West Coast Editor

About a month after buying U.S. rights to three ophthalmology compounds from AcSentient Inc., ISTA Pharmaceuticals Inc. said it can see raising $30 million through an offering for continued development of products - including its own Vitrase for vitreous hemorrhage, for which the first clinical part of a new drug application will be in the FDA's hands by the end of the third quarter.

In fact, the company has four potential NDAs planned in the next 18 months, said Vicente Anido, president and CEO of Irvine, Calif.-based ISTA. He declined to say more about the financing, but noted an investment bank has been engaged to carry it out.

Most of the work on Vitrase has been done, he said.

"The Phase III trials are completed already, but we still have the NDA to finish up," Anido told BioWorld Today. "Then we have to do manufacturing validation. A biologic costs a little more than a straight-up small-molecule drug. And then we'll be introducing it, so there will be some market-seeding things we have to do."

Vitrase is ISTA's formulation of highly purified hyaluronidase, an enzyme that digests certain forms of carbohydrate molecules called proteoglycans. The drug causes liquefaction of the vitreous - the clear, viscous fluid in the back of the eye - clearing or reducing the density of blood that blocks vision.

Currently, the only treatment for such hemorrhages is surgery, and ISTA estimates about 450,000 cases take place in the U.S. each year. Vitrase could benefit about half of those cases, the company said.

Vitrase was granted fast-track status by the FDA, and in January ISTA submitted the nonclinical pharmacology and toxicology section of the NDA. The chemistry, manufacturing and controls (CMC) section will follow by the end of the third quarter, and the final component of the NDA, which has to do with manufacturing validation, will be submitted in the first quarter of 2003.

When approval might be gained is, of course, unclear. The FDA "gets to see some of the information ahead of time, because some of it's embedded in the CMC," Anido said. "As best we can figure out, the timing is anywhere from three to nine months, once the last piece of paper is received [by the agency]."

A pair of Phase III trials with Vitrase had a composite surrogate primary endpoint, for which statistical significance wasn't reached. But further analysis of study results showed that, for the 55 IU dose of Vitrase in both trials, patients showed a decrease in density of the hemorrhage that was clinically meaningful and statistically significant.

Also, in both studies with the same dose, there was a statistically significant difference in the proportion of patients with an improvement in best-corrected visual acuity (BCVA) (measured as three or more lines on an eye chart) at one month and two months. In the study conducted outside North America, the findings lasted to the three-month, post-treatment visit. Apparently, the improvements in BCVA are associated with the decrease in the density of the hemorrhage for Vitrase patients.

"We like our chances [with the FDA]," Anido said. "It's a disease that's pretty debilitating. Patients simply can't see out of the eye."

Ophthalmologists "can't see to the back of the eye to see what happened" because of the hemorrhage, and Vitrase helps clear the way, he said.

"Once they figure out what's causing it, they can use a laser to zap it," Anido said. Another option is surgery.

ISTA next will focus Vitrase on the diabetic retinopathy indication, he said, adding that "we've had some very good results in Phase II." Diabetic retinopathy is one of the major underlying causes of such hemorrhages, he said.

"Probably the largest expenditure is going to be on bromfenac," one of the three drugs acquired last month in the buyout of Research Triangle Park, N.C.-based AcSentient, Anido said. (See BioWorld Today, May 7, 2002.)

"We need to do a Phase III trial," he said. "The FDA has said only one more is required, and it's the largest trial we have yet to do for any of our drugs - 300 to 400 patients" with post-cataract surgery inflammation. That trial is expected in the first half of next year.

A Phase I, four Phase II and three Phase III clinical trials of bromfenac, a topical, twice-daily, non-steroidal anti-inflammatory compound, were conducted in Japan, which led to approval by the Japanese Ministry of Health, Labour and Welfare of bromfenac for the treatment of ocular inflammation. Data from a U.S.-based Phase III clinical study, combined with preclinical and clinical study data from the Japanese trials, is expected to support an NDA in late 2003.

"Getting patients enrolled to see whether an NSAID works shouldn't be that hard," Anido said.

"For Caprogel it's the same thing," he said - one more Phase III study. The patented compound for hyphema (bleeding into the front of the eye) is the second gained from AcSentient, and ISTA plans to start the Phase III trial in the first half of next year.

"It only requires about 100 patients," Anido said. "We don't have a lot left to do." One Phase III study already has been done in the U.S., and the NDA likely will be filed toward the end of 2003.

The third drug from AcSentient is timolol-LA, a patented, once-daily, liquid formulation of the beta-blocker timolol for glaucoma. After talks with Senju Pharmaceutical Co. Ltd., of Osaka, Japan (from which AcSentient had acquired it), ISTA believes that the NDA for timolol-LA will be submitted by Senju early in the fourth quarter of 2002 and will include data from a recent U.S.-based, multicenter Phase III clinical trial.

Anido noted that ISTA, with a such a lineup of late-stage compounds, is rare - but even those with advanced products aren't making the major headlines lately.

"We got caught like everybody else did this year, with all the bad news coming out," he said. "A lot of companies with great things in their pipeline aren't getting the air time."

ISTA's stock (NASDAQ:ISTA) closed Wednesday at 93 cents, up 6 cents.

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