Washington Editor

GAITHERSBURG, Md. - ISTA Pharmaceuticals Inc. failed to convince an FDA advisory panel that Vitrase, a product designed to be injected into the eye for vitreous hemorrhage, helps restore vision and provides an ophthalmologist with an unobstructed view of the retina.

In an 8-to-4 vote, the Dermatologic and Ophthalmic Drugs Advisory Committee said ISTA's data does not support the efficacy of Vitrase (hyaluronidase for intravitreal injection) in vitreous hemorrhage. But in a 7-to-5 vote, the panel said Vitrase's benefits outweigh its risks. The FDA is not bound by the panel's recommendation.

Following the meeting, Vicente Anido, ISTA's CEO, told reporters the data and indication can be somewhat confusing.

"We still did not get any clear-cut answers on [suggested] trial design or endpoints," he said, referring to discussions among panel members recommending additional studies.

Nevertheless, Anido is hoping for FDA approval April 9, the company's Prescription Drug User Fee action date.

As pointed out by Anido, several members of the panel were split on their views of Vitrase. For example, he said, the clinicians seemed to be looking for a solution to vitreous hemorrhage.

"I cannot escape my conclusion that something is happening here," Pat Wilkinson, panel member and physician with the department of ophthalmology, Greater Baltimore Medical Center in Baltimore, said. "This is an exceptionally complicated [indication]. This improves vision indirectly by eliminating blindness and it's a helpful tool, but it's not a cure."

The panel struggled much of the day over ISTA's failure to hit the primary endpoint of eliminating blood to restore vision while giving doctors an unobstructed view of the retina to diagnose and treat a problem. (See BioWorld Today, March 27, 2002.)

When casting her vote against proven efficacy, Emily Ying Chew, of the division of epidemiology and clinical research at the National Eye Institute, a part of the National Institutes of Health, in Bethesda, Md., put it simply, saying, "Given the endpoints, I don't think you have evidence of efficacy."

But Donald Fong, acting chairman and physician with the department of ophthalmology at the Kaiser Permanente Medical Center in Baldwin Park, Calif., said he didn't see any connection between the endpoint and vision.

"The studies show positives in different endpoints, so that suggests to me that chance might be playing a role here," he said.

ISTA, and partners Allergan Inc., of Irvine, Calif., and Otsuka Pharmaceutical Co. Ltd., part of the Otsuka Group, of Tokyo, filed the new drug application based on two randomized, double-blind, placebo-controlled international studies of 1,306 patients. Even though the primary endpoint didn't work out, ISTA filed the NDA based on Vitrase's ability to produce visual acuity and to decrease hemorrhage density. Data indicated a statistically significant difference in the proportion of patients with improvement in best-corrected visual acuity (BCVA), measured as three or more lines on an eye chart at one and two months. (See BioWorld Today, April 11, 2002, and May 7, 2002.)

"We saw efficacy improvement in BCVA at two months and clearance of hemorrhage at two months, but no longer at three months," Jennifer Harris, a medical officer and reviewer with the FDA, said. "But 50 percent of the patients did not have functional vision."

And while the mean age of the trial participants was 61.9 years, Harris said there was a 5 percent death rate in each trial. But the panel unanimously agreed that the death rate observed was not a reason for concern. (Many patients were elderly with diabetes.)

Vitreous hemorrhage is often associated with complications of diabetes, and occurs when retinal blood vessels rupture and bleed into the vitreous humor, the clear gel-like substance that fills the back of the eye. ISTA said the annual U.S. market is $200 million.

Currently, the only treatment for vitreous hemorrhage other than "watchful waiting" is vitrectomy, an invasive surgical procedure that must be performed by a retinal specialist and might result in cataract formation, retinal detachment or other complications, ISTA said. During a vitrectomy, a patient's blood-filled vitreous humor is surgically excised and removed. There currently is no drug treatment for vitreous hemorrhage.

Vitrase also is being studied in a diabetic retinopathy (expected to enter Phase III this year). Elsewhere in its pipeline, ISTA's partner, Senju Pharmaceuticals Co. Ltd., of Osaka, Japan, last September submitted an NDA for Istalol, a special formulation of timolol for treatment of glaucoma. (See BioWorld Today, Sept. 30, 2002.)

Another late-stage ophthalmology compound under development at ISTA is bromfenac, a topical nonsteroidal anti-inflammatory compound for the treatment of ocular inflammations. The company expects to file an NDA by the end of the year.

And finally, the company is developing Caprogel (aminocaproic acid) for hyphema. ISTA expects to begin the Phase III this year.

Istalol, bromfenac and Caprogel were acquired from AcSentient Inc. of Research Triangle Park, N.C. in a cash-stock deal.