rx perspective
Fourth-Generation Upgrade?
A new fluoroquinolone in clinical trials may offer even less bacterial resistance and simpler dosing.
By Christopher Kent, Senior Associate Editor

Since their introduction, fourth-generation fluoroquinolones have been increasingly accepted by the ophthalmic community as the antibiotics of choice. This new class of drugs has the advantage of inhibiting not one, but two enzyme-based processes that allow bacteria to replicate, making it harder for bacteria to develop resistance.

Now, pharmaceutical companies are searching for ways to make the new antibiotics even better. One of the first in line to add advantages is ISV-403, a drug developed by InSite Vision, now owned by Bausch & Lomb and undergoing clinical trials as a treatment for bacterial conjunctivitis and bacterial keratitis.

To find out what advantages this new fourth-generation fluoroquinolone may offer, we interviewed Gary Phillips, M.D., corporate vice president of global pharmaceuticals at Bausch & Lomb.

Avoiding Resistance

Dr. Phillips was quick to point out that the drug is only now entering Phase II clinical trials, so clinical statistics demonstrating the drug's efficacy aren't yet available. How-ever, he was happy to explain the factors that he hopes will set the new product apart from those that are currently available.

"There are two points of differentiation that we're trying to achieve," he says. "First, the fluoroquinolone used in this product has never been used systemically in human beings. The other fourth-generation fluoroquinolones have been available as systemic drugs for about 3 years.

"The active ingredient in ISV-403 works in the same way as gatifloxacin and moxifloxacin do; it inhibits two enzymes that are involved in bacterial replication. However, the longer any antibiotic is available, the more likely it is that bacterial resistance will develop. Because our compound has never been used systemically, bacteria have never encountered it. For that reason, we expect to find virtually no bacterial resistance at all."

Keeping the Drug in the Eye

The second advantage ISV-403 will offer is its method of delivery. The final product will incorporate the Durasite delivery system, which keeps the compound in the eye much longer than a standard drop.

We asked Dr. Phillips to explain how the Durasite system works. "Durasite is a cross-linked polymer with chemical properties that allow it to bind to the corneal surface. ISV-403 is incorporated into the polymer, and the polymer acts as a non-covalently bound linker be-tween the drug and the corneal surface. This results in higher tissue concentration."

Dr. Phillips says that keeping the drug in the eye for a longer period of time should result in two practical advantages. "First, we potentially can use lower doses of the active ingredient for treatment. So far, no toxicities have been seen with topical use of fluoroquino-lones, but if there are any toxicities, the lower dosage should reduce any associated risk.

"Second, and more important, we think we'll be able to have less frequent dosing, for a shorter time, than the other fourth-generation fluoroquinolones. Simpler dosing is appealing both to the patient and the doctor -- it means fewer complaints and better compliance.

"Our target is to dose three times a day for 5 days, or possibly four times a day for 2 days and then twice daily for 3 days. This is significantly simpler than the currently available products."

Improvements that Count

Dr. Phillips says that Bausch & Lomb hopes to reach the U.S. market with the new product by early 2007, with availability in Europe a year or so later. "ISV-403 won't be a 'breakthrough' product, like a new class of therapy" he adds, "but it should offer solid advantages that will benefit both doctors and patients."