Lumigan 0.03% lowers IOP in dosing study

Phase II trials find dose-dependent response for the hypotensive lipid.

LONDON — Lumigan (AGN 192024, Allergan) once daily lowers intraocular pressure (IOP) better than timolol twice daily and at least as well as latanoprost once daily, according to drug dosing trials. Also, the drug’s diurnal IOP control, safety and tolerability profiles were favorable.

In two Phase II studies, the drug was compared with timolol 0.5% twice daily and latanoprost 0.005% once daily.

Mark B. Sherwood, MD, of the University of Florida in Gainesville, presented results of the preliminary dosing trials at the European Glaucoma Society meeting.

Timolol comparison

AGN 192024 is an ocular hypotensive lipid belonging to a new class of compounds, prostamides. Prostamides do not stimulate known prostaglandin receptors, Dr. Sherwood reported.

In the first of two drug dosing studies, researchers in Austin, Texas, compared AGN 192024 with timolol. Eligible patients had open-angle glaucoma or ocular hypertension, with IOP in both eyes between 23 mm Hg and 34 mm Hg after a washout period.

In the study, 100 patients were randomly assigned to one of five treatment groups of 20 people apiece:

• AGN 0.003% once daily for 21 days, followed by twice daily for 7 days
• AGN 0.01% once daily for 21 days, followed by twice daily for 7 days
• AGN 0.03% once daily for 21 days, followed by twice daily for 7 days
• timolol 0.5% twice daily for 28 days
• a vehicle control for 28 days.

Study visits occurred on days 0, 3, 7, 14, 21, 23, 28 and 30 (48 hours post- dosing). IOP was measured at 8 a.m., with a diurnal measurement made on days 0, 14, 21 and 28.

Researchers defined efficacy as a mean reduction in IOP from baseline. Safety was assessed through adverse-event reports, ophthalmoscopy assessment of cup-to-disc ratio, biomicroscopy, laser flare meter and measurements of visual field acuity, heart rate and blood pressure. All patients completed the trial.

Between 75% and 95% of patients in each of the five groups had ocular hypertension. Baseline IOP ranged from 24.5 mm Hg to 27 mm Hg for all groups. Results showed a significant decrease in mean IOP from baseline in all treatment groups.

According to Dr. Sherwood, after 48 hours with no medication, “There’s still about a 4 mm Hg to 5 mm Hg fall in intraocular pressure with the 0.03% Lumigan at that time period.”

The mean IOP decrease at 8 a.m. with the 0.01% group was significantly greater than the timolol group except on day 3. The mean decrease from baseline in the 0.03% group was significantly greater than timolol, except on day 21. There was no apparent increase in efficacy when patients in this group increased dosing to twice daily, according to the poster presentation.

At the end of the once-daily dosing phase at day 21, the mean decrease was significant for all treatment groups at all time points during the day.

Baseline diurnal IOP was comparable among all time points. However, the mean reduction from baseline IOP in the 0.03% group was significantly greater than timolol at every time point, but not statistically significant at 8 a.m. The mean reduction from baseline IOP in the 0.01% group was significantly greater than that of timolol at 8 am and 8 pm.

At the end of the twice-daily dosing phase, the mean IOP reduction from baseline in the 0.03% group was significantly greater than the timolol group at every time point except noon, according to the poster. The mean reduction from baseline IOP in the 0.01% group was significantly greater than the timolol group at 8 am and 4 pm, and tended to be superior at 8 pm.

“There have been very similar results on both of these diurnal curves, with the two mild concentrations of the Lumigan being more effective than the timolol at lowering IOP at most time points,” Dr. Sherwood said. “This is sustained throughout the diurnal curve period.”

Latanoprost comparison

As part of the dosing trials, researchers also compared the product to latanoprost. Researchers at four American study centers enrolled eligible patients with open-angle glaucoma or ocular hypertension between 23 mm Hg and 34 mm Hg. Patients were randomized to five study groups:

• 21 patients received AGN 192024 0.03%
• 22 received latanoprost
• 21 received an inactive control
• Two other groups were not reported because they used another compound or used a formulation of AGN 192024 that was not studied anymore.

All drugs were self-administered once daily at 8 p.m. for 29 days. Researchers followed up with patients on days 14 and 29. IOP was measured at 8 am, and diurnal measurements were made on days 0 and 29.

Both once-daily AGN 192024 0.03% and once-daily latanoprost significantly decreased IOP from baseline after 14 days and 29 days of treatment. Mean baseline IOP values at 8 am were not different between groups.

“When we look at the diurnal curves taken on day 29, again, both are very effective in lowering IOP, somewhere between 5 mm Hg and 8 mm Hg,” Dr. Sherwood said. “At all time points, Lumigan was slightly more effective than latanoprost, although this was not statistically significant, just bordering on significant at the 4:00 pm time period.”

“We can see that Lumigan at the 0.03% once-a-day (dose) appears to lower IOP better than timolol in the twice-a-day regimen and at least as well as, if not better than, latanoprost once daily,” Dr. Sherwood said.

Paul L. Kaufman, MD, of the University of Wisconsin, reviewed the poster and abstracts for the EGS meeting. After the lecture, he spoke to the audience.

“The timolol response was rather small in these patients, which, of course, tends to bias the results in favor of AGN,” he said. “There was no statistical difference (25.6 vs. 25.2 mm Hg.”

However, he added, the hypotensive lipid is clearly an effective compound. Session moderator Carlo E. Traverso, MD, agreed, but added that the claim that it might be more effective on IOP than latanoprost must be confirmed with longer-term data.

“This is going to be, if eventually approved for use, a very important addition to our treatment, with potentially a lot of clinical use for this type of molecule,” Dr. Traverso said.

Safety preserved

Safety evaluation included assessing adverse events by biomicroscopy, ophthalmoscopy, heart rate and blood pressure, and blood chemistry and hematology. In each study, there was a slight increase in mean hyperemia scores during the period of twice-daily treatment in the 0.03% group. This suggested a dose-frequency association, Dr. Sherwood said.

There was a significant increase in laser flare meter measurement from baseline during treatment with timolol, but this measurement did not increase at any time during treatment with AGN 192024.

Three patients were discontinued from the latanoprost comparison study. Two AGN 192024 patients had hyperemia. One latanoprost patient had stomach cramping and body aches.

A slight increase in conjunctival hyperemia was the only consistent finding. The mean severity of hyperemia was in the trace to mild range, similar to levels seen with latanoprost, Dr. Sherwood said.

For Your Information:

• Mark B. Sherwood, MD, can be reached at the University of Florida Department of Ophthalmology, Box 100-284, JHMHC, Gainesville, FL 32610; (352) 846-2100; fax: (352) 392-8554. Dr. Sherwood has no direct financial interest in any products mentioned in this article, nor is he a paid consultant for any companies mentioned..
• Carlo E. Traverso, MD, can be reached at the Clinica Oculista University Genova, Pad 9 OSP, San Martino, Genova, Italy; +390-10-353-8469; fax: +390-10-353-8494. Ocular Surgery News could not confirm whether Dr. Traverso has any financial interest in any products or companies mentioned in this article.
• Paul L. Kaufman, MD, can be reached at the Department of Ophthalmology, University of Wisconsin, 600 Highland Ave., Madison, WI 53792; (608) 263-6074; fax: (608) 263-1466. Dr. Kaufman does not have a direct financial interest in any of the products mentioned in this article. He is a paid consultant for Allergan, Merck and Pharmacia.

• Allergan can be reached at 2525 Dupont Drive, PO Box 19534, Irvine, CA 92623-9534; (714) 246-2389; fax: (714) 246-2205.
• Pharmacia & Upjohn can be reached at 100 Route 206 North, Peapack, NJ 07977; (908) 901-8517; fax: (908) 901-1871.