Update on Prostaglandin Analogues Used for the Treatment of Glaucoma

Learning Objectives Review the structure and mechanism of action of the commonly used prostaglandin analogues for treatment of glaucoma Review the efficacy of the commonly used prostaglandin analogues Know the side effects commonly associated with prostaglandins

Introduction Prostaglandin analogues are currently used as a first-line treatment for glaucoma because they effectively lower IOP Each prostaglandin analogue has a unique receptor-binding profile, but most agents have similar efficacy Compared with other antiglaucoma medications, prostaglandin analogues: Reduce IOP to a greater extent Provide good control over IOP fluctuations Produce few systemic adverse events Prostaglandin analogues have similar side effects Cause different degrees of hyperaemia, iris pigmentation changes, and eyelash growth Prostaglandin analogues have gained attention in recent years for their ability to reduce intraocular pressure (IOP)1 and are now a common first-line treatment option for glaucoma.2 Prostaglandin analogues tend to reduce IOP to a greater extent and produce fewer systemic adverse events than other antiglaucoma medications.1,2 Prostaglandin analogues produce a range of ocular effects by acting on the FP and, to a much lesser degree, EP receptors.3 Studies indicate that the IOP-lowering efficacies of the prostaglandin analogues are comparable,1 although each has a unique receptor-binding profile. The various receptor binding profiles may account for each prostaglandin analogue’s different effects on the eye.4 Conjunctival hyperaemia, which is often associated with the use of prostaglandin analogues, is one side effect with a frequency that varies greatly between agents.4 IOP = intraocular pressure Marquis RE et al. Drugs Aging. 2005;22(1):1–21; Parrish RK et al. Am J Ophthalmol. 2003;135:688–703; Takagi Y et al. Exp Eye Res. 2004;78:767–776; van der Valk R et al. Ophthalmology. 2005;112:1177–1185; Holló G. Expert Opin Drug Saf. 2007;6(1):45–52. FP = prostaglandin F References: 1. van der Valk R, Webers C, Schouten J, et al. Intraocular pressure-lowering effects of all commonly used glaucoma drugs. Ophthalmology. 2005;112:1177–1185. 2. Marquis RE, Whitson JT. Management of glaucoma: focus on pharmacological therapy. Drugs Aging. 2005;22(1):1–21. 3. Ota T, Aihara M, Saeki T, et al. The IOP-lowering effects and mechanism of action of tafluprost in prostanoid receptor-deficient mice. Br J Ophthalmol. 2007;91:673–676. 4. Holló G. The side effects of the prostaglandin analogues. Expert Opin Drug Saf. 2007;6(1):45–52.

Prostaglandin Analogues: Structure There are currently 3 prostaglandin F2α (PGF2α) analogues widely available in various parts of the world: latanoprost, travoprost, and bimatoprost. A new prostaglandin analogue, tafluprost, has also been developed.1 All prostaglandin analogues are prodrugs with an ester and are converted to their acid form by the esterase in the cornea.1 Distinct from its predecessors, tafluprost has a modified carbon skeleton: the hydroxyl group at C15 has been substituted with a difluoro group. This difluoro group may explain why tafluprost has an affinity for the prostanoid FP receptor that is higher than other prostaglandin analogues. In fact, the affinity is 12 times greater than that of latanoprost.1 The fluorine atoms may bestow a higher affinity for the prostanoid FP receptors than that exhibited by other PG derivatives. PGF2α = prostaglandin F2α Adapted with permission from Takagi Y et al. Exp Eye Res. 2004;78:767–776 and Marquis RE et al. Management of glaucoma: focus on pharmacological therapy. Drugs Aging. 2005;22(1):1–21. FP = prostaglandin F Reference: 1. Takagi Y, Nakajima T, Shimazaki A, et al. Pharmacological characteristics of AFP-168 (tafluprost), a new prostanoid FP receptor agonist, as an ocular hypotensive drug. Exp Eye Res. 2004;78:767–776.

Prostaglandin Analogues: Mechanism of Action Once the prodrug enters the structures of the eye and has been converted to its active form, the prostaglandin analogue exerts its effects to reduce IOP. The prodrug form of prostaglandin analogues facilitates their penetration of the cornea, thus allowing delivery of the active carboxylic acid form to the aqueous humor.1 The active metabolite has high affinity for the prostanoid FP receptor. Although the precise mechanism of increased uveoscleral outflow is unclear, prostaglandins appear to activate a molecular transduction cascade that leads to increased biosynthesis of matrix metalloproteinases.2 These proteinases cleave extracellular-matrix components, such as collagen, within the ciliary muscle and sclera. The resulting reduction of the extracellular matrix may contribute to the mechanism of increased uveoscleral outflow.2 FP = prostaglandin F Adapted with permission from Weinreb RN et al. Prostaglandin effects on the uveoscleral outflow pathway. In: Krieglsten GK, ed. Glaucoma Update VI; Springer-Verlag, Berlin. 2000:197–202. FP = prostaglandin F; IOP = intraocular pressure References: 1. Takagi Y, Nakajima T, Shimazaki A, et al. Pharmacological characteristics of AFP-168 (tafluprost), a new prostanoid FP receptor agonist, as an ocular hypotensive drug. Exp Eye Res. 2004;78:767–776. 2. Weinreb RN, Lindsey JD. Metalloproteinase gene transcription in human ciliary cells with latanoprost. Invest Ophthalmol Vis Sci. 2002;43:716–722.

Prostaglandin Receptor-Binding Affinity (Moles per Liter)a SAFLUTAN™† (tafluprost) Has High FP Receptor Affinity: 12 Times Greater Than Latanoprost Prostaglandin Receptor-Binding Affinity (Moles per Liter)a Prostaglandin Analogueb FP EP1 EP2 EP3 IP/DP TP PGF2α 1.2 × 10−8 3.2 × 10−7 6.4 × 10−6 1.6 × 10−7 >10−4 > 10−4 Latanoprost acid 1.0 × 10−8 5.0 × 10−6 2.8 × 10−5 Travoprost 3.5 × 10−9 3.0 × 10−8 2.4 × 10−5 Bimatoprost 4.5 × 10−9 6.5 × 10−7 3.4 × 10−5 Tafluprost 0.5 × 10−9 >10−6 6.7 × 10−8 > 10−6 The profile of SAFLUTAN™† (tafluprost) will be reviewed in the following slides. The prostaglandin analogues have different binding affinities and selectivities for the various prostanoid receptors. The FP receptor is considered an important mediator of the IOP-lowering response.1 The binding profiles of several prostaglandin analogues are shown in this table. Tafluprost displays the highest affinity and is highly selective for the FP receptor with an affinity that is 12 times greater than that of latanoprost acid. Higher FP affinity has not been correlated with an increase in either efficacy or safety EC50 = half maximal effective concentration; FP = prostaglandin F; PGF2α = prostaglandin F2α aReceptor binding assessed according to EC50 values. bData refer to active drug product. Stjernschantz JW. From PGF2α-isopropyl ester to latanoprost: a review of the development of Xalantan. Inv Ophthalmol Vis Sci. 2001;42(6):1134–1145; Stjernschantz JW et al. Mechanism and clinical significance of prostaglandin­induced iris pigmentation. Surv Ophthalmol. 2002;47(suppl 1):S162–S175; Takagi Y et al. Exp Eye Res. 2004;78:767–776. †SAFLUTAN is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. FP = prostaglandin F; IOP = intraocular pressure †SAFLUTAN is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. Reference: 1. Takagi Y, Nakajima T, Shimazaki A, et al. Pharmacological characteristics of AFP-168 (tafluprost), a new prostanoid FP receptor agonist, as an ocular hypotensive drug. Exp Eye Res. 2004;78:767–776.

Substantial IOP-Lowering Efficacy of Prostaglandin Analogues is Consistent Across Products IOP Reduction (%) Prostaglandins are effective IOP-lowering agents.1 This graph slide shows the percentage reduction in mean IOP at 08:00, 12:00, 16:00, and 20:00, in patients with open-angle glaucoma or ocular hypertension after 12 weeks of therapy with latanoprost, bimatoprost, or travoprost. The IOP-lowering efficacy of all 3 compounds was similar at all time points.1 Time IOP = intraocular pressure Parrish RK et al. Am J Ophthalmol. 2003;135(5):688–703. IOP = intraocular pressure Reference: 1. Parrish RK, Palmberg P, Sheu W, for the XLT Study Group. A comparion of latanoprost, bimatoprost, and travoprost in patients with elevated intraocular pressure: a 12-week, randomized, masked-evaluator multicenter study. Am J Ophthalmol. 2003;135(5):688–703.

Prostaglandin Analogues Show Comparable Efficacy IOP Reduction Parrish N = 410 12 weeks Netland N = 390 12 months Gandolfi N = 232 3 months Noecker N = 269 6 months Multi-center, randomized, investigator-masked studies of patients with ocular hypertension or primary open-angle glaucoma. Study drugs given once daily. Mean IOP Reduction (mmHg) at 8:00 Across Published Comparative Trials When the IOP-lowering effects of different prostaglandin analogues are compared across different trials, some variation is observed. However, overall, latanoprost, bimatoprost, and travoprost appear to have similar IOP-lowering effects, as summarized graphically on this slide.1-4 Two head-to-head studies comparing bimatoprost with latanoprost indicated that bimatoprost was more effective than latanoprost.1,2 However, another study demonstrated that latanoprost, bimatoprost, and travoprost had similar efficacies.4 These data indicate that although the strength of the IOP-lowering effect observed with each prostaglandin analogue varies between trials to some extent, the different prostaglandin analogues appear to have comparable effects when assessed as a class. p < 0.001 IOP = intraocular pressure Parrish RK et al. Am J Ophthalmol. 2003;135:688–703; Netland PA et al. Am J Ophthalmol. 2001;132:472–484; Gandolfi S et al. Adv Ther. 2001;18(3):110–121; Noecker RS et al. Am J Ophthalmol. 2003;135:55–63. IOP = intraocular pressure References: 1. Gandolfi S, Simmons S, Sturm R, et al. Three-month comparison of bimatoprost and latanoprost in patients with glaucoma and ocular hypertension. Adv Ther. 2001;18(3):110–121. 2. Noecker RS, Dirks M, Choplin N, et al. A six-month randomized clinical trial comparing the intraocular pressure-lowering efficacy of bitmatoprost and latanoprost in patients with ocular hypertension or glaucoma. Am J Ophthalmol. 2003;135:55–63. 3. Netland PA, Landry T, Sullivan K, et al. Travoprost compared with latanoprost and timolol in patients with open-angle glaucoma or ocular hypertension. Am J Ophthalmol. 2001;132:472–484. 4. Parrish RK, Palmberg P, Sheu W. A comparison of latanoprost, bimatoprost, and travoprost in patients with elevated intraocular pressure: a 12-week, randomized, masked-evaluator multicenter study. Am J Ophthalmol. 2003;135:688–703.

Mean Change From Baseline as % Change in IOP IOP-Lowering Efficacy: Prostaglandin Analogues vs Other Antiglaucoma Treatments Treatment Mean Change From Baseline as % Change in IOP Peak Trough Bimatoprost 33 28 Travoprost 31 29 Latanoprost Timolol 27 26 Brimonidine 25 18 Betaxolol 23 20 Dorzolamide 22 17 Brinzolamide Compared with other antiglaucoma medications, the prostaglandin analogues are the most effective in reducing IOP.1 This table summarizes the results of a meta-analysis of several individual studies in patients with primary open-angle glaucoma or ocular hypertension. Studies were selected in which the drug concentration, timing of application, and frequency of dosing were as recommended by the American Academy of Ophthalmology.1 The efficacy of prostaglandin analogues (latanoprost, travoprost, and bimatoprost) was better than that of other classes of antiglaucoma treatments.1 There was a clear difference between the prostaglandin analogues and the carbonic anhydrase inhibitor dorzolamide but not between the prostaglandin analogues and the beta-blocker timolol.1 This separate analysis of the maximum and minimum IOP reductions indicated that the IOP-lowering effects of the prostaglandin analogues are consistently greater than those of other drug classes. IOP = intraocular pressure Adapted with permission from van der Valk R et al. Ophthalmology. 2005;112:1177–1185. IOP = intraocular pressure Reference: 1. van der Valk, Webers C, Schouten J, et al. Intraocular pressure-lowering effects of all commonly used glaucoma drugs. Ophthalmology. 2005;112:1177–1185.

Adverse Events Associated With Prostaglandin Analogues Prostaglandin analogues have a better systemic safety profile than other antiglaucoma therapies Common side effects of prostaglandin analogues: Conjunctival hyperaemia Iris pigmentation changes Eyelash growth Both efficacy and safety are important parameters to consider when choosing an antiglaucoma medication. Prostaglandin analogues are associated with a lower incidence of systemic side effects than seen with timolol and other antiglaucoma medications1 with the various prostaglandin analogues having similar side effect profiles. Frequent side effects of this class of drugs include conjunctival hyperaemia, iris pigmentation changes, eyelash growth, and eyelash thickening.2 Rare side effects include periocular pigmentation, damage to the blood-aqueous barrier, and cystoid macular edema.2 Conjunctival hyperaemia, eyelash changes, and cystoid macular edema are reversible, but iris pigmentation change is not.2 Marquis RE et al. Drugs Aging. 2005;22(1):1–21; Holló G. Expert Opin Drug Saf. 2007;6(1):45–52. References: 1. Marquis RE, Whitson JT. Management of glaucoma: focus on pharmacological therapy. Drugs Aging. 2005;22(1):1–21. 2. Holló G. The side effects of the prostaglandin analogues. Expert Opin Drug Saf. 2007;6(1):45–52.

Conjunctival Hyperaemia With Prostaglandin Analogues Patients (%) Conjunctival hyperaemia is one of the most important side effects of topical prostaglandin therapy for glaucoma. The incidence of conjunctival hyperaemia varies among the different prostaglandin analogues.1 Parrish et al evaluated the conjunctival hyperaemia associated with latanoprost, travoprost, and bimatoprost in patients with open-angle glaucoma or ocular hypertension. The figure on this slide shows the incidence of hyperaemia reported at the end of the 12-week treatment period. Hyperaemia occurred most often with bimatoprost (68.6% of patients), followed by travoprost (58%), and finally latanoprost (47.1%).1 Taking the mean hyperaemia-severity scores into account, the difference between latanoprost and bimatoprost was statistically significant (p = 0.001). The degree of hyperaemia associated with each treatment remained consistent throughout the 12-week study.1 Similar results were reported by Stewart et al in healthy subjects after 5 days of treatment with latanoprost, bimatoprost, or travoprost.2 Latanoprost Bimatoprost Travoprost Parrish RK et al. Am J Ophthalmol. 2003;135:688–703; Stewart WC et al. Am J Ophthalmol. 2003;135:314–320. References: 1. Parrish RK, Palmberg P, Sheu W, for the XLT Study Group. A comparison of latanoprost, bimatoprost, and travoprost in patients with elevated intraocular pressure: a 12-week, randomized, masked-evaluator multicenter study. Am J Ophthalmol. 2003;135:688–703. 2. Stewart WC, Kolker AE, Stewart JA, et al. Conjunctival hyperemia in healthy subjects after short-term dosing with latanoprost, bimatoprost, and travoprost. Am J Ophthalmol. 2003;135:314–320.

Conjunctival Hyperaemia With Prostaglandin Analogues (cont) Patients (%) The different degrees of conjunctival hyperaemia are also evident from the summaries of product characteristics (SPCs) for each prostaglandin analogue. Lumigan® (bimatoprost) has the highest rate of hyperaemia, reported in 44% of patients, followed by Travatan® (travoprost) with 22%. Conjunctival hyperaemia is considered “very common” with Xalatan® (latanoprost), which means it occurs in 10% of patients or more.1-3 Xalatan® (latanoprost) Travatan® (travoprost) Lumigan® (bimatoprost) Xalatan Summary of Product Characteristics. Pharmacia Ltd., Kent, UK.: 2007; Travatan Summary of Product Characteristics. Alcon Laboratories (UK) Ltd., Hemel Hempstead, UK.: 2006; Lumigan Summary of Product Characteristics. Allergan Ltd., Marlow, Bucks, UK.: 2007. References: 1. Xalantan Summary of Product Characteristics. Pharmacia Ltd, Kent, UK.: 2007. Electronic Medicines Compendium (eMC). Available at: http://emc.medicines.org.uk/document.aspx?documentId=9043. Accessed April 21, 2009. 2. Travatan Summary of Product Characteristics. Alcon Laboratories (UK) Ltd., Hemel Hempstead, UK.: 2006. Electronic Medicines Compendium (eMC). Available at: http://www.emc.medicines.org.uk/medicine/8031/SPC/TRAVTAN. Accessed April 21, 2009. 3. Lumigan Summary of Product Characteristics. Allergan Ltd. Marlow, Bucks, UK.; 2007. Electronic Medicines Compendium (eMC). Available at: http://www.emc.medicines.org.uk/medicine/8925/SPC/Lumigan. Accessed April 21, 2009.

Conclusions The IOP-lowering effect of prostaglandin analogues is primarily mediated by the FP receptor Prostaglandin analogues have similar and substantial IOP lowering effects Compared with other antiglaucoma medications, prostaglandin analogues: Reduce IOP to a greater extent Produce fewer systemic adverse events Ocular side effects are common to all prostaglandin analogues Conjunctival hyperaemia, which occurs with varying frequencies among these medications Iris pigmentation changes Eyelash growth Prostaglandin analogues lower IOP primarily by binding to the FP receptor. Although they bind to the FP receptor with varying affinities,1 most prostaglandin analogues (except unoprostone) are highly effective at reducing IOP.2 Studies have demonstrated the comparable IOP-lowering effects of the commonly used glaucoma medications latanoprost, travoprost, and bimatoprost.2,3 A meta-analysis conducted by van der Valk et al demonstrated that prostaglandin analogues reduce IOP to a greater extent than do other classes of ocular hypotensive medications.3 Furthermore, prostaglandin analogues are associated with very few systemic side effects.4 Ocular side effects, such as conjunctival hyperaemia, iris pigmentation changes, and eyelash growth are common to all prostaglandin analogues.5 The incidence and severity of hyperaemia differs, however, according to the prostaglandin analogue used.2 Ocular side effects are important to monitor because they are associated with the development of ocular surface disease.6 FP = prostaglandin F; IOP = intraocular pressure Takagi Y et al. Exp Eye Res. 2004;78:767–776; Parrish RK et al. Am J Ophthalmol. 2003;135:688–703; van der Valk R et al. Ophthalmology. 2005;112:1177–1185; Marquis RE et al. Drugs Aging. 2005;22(1):1–21; Holló G. Expert Opin Drug Saf. 2007;6(1):45–52. FP = prostaglandin F; IOP = intraocular pressure References: 1. Takagi Y, Nakajima T, Shimazaki A, et al. Pharmacological characteristics of AFP-168 (tafluprost), a new prostanoid FP receptor agonist, as an ocular hypotensive drug. Exp Eye Res. 2004;78:767–776. 2. Parrish RK, Palmberg P, Sheu W, for the XLT Study Group. A comparion of latanoprost, bimatoprost, and travoprost in patients with elevated intraocular pressure: a 12-week, randomized, masked-evaluator multicenter study. Am J Ophthalmol. 2003;135:688–703. 3. van der Valk, Webers C, Schouten J, et al. Intraocular pressurelowering effects of all commonly used glaucoma drugs. Ophthalmology. 2005;112:1177–1185. 4. Marquis RE, Whitson JT. Management of glaucoma: focus on pharmacological therapy. Drugs Aging. 2005;22(1):1–21. 5. Holló G. The side effects of the prostaglandin analogues. Expert Opin Drug Saf. 2007;6(1):45–52. 6. Tsai JH, Derby E, Holland EJ, et al. Incidence and prevalence of glaucoma in severe ocular surface disease. Cornea. 2006;25:530–532.