Reports

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7th International Symposium on Ocular Pharmacology and Therapeutics

Budapest, Hungary / February 28-March 2, 2008

Among research discussed here this week were results from a recently completed Canadian multicentre trial assessing the effectiveness of treatment with fixed-combination dorzolamide/timolol alone or in combination with a prostaglandin as first-line therapy for reducing intraocular pressure (IOP) in untreated primary open-angle glaucoma (POAG) or ocular hypertension with IOP <u>></u>27 mm Hg.

According to investigators under lead author Dr. Andrew Crichton, Clinical Professor of Surgery, Division of Ophthalmology, University of Calgary, Alberta, contemporary clinical research supports the concept of aggressive IOP lowering to help prevent optic nerve damage and blindness. Each change in IOP is associated with about a 10% increased or decreased risk of progression of disease. Many patients require more than one medication to maintain IOP control and avoid optic nerve damage or visual field loss.

“In the present study, 164 treatment-naive POAG or ocular hypertension patients with IOP of <u>></u>27 mm Hg were treated with fixed-combination dorzolamide/timolol for 12 weeks as first-line therapy,” researchers explained. “Subjects in this trial who did not achieve target IOP by the end of six weeks also received a prostaglandin for the remaining six weeks.”

Primary efficacy end points were the absolute and per cent decrease in IOP from baseline after 12 weeks of treatment. Secondary end points included an evaluation of the efficacy of the dorzolamide/timolol fixed combination in reducing IOP (absolute and per cent decrease) after six weeks of treatment, as well as a description of the efficacy of the fixed combination over six weeks as both monotherapy and with an added prostaglandin.

Achieving End Point Targets

Researchers reported that among those assigned to the fixed-combination monotherapy arm, mean IOP dropped significantly from 29.8 mm Hg at baseline to 17.6 mm Hg by week 12 (P<0.001). In those receiving added prostaglandin, mean IOP dropped from 33.1 mm Hg to 19.7 mm Hg (P<0.001). A total of 136 patients in the dorzolamide/timolol fixed-combination arm completed six weeks of the study, while 134 completed all 12 weeks of the trial. Of this cohort, a 39.7% IOP reduction was achieved at six weeks and maintained through to week 12, at which time it was measured as a reduction of 40.4%. Among the 28 patients who received an additional prostaglandin, 21 patients (75%) achieved the same secondary end point at week 6, while 21 out of 24 patients (87.5%) achieved it by week 12.

Figure 1. Per Cent Change in IOP (Morning Peak) by Treatment Group

No serious adverse events were reported during the course of this study, although treatment-related non-serious adverse events were documented in 14% of the dorzolamide/timolol monotherapy arm and in 21.4% of those receiving the combination strategy. The most common observed were irritation, pain and increased lacrimation.

Investigators concluded that treatment of patients with untreated POAG or ocular hypertension and IOP <u>></u>27 mm Hg with fixed-dose dorzolamide/timolol for six or 12 weeks achieved reductions in IOP that were both statistically significant and clinically beneficial. They also suggested that the study supports a strategy of aggressive IOP treatment with dorzolamide/timolol monotherapy: first-line treatment using this fixed combination achieved a significant IOP reduction of approximately 40% at six weeks and was maintained until 12 weeks in patients with newly diagnosed POAG or ocular hypertension with high IOP.

Pioneering studies have also demonstrated that blood flow dysregulation, including impaired perfusion to the optic nerve and defects in retinal circulation, is also linked to glaucoma and must be addressed when treating it. As many as 25% of glaucoma patients display little or no elevation of IOP and only about 10% of individuals with raised IOP actually suffer visual loss. The simultaneous modification of the two main control systems within the eye—decreasing IOP and increasing ocular blood flow—may prove to be an important treatment target.

These studies provide significant evidence indicating that abnormalities, chiefly of vascular origin, other than IOP play a significant role in glaucoma. The carbonic anhydrase inhibitor (CAI) dorzolamide has been shown to improve optic nerve oxygen tension as well as retinal circulation while reducing IOP at the same time.

Reviewing Dosing Frequency

During another presentation during the scientific sessions, Dr. Alvaro Lupinacci, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, noted that the CAI dorzolamide is often used clinically twice or three times daily as adjunctive therapy with prostaglandins, so his study aimed at determining the relative effect of the compound on IOP when added to latanoprost 0.004% prostaglandin analogue treatment delivered either twice or three times daily. No significant patient differences at baseline were observed in gender, race or diagnosis between the groups started on either treatment regimen.

Fifteen ocular hypertensive or POAG patients with IOP levels <u>></u>20 mm Hg and who were on latanoprost therapy were randomized to b.i.d. (8 a.m. and 8 p.m.) or t.i.d. (8 a.m., 4 p.m. and 8 p.m.) dosing of dorzolamide 2% in both eyes for four weeks before a month-long washout period and then switched to the opposite dosing frequency for four weeks. Mean baseline IOP was 20.9 mm Hg, which was measured at baseline and diurnal time points at the end of each treatment period (8 a.m., 10 a.m., 12 a.m., 2 p.m., 4 p.m. 6 p.m. and 8 p.m.). “Patient baseline characteristics were essentially the same between groups. They had a range of optic nerve head appearances with an intact neural rim,” Dr. Lupinacci noted.

After b.i.d. and t.i.d. dosing of the CAI, mean IOP was 17.7 mm Hg (13.5% reduction) and 17.8 mm Hg (16.6% reduction), respectively, both of which were significant (P<0.001) improvements from baseline. Diurnal IOP control was similar between the two groups, although mean IOP reduction was significantly greater at 6 p.m. on the t.i.d. regimen than with b.i.d. administration. No significant differences between groups were observed at other measured time points.

“While mean IOP reduction was significantly [P=0.038] lower at 8 p.m. after t.i.d. treatment [-4.7 ± 3.3 mm Hg] compared with b.i.d. treatment [-2.3 ± 2.7 mm Hg], diurnal IOP reduction ranged from -2.5 to -4.7 mm Hg after b.i.d. dosing and -2.3 to -3.1 after t.i.d. dosing,” Dr. Lupinacci observed. “The fact that we found similar results with b.i.d. and t.i.d. dosing of dorzolamide except for one time point during the day suggests that b.i.d. rather than t.i.d. dosing would be sufficient therapy for many patients, as is commonly recommended in clinical practice.”

Dr. Lupinacci concluded that b.i.d. vs. t.i.d. dosing of dorzolamide 2% added to latanoprost 0.004% did not significantly effect the change of IOP except at one time point. Dorzolamide 2% added to latanoprost 0.004% resulted in a significantly decreased IOP, he reported.