SUBSPECIALTY NEWS

Anecortave Acetate Has New Target

A Potential Treatment for Dry AMD Is Now Also in Glaucoma Study.

■ Several years ago, Alcon conducted a highly encouraging phase 2 clinical study using the glucocorticoid-steroid derivative anecortave acetate (then called Retaane) for the treatment of the wet form of AMD. However, when the phase 3 trial for wet AMD did not replicate the positive earlier results, Alcon said it would continue to study anecortave acetate as a treatment to prevent dry AMD from progressing to wet AMD and for other indications.

The study to determine if anecortave acetate can prevent dry AMD from progressing is fully enrolled. And, in an interesting twist, anecortave acetate has also been given a new target as a potential treatment for open-angle glaucoma — a steroid derivative that actually lowers IOP.

For the glaucoma indication, the drug is being administered as an anterior juxtascleral depot in the sub-Tenon's space, and has demonstrated an impressive duration of response in a new study.

In this safety and efficacy study for anecortave acetate, 89 patients were randomly assigned to 1 of 3 arms: 7.5 mg of anecortave acetate dosed with 0.25 mL of 30 mg/mL suspension, 15 mg of anecortave acetate dosed with 0.5 mL of 30mg/mL suspension, or 0.5 mL of vehicle. Prior to enrolling in the study, all patients had been diagnosed with open-angle glaucoma, had confirmed visual field changes and had off-therapy IOP between 24 mmHg and 36 mmHg. One injection of drug or vehicle (placebo) was administered to each patient and IOP was assessed at 2 weeks, 6 weeks, and at month 3, with month 3 predefined as the visit for primary efficacy. The study design also allowed for a patient to be retreated if more than 42 days had passed since the last administration of anecortave acetate and the patient's IOP exceeded 18 mmHg in 2 consecutive visits scheduled 1 week apart. The study will continue with clinical assessments at 6-week intervals, potentially through month 24.

The primary conclusion was that both the 7.5 mg and 15 mg doses of anecortave acetate demonstrated statistically significant lower mean IOP than vehicle at the month 3 primary efficacy end-point. Additional data in the presentation supported the activity of anecortave acetate in lowering IOP. Approximately 55% of patients in the 7.5 mg and the 15 mg arms who were treated with anecortave acetate according to the study design were deemed successes at month 3. These data contrast with the vehicle treatment group, where approximately 50% of patients were treatment failures by week 2 and 2 patients (6.4%) were treatment successes at month 3. Treatment success was pre-defined in the study as maintenance of IOP at or below the 21 mmHg.

Taken together, these data support the activity of anecortave acetate and also the company's prior decision to conduct additional clinical trials involving higher concentrations of drug.

In terms of safety, the most frequently reported adverse events were related to the procedure and included eye pain, foreign body sensation, hyperemia, and blurred vision, which were reported at an incidence of 5% to 15%. The most frequently reported events related to test article were conjunctival deposits and eye pain which were reported at an incidence of less than 5%.

"The safety and efficacy demonstrated in this second controlled clinical study of anecortave acetate are encouraging because they confirm a prolonged treatment benefit for anecortave acetate administered by anterior juxtascleral delivery," said Scott Krueger, PhD, Alcon's vice president, R&D, Pharmaceutical Development. "These results, together with our recently conducted phase 1 safety evaluation of larger doses and injection volumes, allows us to proceed in 2008 with studies that evaluate higher doses and injection volumes in our phase 2/3 clinical development program."

Our Man in Saipan

Dr. Khorram Finds His Tropical Island.

■ David Khorram, MD, who received his retina training during residency at Northwestern University under Lee Jampol, MD, is the only ophthalmologist on the Pacific island of Saipan. Dr. Khorram passed up a retina fellowship because he wanted to practice in a part of the world that had a great need for an ophthalmologist. After doing some research, he chose the Pacific islands and, after a year practicing in American Samoa, he made his way to Saipan.

Over the course of the past 15 years, Dr. Khorram has built the Marianas Eye Institute into one of the best-equipped eyecare practices in the Asia-Pacific region, offering a full range of both retina and general ophthalmology procedures.

He has also been active in civic activities on the island, writing a weekly newspaper column and organizing a national soccer team. He recently published a collection of his columns in a book titled "World Peace, a Blind Wife and Gecko Tails" (available through amazon.com). Dr. Khorram and his wife, Mara, have 4 children, ages 3, 5, 7, and 9.

Dr. Khorram enjoys life on a Pacific island.

Dr. Khorram reports that he sees "a ton" of diabetes-related eyecare problems but almost no cases of macular degeneration, which he attributes to the island's relatively young population as well as genetic factors.

Saipan, located about 120 miles north of Guam, is the capital of the United States Commonwealth of the Northern Mariana Islands and has a population of approximately 60,000, many of whom are contract workers and not permanent residents.

The island was the site of fierce fighting in World War II as the United States established a base on Saipan for B-29 bombers that could reach the home islands of Japan.

OPKO Gets Key Patent for siRNA Drugs

But Controversy Erupts Over siRNA Concept.

■ OPKO Health has been issued a key patent for methods related to the use and administration of small interfering RNAs (siRNAs) for targeting vascular endothelial growth factor (VEGF). This patent also includes bevasiranib, which is currently in a phase 3 trial as a treatment for the wet form of AMD.

However, as Retinal Physician was about to go to press, word came that Jayakrishna Ambati, MD, of the University of Kentucky, has published a paper in the journal Nature, questioning the potential of siRNA drugs in treating diseases. He contends that these drugs could inhibit necessary blood vessel growth in healthy areas of the body. He also contends that siRNAs are generic and do not target specific genes. OPKO immediately disputed these findings. Retinal Physician will have a more detailed report on Dr. Ambati's research and the response of companies developing siRNA drugs in the May issue.

The claims of the newly issued OPKO patent cover a broad range of methods for the use of a specific sequence of siRNA, including bevasiranib, to target VEGF. The patent also covers application of this specific sequence of siRNA to inhibit the expression of VEGF and to treat VEGF-related angiogenic disorders including age-related macular degeneration, diabetic retinopathy, and cancer. In addition, the claims cover any methods of administering the siRNA, including intravenous administration, retinal injections, and oral administration. This newly issued patent broadly protecting the applications of OPKO's siRNA bevasiranib is the second for the compound. In late 2006, the patent office issued a patent covering bevasiranib's composition of matter.

"This patent marks another important step in establishing OPKO's leadership position in the promising field of siRNA-based therapeutics," said Samuel Reich, executive vice president of OPKO Ophthalmics. "Bevasiranib was the first siRNA to enter human trials, the first siRNA to demonstrate clinically relevant activity in patients, the first siRNA to enter a phase 3 pivotal trial and now, one of the first siRNAs to receive a US patent covering its broad therapeutic use."

In a related development, OPKO announced that Naveed Shams, MD, PhD, who was instrumental in shepherding the leading wet AMD treatment Lucentis through its clinical studies while with Genentech, has joined OPKO as its chief medical officer and senior vice president of Research and Development.

Dr. Shams will play a key role in advancing OPKO's clinical trials for bevasiranib and in leading the company's research and development programs.

"Dr. Shams brings 14 years of global drug development experience to OPKO that spans the entire development process, including discovery research, early development, phase 1 through phase 4 clinical studies and interaction with regulatory authorities across all stages of R&D," said Phillip Frost, MD, OPKO's CEO.

Prior to his joining OPKO, Dr. Shams led the clinical team at Genentech, Inc. that developed and launched Lucentis. His team successfully conducted the SAILOR study for Lucentis, one of the largest safety studies in the history of ophthalmology, and supported over 50 trials to investigate the safety and efficacy of anti-VEGF treatments in various diseases of the eye.

Previously, Dr. Shams, was a member of the Novartis Ophthalmics Clinical R&D Group, where he led global clinical development and registration efforts for the anti-allergy ophthalmic drug Zaditor and the IOP-lowering agent Rescula. He provided post-marketing clinical and regulatory support to Visudyne for use in patients with wet AMD.

"I am pleased to join OPKO Health at this exciting stage in the development of bevasiranib, a first-in-class drug candidate that has the potential to provide important benefits to patients with age-related macular degeneration," said Dr. Shams.

Bevasiranib is designed to silence the genes that produce VEGF, believed to be largely responsible for the vision loss of wet AMD. Bevasiranib is the first therapy based on the Nobel Prize-winning RNA interference (RNAi) technology to advance to phase 3 clinical trials. The multinational phase 3 COBALT (Combining Bevasiranib And Lucentis Therapy) clinical trial of bevasiranib for the treatment of wet AMD is currently enrolling patients at multiple clinical sites. RP