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Trials for siRNA drug


Bevasiranib (Opko Health Inc.), the first small interfering RNA compound to be tested in humans, was well-tolerated and demonstrated good safety and biologic activity in phase II trials of patients with subfoveal exudative age-related macular degeneration (AMD) or diabetic macular edema. A phase III study investigating bevasiranib as maintenance therapy after ranibizumab (Lucentis, Genentech) treatment is under way in patients with AMD, and a second AMD protocol is under development.

Key Points

Bevasiranib, formerly known as Cand5 and being developed by Opko Health Inc., Miami, is an innovative and potent inhibitor of vascular endothelial growth factor (VEGF) production at the cellular level.

Based on the RNA interference technology that captured the 2006 Nobel Prize in Physiology or Medicine for Andrew Z. Fire, PhD, and Craig C. Mello, PhD, bevasiranib is the first siRNA agent to enter clinical testing, said Dr. Singerman, whose center, Retina Associates of Cleveland, treated the first patients in a phase I clinical trial.

Complementary therapy

Because of its distinct mechanism of action, bevasiranib is considered complementary to pharmacotherapies that bind existing VEGF. In fact, optimum benefit is expected to depend on the synergy of combining the siRNA drug to block future VEGF production with an extracellular protein antagonist able to inhibit the activity of preformed VEGF.

"Blocking protein production with siRNA technology may represent a groundbreaking approach to treating AMD, DME, and other VEGF-driven ocular diseases, but it also has huge potential to treat a large number of other human diseases, and that is the reason that Drs. Fire and Mello received the Nobel Prize for their research," said Dr. Singerman, who also is a clinical professor of ophthalmology at Case Western Reserve University, Cleveland.

"We are excited to have been the first site to treat a patient with an siRNA agent and that ophthalmology can be credited with being the pioneering leaders in this new field in medicine," he continued. "We are encouraged by the positive results achieved in testing so far and look forward to the pivotal studies because of the promise this agent holds for providing patients with a major therapeutic advance."

The phase II trials investigated bevasiranib as monotherapy and featured a dose-comparison, double-masked design. Patients were randomly assigned to receive intravitreal treatment with 0.2, 1.5, or 3.0 mg per eye. Patients with subfoveal exudative AMD received two injections at baseline and week six, and patients with DME were treated at baseline and weeks four and eight.

Results from follow-up through week 12 showed an excellent ocular safety profile and lack of systemic exposure. Inhibition of the growth of neovascular AMD lesions, reduction in macular thickness in eyes with DME, and vision outcomes demonstrated biologic activity of bevasiranib as well as a dose-related response. Bevasiranib also was associated with a good safety profile. A lag to time of onset of benefits occurred, however, demonstrating that clinical effect is not seen until preformed VEGF is cleared.

"Now, randomized, controlled, phase III studies that are powered to detect significant efficacy are needed to confirm a role for bevasiranib as a maintenance approach," Dr. Singerman said. "The COBALT [COmbining Bevasiranib And Lucentis Therapy] trial is now enrolling patients with exudative AMD, and we are completing the protocol for a second phase III trial that will investigate bevasiranib in patients with AMD."

A second phase III study for AMD and phase III studies of bevasiranib for DME are anticipated for the future.

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