at Acuity and assistant professor at the University of Pennsylvania's Scheie Eye Institute.

In wet AMD, neovascularization and vascular leakage lead to loss of vision. Significantly, this study measured both of these important clinical endpoints, and is the first demonstrating a therapeutic effect for siRNA in a large animal model. The study included three dose levels and was both double-blinded (masked) and randomized while employing a rigorous ophthalmic clinical grading system.

"The results of this pioneering study, which to our knowledge represents the first in vivo demonstration of siRNA efficacy in a non-human primate using a clinically relevant mode of administration, provide initial confirmation that siRNA therapeutics have the potential to offer significant advantages in potency, efficacy, safety and duration compared to conventional approaches for the treatment of wet AMD," said Dale Pfost, Ph.D., president and CEO of Acuity Pharmaceuticals. "With these data in hand, and with our recently published patent applications covering the therapeutic use of siRNA targeted to VEGF and its receptors, we feel confident that our plans to advance Cand5 into human clinical trials for wet AMD later this year are firmly on track."

According to the study, Cand5 inhibited blood vessel leakage at all doses in a dose-dependent manner, so that at the highest dose used in the study (350 5g), at two weeks Cand5 reduced clinically significant leakage to four percent compared to 70 percent for the untreated control eyes, and by three weeks and for the rest of the study leakage was reduced to zero. The study also demonstrated that a single Cand5 injection produced clinically significant inhibition of neovascularization, as measured by lesion growth around laser spots, at all dose levels throughout the 36 day follow-up period in a dose-dependent manner (p<.0001). In the high dose group specifically, at day 35 (the last time point assessed after dosing), lesion growth was inhibited by greater than 65 percent. Researchers believe that the effectiveness of Cand5 in significantly reducing both key parameters -- neovascularization and leakage -- makes these study results more predictive of the potential performance of Cand5 in a clinical setting.

"We believe that these study results highlight the potential superiority of our Cand5 RNAi anti-angiogenesis approach and put us on a rapid path to be the first siRNA ophthalmic compound to enter clinical trials, supported by a body of preclinical efficacy and safety evidence that go well beyond that which has traditionally been generated for therapies targeting wet AMD," said Dr. Tolentino.

The study subjects showed no evidence of inflammation or any other form of toxicity at all the dose levels used. The authors conclude that this proof-of-principal study provides guidance for Cand5 dosing in humans, as well as strong support for advancing this molecule into clinical trials.

End of article.

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