Rx Perspective
A Banner Year in Glaucoma
Use this primer to bring yourself up to date on new therapies.

It's an exciting time to be treating our glaucoma patients. Several new topical eye drops have become available since late last year. They potentially offer us new ways to achieve monotherapeutic treatment and a new definition of "maximum tolerated medical therapy" before we have to resort to laser trabeculoplasty or incisional microsurgery.

I've attended several presentations about these new drugs at national meetings of the American Academy of Ophthalmology, American Glaucoma Society (AGS), Association for Research in Vision and Ophthalmology (ARVO) and various pharmaceutical company-sponsored seminars.

I've also had the privilege of corresponding with some of the clinical investigators who participated in the FDA Phase III trials that led to the approval of these new medications. Drs. James Brandt, Carl Camras, Peter Netland and Tom Mundorf have all kindly provided information that I've incorporated into this article, although the views expressed are mine.

SUMMARIES OF THE LATEST DATA

In this column, I'll familiarize you with the newest pharmaceutical agents -- Lumigan (Allergan), Rescula (Novartis Ophthalmics) and Travatan (Alcon) -- and provide a refresher on Xalatan (Pharmacia), the prostaglandin analog against which the newer medications are being compared. The column isn't intended to compare the relative merits of the medications. We'll leave that to further studies and you.

Here's a closer look at the drops:

• Lumigan (bimatoprost 0.03%). This analog of prostamides, naturally occurring compounds in the eye, was approved in March, 2001.
  Allergan believes the intact molecule of bimatoprost directly binds to a new class of "prostamide receptors" that have not yet been cloned, and that it doesn't lower intraocular pressure (IOP) by either it or its metabolites binding to FP receptors.
  In two of the other medications we'll discuss in this column, latanoprost (Xalatan) and travaprost (Travatan), molecules are enzymatically hydrolyzed to free acids before tightly binding to and activating FP prostanoid receptors. Unoprostone (Rescula) undergoes a similar hydrolysis but only weakly binds to the FP receptor. (It may also activate a distinctly separate "docosanoid receptor," as we'll discuss later.)
  Researchers are trying to determine whether the bimatoprost molecule is partially hydrolyzed in the eye (the amide group cleaved enzymatically) in sufficient amount to the free acid to cause a biologically important activation of the FP prostaglandin receptors.
  The 6-month results of the Phase III studies (AGS meeting, March 2001) and a poster of 12-month data (ARVO, May 2001) summarize the clinical findings to date. Patients in the Phase III study were randomized to receive either Lumigan once at night and placebo drops in the morning or timolol twice daily. At their 6-month visits, at the 10 a.m. time point, the patients receiving Lumigan achieved an average drop in IOP of 33% (8.1 mm Hg) compared with 23% (5.6 mm Hg) for the patients treated with timolol.
  Twelve-month data showed continued and comparable efficacy. Mild hyperemia was the most common side effect (15% to 45% of patients). The hyperemia was well tolerated by the majority of patients and led to only a handful of discontinuations.
  Lumigan doesn't require refrigeration, before or after opening. Eyelash growth and iris color changes, common to all prostaglandin analogs, were also seen with Lumigan.
• Rescula (unoprostone isopropyl 0.15%). The FDA approved Rescula in August 2000. This compound is a docosanoid and is based on two extra carbon atoms added to the carbon chain common to Lumigan, Travatan and Xalatan. (Each of these compounds has different modifications to its backbone carbon chain.) Unoprostone free-acid has little affinity for FP receptors (compared with travaprost free-acid and latanoprost free-acid) and Novartis believes that it may also work primarily by activating as yet unidentified "docosanoid receptors." (Remember that Alleregan maintains that bimatoprost is clinically active without first being enzymatically cleaved to its free-acid). Like Lumigan, Travatan and Xalatan, published studies suggest that unoprostone acts primarily on uveoscleral outflow, although there may also be a secondary mechanism of action.
  Some early data supplied to me by Novartis suggests that Rescula may facilitate enhancement of trabecular meshwork function although the exact mechanism for this is still being studied. In vitro data suggest that Rescula may block the action of endothelin I on the resting tone of the trabecular meshwork. (Latanoprost and bimatoprost also have some effect on increasing conventional outflow facility, although the mechanisms aren't well understood.)
  In Phase III clinical trials, Rescula given twice daily reduced IOP by 3 to 4 mm Hg. Rescula causes less hyperemia, eyelash growth and iris color change than the other three prostaglandin analogs. Although its IOP-lowering efficiency is less than the other compounds, its advantage may be its better topical safety profile. Rescula doesn't require refrigeration before or after opening.
• Travatan (travoprost 0.004%). This prostaglandin analog was approved in March 2001. Its free acid has potent FP receptor agonist activity, with higher affinity for the FP receptor compared to both latanoprost and unoprostone. The medication also requires no refrigeration before or after opening by the patient.
  In the major 1-year Phase III clinical trial, 801 patients were randomized to one of four groups: timolol 0.5% twice daily, latanoprost 0.005% once in the evening, travoprost 0.0015% once in the evening, and travoprost 0.004% once in the evening. The IOP-lowering effect of travoprost (both 0.0015% and 0.004%) was found to be greater than timolol at all time points in the study (also about 8 mm Hg, similar to Lumigan). The 0.004% travoprost was found to have a similar ocular hypotensive effect compared with latanoprost. Alcon decided to market the 0.004% strength.
  Nearly half of the patients had some hyperemia, but this was mild. Changes in eyelash length and iris color occurred with Travatan, as with other prostaglandins.
  A prospectively planned analysis was performed comparing the different subgroups in the study. Approximately 20% to 25% of the subjects in the study were African-American. The baseline IOPs were similar among the subgroups. The mean IOP was significantly lower in African-Americans (about 1.8 mm Hg) after treatment with travoprost compared with timolol or latanoprost. The reason for this difference wasn't identified, but the differences couldn't be attributed to differences in iris color among the groups.
• Xalatan (latanoprost 0.005%). This medication was the first commercially available prostaglandin analog, coming to market in September 1996. Since its debut, latanoprost has become the most widely prescribed single agent for the treatment of glaucoma in the United States. The original, large, multicenter, randomized, controlled clinical trials that led to FDA approval, coupled with extensive clinical experience, have led to its wide acceptance. Xalatan is the prototypical prostaglandin analog, developed after 10 years of laboratory and clinical research. Its free acid has potent FP receptor activity that results in increased uveoscleral outflow.
  It lowers IOP 6 to 8 mm Hg. Xalatan, like Lumigan and Travatan, causes mild conjunctival hyperemia, but at about half the rate of these other two compounds. It's administered once daily, usually at bedtime. It does require refrigeration before being opened. As I mentioned earlier, its long clinical track record and established patient base make it the prostaglandin analog against which the newer medications are being compared.

WITH TIME, MORE KNOWLEDGE

Numerous FDA Phase IV clinical trials are under way by each of the drug manufacturers to compare these products with each other directly and to determine additivity of these drugs with other glaucoma medications. Some side-effects and contraindications are likely to be discovered as we obtain real-world familiarity with these glaucoma agents. The results of large, long-term comparative clinical trials will spell out the relative roles of the various prostaglandin agonists in the management of our glaucoma patients. 

Dr. Schacknow, coordinator of Rx Perspective, is Chief of Glaucoma Services at Visual Health & Surgical Center in Lake Worth, Fla. He specializes in the medical, laser and surgical treatment of glaucoma.