CLINICAL TRIAL SPOTLIGHT

OPKO Launches First Phase 3 siRNA Trial

Gene therapy for AMD begins the final stage for FDA approval.

ANDREW E. MATHIS, PhD, MEDICAL EDITOR

Since the mapping of the human genome, and even earlier, scientists have hoped to find genetic treatments for a variety of disorders. In 1999, British scientists Andrew Hamilton and David Balcomb first published on the topic of small interfering RNA (siRNA), the mechanism of action of which is to interfere with the expression of certain genotypes. In the posterior-segment community, the interest in siRNA has been in its ability to suppress the expression of the gene or genes that cause choroidal neovascularization in age-related macular degeneration (AMD).

In this vein, OPKO Health, Inc. (Miami) has announced the first phase 3 trial to test a siRNA molecule, bevasiranib, in the treatment of wet AMD. The Safety & Efficacy Study Evaluating the COmbination of Bevasiranib And Lucentis Therapy in Wet AMD (COBALT) is already enrolling patients, expecting to enroll a total of 330 people with AMD.

Bevasiranib is the siRNA molecule OPKO is testing in the COBALT trial, in conjunction with ranibizumab (Lucentis, Genentech). The 330 patients will be randomized into 3 arms: The first arm will consist of patients who will receive bevasiranib injections every 8 weeks after 3 monthly injections of ranibizumab; the second arm will also receive pretreatment with ranibizumab but will receive bevasiranib injections every 12 weeks instead of 8 weeks. The third arm will receive only ranibizumab and will act as an effective control group.

Lawrence J. Singerman, MD, clinical professor of ophthalmology at Case University School of Medicine, president of Retina Associates of Cleveland, and an investigator on the COBALT study, says the key goal of the study is to decrease the number of intravitreal injections that AMD patients will have to undergo to improve their condition and sustain these improvements. "The frequency of injections is going to be much less than with ranibizumab,"Dr. Singerman predicts. "We don't know how many we're going to need, but if 12 weeks does it, then that's better than every 4 weeks."

Patients enrolled in the COBALT study will be followed for up to 60 weeks. "The efficacy measure is the proportion of people at week 60 in each group with a successful visual acuity (VA) outcome defined as avoiding 3 or more lines of vision loss," says Dr. Singerman. "That's the primary endpoint. The secondary efficacy endpoint will include the proportion who have a successful VA outcome and no need for rescue therapy with ranibizumab." Dr. Singerman noted that OPKO will be covering the cost of ranibizumab for the study.

Asked about possible side effects of bevasiranib, Dr. Singerman says they are "almost none. There are no systemic side effects and just the rare endophthalmitis or cataract anticipated in any intravitreal drug injection. It's really very safe. The way the pharmacokinesis of the drug is, it should be much safer than the anti-vascular endothelial growth factor (VEGF) antibodies in terms of systemic complications because it's very short acting."

Another large question looming in all AMD trials is whether the agent being studied has the potential to improve vision, as ranibizumab has shown it can do."We think that bevasiranib is going to maintain the vision improvement that ranibizumab injections bring,"Dr. Singerman says. "The final efficacy endpoint is the number of patients at week 60 who maintain a 3-line gain."

If all goes according to plan, Dr. Singerman predicts Food & Drug Administration (FDA) approval for bevasiranib in 2 years. Noting that a second phase 3 trial is necessary before the FDA will approve a treatment,Dr. Singerman says, "The protocol for the second phase 3 trial is being finalized right now, and both phase 3 trials can be run concurrently." RP