RX Perspective

New Glaucoma Treatment Paradigm Embraces Combination Therapy

Two-in-one drug reduces production of aqueous humor while enhancing drainage.

By Andrew Crichton, M.D.

The number of glaucoma cases worldwide is estimated at 65 million, and with no cure in sight, topical IOP lowering eye drops remain the first-line treatment. While monotherapy avoids the burden of a complicated treatment regimen, a large proportion of glaucoma patients require more than one drug. Fixed combination medications with complementary mechanisms of action offer the advantage of a simplified regimen, which often translates to improved compliance.

While patient compliance is crucial to effective disease management, even the strictest adherence is only worthwhile if the therapy reduces and controls IOP. Combigan (brimonidine tartrate 0.2%/timolol maleate ophthalmic solution 0.5%) is the newest fixed combination glaucoma therapy, and although it has only recently gained FDA approval in the United States, I have been using it for several years with great success in my Canadian glaucoma practice.

Clinical Trial Data

Combigan is unique in that it is an alpha adrenergic agonist with a beta adrenergic receptor blocker, which enables it to provide a dual mechanism of action to lower IOP by reducing production of aqueous humor while simultaneously enhancing aqueous humor drainage via the uveoscleral pathway.

This novel agent has been shown in clinical trials to lower IOP more than either of its components individually.¹ In the 12-month pivotal trials of 1,159 patients, Combigan ophthalmic solution significantly reduced mean IOP up to 33% (7.6 mm Hg) from baseline and was well tolerated with a low ocular allergy rate of 5.2%. This secondary finding was demonstrated in 385 patients.¹

In addition, investigators found that mean IOP reductions were significantly greater with Combigan compared with timolol at all intervals and with brimonidine at three of the four measurement intervals. For this analysis, data were pooled from two identical prospective, randomized, investigator-masked, multicenter studies. Patients with glaucoma or OHT were randomized following washout of any previous medications to receive Combigan b.i.d.; brimonidine t.i.d.; or timolol b.i.d. The mean decrease from baseline IOP during 12-month follow-up was 4.4 to 7.6 mm Hg with Combigan; 2.7 to 5.5 mm Hg with brimonidine, and 3.9 to 6.2 mm Hg with timolol. Perhaps most noteworthy of all was the finding that significantly more Combigan patients achieved IOPs <18 mm Hg at all visits and all time points measured than those treated with brimonidine or timolol. According to the Advanced Glaucoma Intervention Study (AGIS), IOP <18 mm Hg correlates to reduction of visual field defect progression. This analysis showed that Combigan b.i.d. provided superior IOP-lowering efficacy compared to brimonidine t.i.d. or timolol b.i.d. monotherapy, and Combigan's safety profile was comparable to or better than that of either monotherapy.¹

In a randomized, multicenter, double-masked study of patients who had inadequate IOP control after three weeks of monotherapy, patients were treated with either Combigan b.i.d. or concomitant brimonidine tartrate 0.2% b.i.d. and timolol 0.5% b.i.d. Investigators found that Combigan is as safe and effective as concomitant treatment with its individual components and that the fixed combination therapy provides significant additional IOP lowering when initiated after a run-in on monotherapy.²

Another notable finding resulting from non-published, pooled 3-month studies illustrated that Combigan reduced IOP to a greater degree than the other available fixed combination glaucoma therapeutic agent.3 This data set demonstrated in 101 subjects that Combigan reduced mean IOP to 15.6 mm Hg vs. a reduction to 17.2 mm Hg with Cosopt, at 3 months. In the same study, Combigan was also shown to be an effective adjunct to prostaglandin analogues — it significantly reduced mean IOP up to 29% or 6.9 mm Hg from baseline when added to a prosta-glandin analogue. Investigators also found that Combigan demonstrated low burning and stinging, and 91% of patients reported that Combigan was comfortable or very comfortable.³

The open label Canadian CEED (Combigan Early Experience Data) trials (1 and 2) of which I was an investigator provided practical clinical information about the fixed combination therapy's efficacy, tolerability and safety in clinical settings. CEED 1 and 2 comprised 453 patients at 47 centers and 2,133 patients at 123 centers across Canada respectively. In CEED 1, 45% of all eyes had an additional >15% IOP decrease, and patients who switched from Cosopt to Combigan whether as monotherapy or adjunctive therapy achieved an additional 2.7 mm Hg (or 12%) mean IOP reduction.⁴ Furthermore, the number of treated eyes that achieved the ≤18 mm Hg target IOP more than doubled from 29% to 64% once patients were switched to Combigan adjunctive therapy from Cosopt adjunctive therapy.

In CEED 2, 44% of all eyes achieved additional IOP reductions of ≥15%, and target pressures of ≤18 mm Hg were reached by 77% of eyes treated with Combigan compared to 41% at baseline.⁵ When Combigan monotherapy was compared to Cosopt monotherapy, additional mean IOP reductions of 2.7 mm Hg or 10.8% were achieved. Improved tolerability was found as well, with less burning, stinging, metallic taste and itchiness reported by the Combigan cohort.

My Experience

I have found Combigan to be an effective initial IOP lowering agent for some patients as well as an ideal adjunctive therapy to a prostaglandin analogue, which is my preferred first-line treatment. In addition, Combigan is particularly effective in the management of the more difficult-to-treat secondary glaucomas, such as uveitic glaucoma or neovascular glaucoma, as well as for post-surgical IOP control. While Cosopt, too, is effective in the post-surgical scenario, my clinical impression is that there is less discomfort associated with Combigan, which of course has added importance in the postoperative period. My own anecdotal experience supports the pivotal trials' finding regarding patient comfort and a low incidence of ocular allergy associated with administration of Combigan.

The Advantage of Two in One

Administration of two drugs in a single bottle has advantages over two drugs administered separately, including convenience, the potential for improved patient compliance and diminished risk of washout from a second drug being administered too soon after the first.⁶ Another advantage is that it limits the patient's lifetime exposure to potentially damaging preservatives.⁷

The glaucoma treatment paradigm is shifting and combination therapy will play a central role in the new model. Many physicians who treat glaucoma are starting patients on a fixed-combination therapy rather than starting with a monotherapy, such as a prostaglandin analogue and adding drugs one at a time until a satisfactory target pressure is finally achieved. Today's physicians who treat glaucoma will usually start with a monotherapy, but may add a fixed combination to reach that target IOP sooner rather than later.

Combigan is an efficacious and well-tolerated therapy ideal for patients who require an additional amount of pressure lowering and would benefit from a simplified regimen. Its recent FDA approval will enable ophthalmic specialists in the United States to fully implement this promising new glaucoma treatment paradigm to their patients' fullest advantage. OM

References

1. Sherwood MB, Craven ER, Chou C, et al. Twice-daily 0.2% brimonidine-0.5%/timolol fixed-combination therapy vs. monotherapy with timolol or brimonidine in patients with glaucoma and ocular hypertension: a 12-month randomized trial. Arch Ophthalmol. 2006;124:1230-1238.
2. Goni FJ for the Brimonidine/Timolol Fixed Combination Study Group. 12-week study comparing the fixed combination of brimonidine and timolol with concomitant use of the individual components in patients with glaucoma and ocular hypertension. Eur J Ophthalmol. 2005;15:581-590.
3. Nixon DR, Hollander DA. Comparison of the efficacy and tolerability of twice-daily COMBIGAN versus Cosopt fixed-combination therapies. Poster presented at 111th Annual Meeting of the American Academy of Ophthalmology; November 10-13, 2007; New Orleans, LA.
4. Crichton ACS. Timolol/Brimonidine combination therapy in glaucoma management. Clinical & Surgical Journal of Ophthalmology. 2005;23:356-359.
5. Ahmed I. Combigan early experience data. Clinical & Surgical Journal of Ophthalmology. 2007;25:50-54.
6. Choudhri S, Wand M, Shields MB. A comparison of dorzolamide-timolol combination versus the concomitant drugs. Am J Ophthalmol. 2000;130:832-833.
7. Cvenkel B, Ihan A. Ocular surface changes induced by topical antiglaucoma monotherapy. Ophthalmologica. 2002;216:175-179.