With the advent of the prostaglandin analogues (PGA) in the mid- to late 1990s, there was a lot of speculation about a new frontier in glaucoma pharmacology. The prostaglandins were truly a new concept mechanism involving uveoscleral outflow, and early work on these compounds helped in clarifying aqueous flow dynamics. The ability to control intraocular pressure with little diurnal fluctuation at a once-a-day dose has redefined our standards for new glaucoma agents.

Though these drugs have dramatically decreased the rates of incisional surgery, primary monotherapy continues to fail for too many glaucoma patients. The time has come for addtional new concept drugs to enter our offices.

 

Old Drugs, New Tricks

Some upcoming and currently available drugs have been given new twists to deliver improved therapy.

Travatan Z (travoprost, Alcon). The effect of preservatives on the cornea is a concern when considering the chronic nature of glaucoma treatment. In the first attempt of preservative-free glaucoma treatment, Alcon has released Travatan Z, a modified version of its Travatan ophthalmic solution but without the benzalkonium chloride (BAK) preservative. Travatan Z is preserved with Alcons proprietary SofZia preservative system, which breaks up upon contact with the eye. The pivotal trials of Travatan Z demonstrated equal intraocular pressure lowering efficacy, but lower rates of local side effects, such as hyperemia, when compared with the original formulation.1

Tafluprost (Santen). Santen is in phase III clinical trials of this new prostaglandin compound. In April, the company submitted a marketing application to 13 European countries. This agent appears similar in structure and mechanism to latanoprost. However, talfluprost lowers intraocular pressure (in mice) more than latanoprost.2

Alphagan P (brimonidine tartrate, Allergan). Last year, Allergan released a lower 0.1% formulation of its Alphagan P. The original 0.2% preservative, is now available generically. Be alert to the high allergy rate of the old 0.2% formulation.3

Studies of the new concentration have demonstrated equal efficacy at lowering intraocular pressure between the previous 0.15% Alphagan P formulation and the 0.2% original formulation, but with fewer reported side effects.

 

The Next Generation

Nitric oxide agents. New compounds consisting of nitric oxide-donating derivatives of latanoprost are generating much interest. Preclinical data of PF-03187207 demonstrated improved ability when used with lantanoprost to lower intraocular pressure.4 Besides the PGA-related remodeling of the ciliary spaces, which increases uveoscleral outflow, NicOx, as this chemical is being called, may also help improve outflow by other mechanisms. Plus, NicOx may someday help combat other ocular disease states, such as dry eye and diabetic retinopathy. Researchers that specialize in hypertension, prostate disease and cancer are also investigating NicOx products.

For glaucoma, Pfizer is collaborating with the French company NicOx SA. In March the duo launched a phase II dose-finding and safety study for a nitric oxide compound that lowers intraocular pressure.

Combigan (brimonidine tartrate 0.2%/timolol 0.5%, Allergan). In December 2006, Allergan received an approvable letter from the FDA for its new combination glaucoma medication, Combigan. The FDA letter calls for further confirmatory study data, which Allergan says it is supplying. This combination formulation is well tolerated and lowers intraocular pressure just as effectively as concomitant administration of the two agents separately.5

Cosopt (dorzolamide 2%/timolol 0.5%, Merck). To date, Cosopt remains the only combination glaucoma therapy that is approved by the FDA. Other drugs that combine PGA and timololsuch as Xalcom (lantoprost/ /timolol, Pfizer) and Extravan (travoprost/timolol, Alcon)have yet to attain final FDA approval.

OT-730 (Othera Pharmaceuticals). Beta-blockers are frequently avoided in glaucoma treatment today due to their potential systemic side effects. Othera Pharmaceuticals has a non-selective beta-blocker that breaks down as it enters the bloodstream. OT-730 has a decreased risk associated with systemic conditions, such as advanced cardiac disease and pulmonary disease. The early preclinical data on this compound confirms that, when compared to timolol, there is neither a decrease in heart rate nor an increase in blood pressure.6

Serotonin agents. Researchers are investigating serotonin 5-HT receptor site agonists and antagonists to determine their viability for the topical treatment of glaucoma. Biovitrum, a Stockholm-based biopharmaceutical company, has started phase II clinical trials in Sweden and the Ukraine on its compound BVT.28949, which is a serotonin 5-HT2A antagonist. However, this receptor system is very complicated, and it will take both considerable time and money to reduce the number of possible pathways for glaucoma.

Rho-kinase inhibitors. Another new class of glaucoma agents may be found in the Rho-kinase inhibitor family. Similar to the prostaglandins, the Rho-kinase inhibitors work by increasing uveoscleral outflow. The drugs target enzymes in the trabecular meshwork and ciliary body. Studies presented at ARVO in the last few years showed increases similar to the prostalandins effects on both uveoscleral and aqueous outflow in monkeys.7 As with the serotonin compounds, the Rho-kinase inhibitors have many different potential pathways, meaning a longer road to an approved drug.

Latrunculins. These macrolides are isolated from the marine sponge Latrunculia magnifica. How can a marine sponge treat glaucoma? Latrunculins are potent actin-disrupting agents that sequester G-actin, leading to disassembly of actin filaments. The trabecular meshwork is built upon a cytoskeletal network of actin filaments. In very low concentrations, similar to those of the currently available prostaglandins, latrunculins lower IOP by decreasing trabecular resistance.8 This class of agents comes from the work of Paul Kaufman, M.D., at the University of Wisconsin. He is currently working with Inspire Pharmaceuticals to help bring this drug class to the market. It is currently in phase I human trials.

During the last 20 years, we have seen tremendous progress in pharmacological treatment of glaucoma. But, there is still room for improvement. In the next 10 years, we can expect glaucoma drugs that will offer once-daily dosing (or less), minimal local side effects, 24-hour intraocular pressure control and therapeutic synergy with other topical and systemic medications.

 

1. Lewis RA, Katz GJ, Weiss MJ, et al; Travoprost BAC-free Study Group. Travoprost 0.004% with and without benzalkonium chloride: a comparison of safety and efficacy. J Glaucoma 2007 Jan;16(1):98-103.

2. Ota T, Murata H, Sugimoto E, et al. Prostaglandin analogues and mouse intraocular pressure: effects of tafluprost, latanoprost, travoprost, and unoprostone, considering 24-hour variation. Invest Ophthalmol Vis Sci 2005 Jun;46(6):2006-11.

3. Katz, LJ. Twelve-month evaluation of brimonidine-purite versus brimonidine in patients with glaucoma or ocular hypertension. J Glaucoma 2002 Apr;11(2):119-26.

4. Poster, 8th Meeting of the Associatio of Ocular Pharmacology and Thereapeutics.  Feb 8, 2007, San Diego, CA.

5. 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 or ocular hypertension. Arch Ophthalmol 2006 Sep;124:1230-8.

6. Othera Pharmaceuticals Inc. Products. OT-730: A Safer Beta-Blocker for Glaucoma without Systemic Side-Effects. Available at: http://www.othera.com/products_ot730.html. (Accessed June 25, 2007)

7. Toris CB, Fan S, McLauglin MA.  The Rho kinase inhibitor AL-38565A reduces aqueous flow in monkeys. ARVO 2006.  E-Abstract 2945.
8. Okka M, Tian B, Kaufman PL.  Effect of low-dose latrunculin B on anterior segment physiologic features in the monkey eye.  Arch Ophthalmol 2005 Oct;123(10):1456-7.