Washington Editor

Although it's unclear at this point, the FDA may require a confirmatory study for ISTA Pharmaceuticals Inc.'s Vitrase, a single injection to the eye for vitreous hemorrhage.

The mere mention of another trial sent ISTA's stock (NASDAQ:ISTA) falling 21.2 percent Monday, down $1.25 to close at $4.65.

ISTA, of Irvine, Calif., said the FDA's "approvable" letter requested additional analysis of the existing data and possibly an additional confirmatory clinical study based on that analysis.

When asked to discuss ISTA's next step, Vicente Anido, company president and CEO, told BioWorld Today, "We're going to do the subanalysis or further analysis that they've requested. That's fairly clear. Then we are going to go in and talk to them based on that analysis and we'll see where we are from there."

Anido said the company should know in 30 to 90 days whether another trial will be necessary.

And while Vitrase (hyaluronidase for intravitreal injection) may not receive immediate approval in the requested broad indication, Anido said it's possible the company may receive approval in a subgroup.

Donald Ellis, managing director with Thomas Weisel Partners in San Francisco, told BioWorld Today the FDA's letter suggests two potential outcomes. In the first scenario, the agency would approve a limited label for improvement in best-corrected visual acuity (BCVA) at two months for the 55-unit dose and reduction in vitreous hemorrhage density. (BCVA was measured as the ability to read three or more lines on an eye chart at one and two months.) The FDA's Dermatologic and Ophthalmic Drugs Advisory Committee last month said ISTA reached statistical significance in both those areas. (See BioWorld Today, March 18, 2003.)

In a second scenario, the FDA could ask for a confirmatory trial on a broader label, Ellis said. "We can't predict the length of the trial now because we don't know how many patients the FDA would want, and we don't know what the endpoints would be," he said.

ISTA failed to hit its primary endpoint in two Phase III trials of eliminating blood to restore vision while giving a doctor an unobstructed view of the retina to diagnose and treat a problem. (See BioWorld Today, March 27, 2002.)

Nevertheless, 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 Vitrase's ability to produce visual acuity and to decrease hemorrhage density. (See BioWorld Today, April 11, 2002, and May 7, 2002.)

The advisory panel voted 7-5 saying Vitrase's benefits outweigh its risks. However, in an 8-4 vote, the panel said ISTA's data did not support efficacy in vitreous hemorrhage.

The approvable letter cited issues related primarily to the "sufficiency of the efficacy data." However, no deficiencies were cited regarding safety data.

When used as a single injection to the eye for vitreous hemorrhage, Vitrase is not intended to permanently restore sight. In diabetic retinopathy, Anido said researchers believe Vitrase may slow the progression to blindness. "But that hasn't been proven yet," he said.

The company intends to initiate a Phase III trial in diabetic retinopathy - a U.S. market estimated at $1.2 billion - this year. But on Friday's news, Anido said the company would hold off until issues surrounding vitreous hemorrhage are settled. (The U.S. market for vitreous hemorrhage is estimated at about $200 million annually.)

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.

Currently, the only treatment other than "watchful waiting" is vitrectomy, an invasive surgical procedure that must be performed by a retinal specialist and may result in cataract formation, retinal detachment or other complications, ISTA said in a prepared statement. During a vitrectomy, a patient's blood-filled vitreous humor is surgically excised and removed.