Efficacy and safety of tafluprost 0.0015% and timolol maleate 0.5% fixed combination in patients with ocular hypertension or open-angle glaucoma

Abstract

Introduction: Lowering intraocular pressure (IOP) is at present the only therapeutic approach to the treatment of glaucoma proven to be successful. The choice of therapy must take into account efficacy, tolerability, safety, quality of life, adherence and cost. Monotherapy fails to achieve a satisfactory IOP reduction in 40 – 75% of glaucoma patients after > 2 years of therapy. So far, three prostaglandin/timolol maleate 0.5% fixed combinations (FCs) are available.

Areas covered: This review provides a background on the tafluprost–timolol FC (TTFC, Santen Oy) and its individual compounds. It summarizes the data on efficacy and safety, including comparative data with prostaglandin/timolol FCs already available.

Expert opinion: Tafluprost is a preservative-free prostaglandin analog with a similar IOP efficacy when compared with other prostaglandin analogs. However, its improved adverse effect profile seems to be beneficial in patients sensitive to preservatives. The preservative-free TTFC has no market authorization yet. Only one Phase III trial was published so far, but results are promising in terms of efficacy, tolerability and safety. It is likely that the TTFC will play a role in the treatment of open-angle glaucoma and ocular hypertension.

Keywords::

• efficacy
• glaucoma
• intraocular pressure
• ocular hypertension
• safety
• tafluprost
• timolol maleate

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Erratum

1. Introduction

Glaucoma is a progressive optic neuropathy caused by the degeneration and death of retinal ganglion cells and their axons that form the optic nerve, causing loss of visual function up to blindness [1]. Primary open-angle glaucoma is the most common form of all glaucoma and the second leading cause of blindness worldwide [2]. It has been estimated that in the year 2010 there were ∼ 60 million glaucoma patients worldwide, and that this figure is expected to rise to 80 million by 2020 owing to aging [3]. At present, intraocular pressure (IOP) is the only modifiable risk factor of progression. Sufficiently high IOP reduction reduces the risk of progression of visual field loss [4-6]. The goal of glaucoma treatment is to preserve vision. To reach this goal, it is essential to sufficiently reduce IOP and at the same time to provide good long-term tolerance to therapy [7]. For many years, β-adrenoceptor antagonists (β-blockers) have been a first choice in medical treatment of ocular hypertension and primary open-angle glaucoma. Because of their efficacy, convenience (once-daily application) and minimal systemic side effects, prostaglandin analogs launched in the last decade have nowadays become the first line of treatment [8]. Many clinical trials and meta-analyses have found that prostaglandin analogs have a greater ability to reduce IOP than the other prescribed therapeutic classes, including β-blockers [9-11]. A meta-analysis has shown that the three available prostaglandin analogs can provide an IOP reduction of −31 to −33% at peak and from −28 to −29% at trough [9]. Prostaglandin analogs are recommended as first-line therapy by medical society guidelines (European Glaucoma Society guideline [12], American Academy of Ophthalmology preferred practice [13]). Despite the efficacy of prostaglandin analogs, a significant proportion of patients require more than one medication to reach an IOP at which optic nerve damage will not progress the so-called ‘target IOP.’ The Ocular Hypertension Study found that almost 40% of patients require two or more medications to reach a given target IOP [14]. Prostaglandin analogs are frequently combined with other classes; several unfixed combinations are available. However, unfixed combinations increase regimen complexity and can cause decreased adherence and persistence. Moreover, they require a waiting time between two instillations in order to avoid drug washout [15-18]. Fixed combinations (FCs) simplify the dosing regimen and may thus improve compliance and persistence. This is important as glaucoma is a chronic asymptomatic disease and affected patients are more prone to nonadherence than patients with a symptomatic disease [19]. FCs also decrease the daily exposure to preservatives such as benzalkonium chloride, which is known to have toxic effects on the ocular surface and to increase treatment side effects [20]. Ocular surface disease is very common in glaucoma and ocular hypertensive patients chronically treated with preserved topical IOP-lowering medications. The prevalence rates varied between 45 and 60% in different studies [21-23]. Another benefit of FCs is elimination of the washout effect, which occurs when patients instill medications in succession so that the first-administered medication is washed out by application of the second medication. They therefore often provide better IOP control than unfixed combinations in real life [24]. Finally, the cost of a FC is frequently less than the combined cost of the two ingredients prescribed separately [8].

2. Overview of the market

So far, three FCs containing prostaglandin analogs are available on the market. They include bimatoprost and timolol maleate FC (available with and without benzalkonium chloride), latanoprost and timolol maleate FC (containing benzalkonium chloride) and travoprost and timolol maleate (containing polyquaternium-1) [25,26]. A meta-analysis demonstrated that all three available prostaglandin/timolol FCs provide greater IOP reduction than the three respective prostaglandin monotherapies [27]. This meta-analysis, together with a more recent meta-analysis, has also observed that prostaglandin/timolol FCs can significantly reduce conjunctival hyperemia [28]. In various studies, the latanoprost/timolol FC has shown a mean daytime IOP-lowering efficacy of 30 – 39% from untreated baseline [28,29]. In patients inadequately controlled by prostaglandin analog monotherapy, evening-dosed bimatoprost/timolol FC provided significantly greater mean diurnal IOP reduction as compared to latanoprost/timolol FC dosed in the evening (2.8 ± 0.9 mmHg vs 2.1 ± 0.6 mmHg; p = 0.021) at the end of a 4-week trial [30]. Martinez and Sanchez compared the efficacy of bimatoprost/timolol FC with latanoprost/timolol FC in patients with primary open-angle glaucoma and pseudoexfoliative glaucoma and found a small but statistically significant difference in IOP reduction after a period of 12 weeks (mean 12-h IOP difference: 0.8 mmHg) [31]. In a prospective, investigator-masked multicenter study with 82 glaucoma patients inadequately controlled on prostaglandin monotherapy, latanoprost/timolol FC provided an additional 13.7% IOP lowering effect after 12 weeks, whereas the bimatoprost/timolol FC provided an additional 21.4% ocular hypertensive effect [32]. A meta-analysis compared the mean differences in IOP lowering of the three FCs versus their corresponding prostaglandin monotherapy alone: depending on measuring time (9 am, noon, 4 pm or mean diurnal curve), mean differences were 1.31 – 2.01 mmHg for latanoprost versus FC (p < 0.01), 2.02 – 2.59 mmHg for travoprost versus FC (p < 0.001) and 0.00 – 1.14 mmHg for bimatoprost versus FC (p > 0.1 to p < 0.001) [27]. So far, only one FC ophthalmic solution without preservatives is available. Previous clinical trials suggested the important benefit associated with the use of benzalkonium chloride-free formulations of prostaglandin analogs, as they significantly diminished the incidence of conjunctival irritation [33-35]. Clearly, there is a need to offer more prostaglandin analogs FCs containing no preservatives.

3. Introduction of the compound

Tafluprost–timolol FC (TTFC) ophthalmic solution is a fixed-dose combination of tafluprost 15 µg/ml and timolol 5 mg/ml without preservatives (Box 1). This preservative-free FC will be labeled as a once-daily agent for glaucoma patients whose IOP is inadequately controlled with a monotherapy. It has no marketing authorization yet. Tafluprost ophthalmic solution 0.0015% is the most recently introduced prostaglandin analog [34,36,37]. Tafluprost was the first prostaglandin analog produced in a preservative-free formulation. It has been shown that IOP-lowering efficacy of tafluprost, in both preserved and preservative-free formulations, is similar to that of latanoprost [36-38]. Tafluprost was first introduced in Japan in 2008 as a benzalkonium chloride containing multidose formulation and in Germany in 2008 with approval for both a preserved and an unpreserved tafluprost formulation [39]. Currently, however, throughout the rest of the world, only unpreserved tafluprost is marketed [39]. Both formulations seem to be equally effective. Hamacher et al. found an overall efficacy difference of only 0.01 mmHg (95% CI −0.46 – 0.49; p = 0.96) at 4 weeks [40]. Several open-label studies have examined the efficacy and tolerability of unpreserved tafluprost in naïve [41] or previously treated patients with open-angle glaucoma or ocular hypertension, who were either poorly controlled or had tolerability issues with other medications [34,35,42-44]. These studies have reported a mean diurnal IOP reduction of 22.9 – 32.1% from untreated baseline [41,42,44]. Although these studies were uncontrolled, they indicate that preservative-free tafluprost has almost comparable efficacy to latanoprost and will likely benefit patients facing tolerability problems with other medications [38]. Reduction of IOP starts ∼ 2 – 4 h after the first administration, with the peak effect within ∼ 8 – 12 h. Evening administration of prostaglandins is generally preferable because of a better circadian IOP profile [45].

Box 1. Drug summary.

Drug name	Tafluprost and timolol maleate
Phase	III
Indication	Open-angle glaucoma and ocular hypertension
Pharmacology description/mechanism of action	Fluorinated analog of prostaglandin F2α/β-receptor blocker
Route of administration	Topical application of eye drops in the affected eye(s)
Chemical structure	Tafluprost: C25H34F2O5 Timolol maleate: C13H24N4O3S·C4H4O4
Pivotal trial(s)	ClinicalTrials.gov Identifiers: NCT01434888, NCT01306461 [50], NCT01292460

Timolol has been topically used for the treatment of glaucoma and increased IOP for over 30 years [46]. β-blockers and prostaglandin analogs are used as first-line therapy in glaucoma. Of the glaucoma and ocular hypertension patients, about 70% are timolol responders [47]. Timolol has been reported to decrease the aqueous humor production by up to 48% in the normal human eye, the mean suppression being 34% [48]. The European Glaucoma Society quotes a mean IOP reduction of 20 – 25% [12]. After the initial fall in IOP, there may be some loss in effect [46]. However, it has been reported that a persistent effect is present even after years of use [49]. It is usually given twice daily [12].

Past clinical randomized studies suggested that both FCs of latanoprost/timolol and travoprost/timolol provided greater IOP reduction at evening dosing than at morning dosing [50,51]. The TTFC is tested at 08:00 am in clinical trials [52].

4. Chemistry

The preservative-free TTFC is a combination of two well-known ophthalmic drugs, namely tafluprost (15 µg/ml) and timolol maleate (5 mg/ml) [52]. Tafluprost is a fluorinated analog of prostaglandin F2α. The chemical name for tafluprost is 1methylethyl (5Z)-7-{(1R, 2R, 3R, 5S)-2-[(1E)-3,3-difluoro-4-phenoxy-1-butenyl}-3,5-dihydroxycyclopentyl]5-heptenoate. The molecular formula of tafluprost is C₂₅H₃₄F₂O₅ and its molecular weight is 452.53. Its structural formula is shown in Figure 1.

Figure 1. Tafluprost.

Tafluprost is a colorless to light yellow viscous liquid that is practically insoluble in water. Tafluprost ophthalmic solution 0.0015% without preservatives is supplied as a sterile solution of tafluprost with a pH range 5.5 – 6.7 and an osmolality range 260 – 300 mOsmol/kg. It contains active: tafluprost 0.015 mg/ml; inactives: glycerol, sodium dihydrogen phosphate dihydrate, disodium edetate, polysorbate 80, hydrochloric acid and/or sodium hydroxide (to adjust pH) and water for Injection.

Timolol maleate ophthalmic solution is a noncardioselective, competitive β-adrenergic receptor blocking agent. Its chemical name is (-)-l-(tert-butylamino)-3- [(4-morpholino-l, 2, 5-thiadiazol-3-yl)oxy]-2-propanol maleate (1:1) (salt). Timolol maleate possesses an asymmetric carbon atom in its structure and is provided as the levo-isomer. The optical rotation of timolol maleate is:

Its molecular formula is C₁₃H₂₄N₄O₃S•C₄H₄O₄ and its structural formula is shown in Figure 2.

Figure 2. Timolol maleate.

Timolol maleate has a molecular weight of 432.50. It is a white, odorless, crystalline powder, which is soluble in water, methanol and alcohol. It is stable at room temperature and is supplied as a sterile, isotonic, buffered, aqueous solution of timolol maleate in two dosage strengths: Each ml of timolol maleate 0.5% contains 5 mg of timolol (6.8 mg of timolol maleate). The pH of the solution is ∼ 7, and the osmolarity is 274 – 328 mOsm. Inactive ingredients: monobasic and dibasic sodium phosphate and water for injection. It contains no preservatives.

5. Pharmacodynamics

The TTFC contains two active substances. No published evidence regarding pharmacodynamics of the TTFC is available so far. Therefore, pharmacodynamics of both active substances used as monotherapy will be described.

Tafluprost acid, a prostaglandin analog is a selective FP prostanoid receptor agonist, which is believed to reduce IOP by increasing uveoscleral outflow. The exact mechanism of action is unknown at this time [53]. Reduction of the IOP starts ∼ 2 – 4 h after the first administration with the maximum effect reached after 12 h [53]. In clinical studies up to 24 months in duration, patients with open-angle glaucoma or ocular hypertension and baseline pressure of 23 – 26 mmHg who were treated with tafluprost dosed once daily in the evening demonstrated reductions in IOP at 3 and 6 months of 6 – 8 and 5 – 8 mmHg, respectively [53]. The reduction in IOP achieved by preservative-free tafluprost is equivalent to that obtained with the preserved formulation [40].

The β-adrenergic receptors (β1 and β2) are widely distributed throughout the body, including the eye. In the eye, β-receptors are found on the ocular surface, in the ocular blood vessels, trabecular meshwork, lens epithelium, ciliary body and retina. In the ciliary processes, 75 – 90% of the β-receptors are β2-receptors [54]. Timolol is a nonselective β-adrenergic blocker that blocks the activity of both β-1 and β-2 receptors [46]. Timolol has been shown to lower IOP by reducing aqueous humor production by the nonpigmented ciliary epithelium [55,56]. The IOP-lowering effect of timolol begins 20 min post-dosing, reaches its maximal effect 2 h after instillation and continues in a waning manner for up to 24 h [56,57].

6. Pharmacokinetics and metabolism

No data is yet available on the pharmacokinetics and metabolism of TTFC. Therefore, the individual compounds are described. Tafluprost is an ester prodrug that is hydrolyzed into the biologically active metabolite, tafluprost acid, in the eye [53]. The acid compound is further metabolized via β-oxidation and Phase II conjugation. Plasma concentrations of tafluprost acid peak about 10 min after instillation of one drop of eye drop solution. Plasma tafluprost acid concentrations are below detectable levels (10 pg/ml) 30 min following topical administration [53]. The IOP decrease of timolol maleate 0.5% begins 30 – 60 min after administration and lasts for at least 24 h [58]. Timolol is absorbed systemically, mainly from the nasal mucosa. Peak plasma concentration after a single instillation varies between 2.5 and 5 ng/ml in humans [59,60]. Timolol is distributed in various tissues like conjunctiva, cornea, sclera, iris, aqueous humor, liver, kidney and lung. Its half-life is 2.5 – 5.0 h [61]. Timolol and its metabolites are mainly excreted by the kidneys [61].

7. Clinical efficacy

Only one publication on the TTFC ophthalmic solution is available so far [52]. Three clinical trials testing this FC including the published trial are listed in clinicaltrials.gov (ClinicalTrials.gov Identifiers: NCT01434888, NCT01306461 [52], NCT01292460). All of them were sponsored by Santen Oy, Finland. A Phase I study in healthy volunteers was completed in 2011 – 2012 to evaluate the pharmacokinetics, safety and tolerability of the preservative-free FC. Fifteen healthy volunteers were included and received tafluprost 0.0015%, timolol 0.5% and fixed-dose combination of both (all preservative-free) in a crossover assignment. The primary outcome measure was pharmacokinetics (plasma concentrations) after single and repeated administration of tafluprost and timolol. Safety and tolerability served as secondary outcome measures. No results were published so far. One Phase III study was performed to prove superiority of the TTFC against monotherapies in ocular hypertension and open-angle glaucoma. Six hundred patients were included in nine countries. After washout, prior timolol users received either timolol or TTFC, prior tafluprost users received either tafluprost or TTFC (all preservative-free) for a duration of 6 months. Primary outcome measure was the change from baseline in the average diurnal IOP at 3 months. Secondary outcome measures included change from baseline in average diurnal IOP at 2 weeks, 6 weeks and 6 months and change from baseline in timewise IOP, measured at 08:00, 10:00, 16:00 and 20:00. The study was finished in March 2013. No results are published so far. Another Phase III study compared the TTFC against concomitant administrations in a noninferiority design. This 6-month, prospective, randomized, double-masked, active-controlled, parallel group, multicenter Phase III study was performed in patients with ocular hypertension and open-angle glaucoma with untreated IOP ≥ 23 and ≤ 36 mmHg at baseline [52]. The purpose was to compare efficacy, safety and tolerability of the preservative-free FC and non-FC (NFC) of tafluprost 0.0015% and timolol 0.5% in patients with open-angle glaucoma or ocular hypertension. Four hundred patients washed out from IOP-lowering medication (if not treatment-naïve) were randomized, 201 received the FC and 199 received the NFC. Mean IOP decreases from baseline ranged from −7.3 to −9.1 mmHg (29.6 – 34.6%) in the FC and from −7.5 to −9.4 mmHg (30.7 – 36.0%) in the NFC arm (per-protocol [PP] dataset, P <0.0001 compared with baseline for both groups). At month 6, the estimated overall treatment difference (FC–NFC) was 0.308 mmHg (PP dataset, 95% CI from −0.194 to 0.810 mmHg). An IOP decrease ≥ 30% was achieved in 58.3 and 66.9% of the patients in the FC and NFC groups, respectively (PP dataset; p = 0.105); an IOP decrease ≥ 35% was achieved in 36.6 and 43.1% of patients in the FC and NFC groups, respectively (PP dataset; p = 0.297). All measures of IOP reduction for FC of preservative-free tafluprost/timolol were statistically and clinically significant and noninferior to those of the NFC, throughout the 6-month study period.

8. Safety and tolerability

Only one Phase III trial describing the safety and tolerability of the TTFC was published so far [52]. Patients with ocular adverse events were evenly distributed in both groups. A total of 169 adverse events (89 ocular, 80 nonocular) were reported by 84 patients (41.8%) in the FC treatment group, and 175 adverse events (98 ocular, 77 nonocular) were reported by 88 patients (44.2%) in the NFC treatment group (p = 0.624). Nonocular treatment-related adverse events were observed in a few subjects. In total, seven patients in the FC group and four patients in the NFC group discontinued the study due to adverse events (ocular discomfort, conjunctival/ocular hyperemia, eye irritation, eye discharge, dry eye symptoms, erythema of the eyelid, allergic conjunctivitis, foreign body sensation, eye pain and photophobia; mostly mild severity). The most common side effect, conjunctival/ocular hyperemia was found in 8 and 5% of patients in the FC and NFC arms, respectively. The severity of hyperemia was generally mild to moderate and comparable in both treatment groups. For both treatment groups, blood pressure and heart rate decreased slightly from the 08:00 to the 10:00 am measurement. No clear trends (from baseline to month 6) could be seen either in the blood pressure or heart rate in either group. However, the heart rate for the NFC group decreased slightly (−1.9 beats per minute [bpm] for FC and −4.9 bpm for NFC at 10:00; p < 0.001). Both treatment regimens were generally well tolerated with ∼ 75 – 80% of patients experiencing no drop discomfort on instillation during the study. The results are in line with the safety and tolerability described for tafluprost and timolol used as monotherapy. Timolol is topically well tolerated by most patients [46]. Approximately 80% of a topically administered eye drop is reported to drain through the nasolacrimal duct and is systemically absorbed [62]. This can cause severe cardiac and respiratory adverse events such as bradycardia, hypotension and syncope, bronchospasm, respiratory failure and increased cough [63,64]. Cardiac and respiratory adverse effects should always be anticipated whenever timolol or other β-blockers are used, especially in susceptible patients with underlying pertinent systemic disease [65].

9. Regulatory affairs

So far, Phase I and Phase III studies were conducted, one Phase III trial was published (ClinicalTrials.gov Identifiers: NCT01434888, NCT01306461 [52], NCT01292460). The preservative-free tafluprost/timolol maleate FC has no market authorization yet.

10. Conclusion

So far, only one publication on the TTFC is available. This 6-month, prospective, randomized, double-masked, active-controlled, parallel group, multicenter Phase III study was performed in patients with ocular hypertension and open-angle glaucoma and compared the FC versus both ingredients as NFC. All measures of IOP reduction for FC of preservative-free tafluprost/timolol were statistically and clinically significant and noninferior to those of the NFC, throughout the 6-month study period. Both treatment arms showed a good and comparable safety and tolerability profile.

11. Expert opinion

The choice of therapy in glaucoma must take into account not just IOP lowering, but also tolerability, cost and compliance. FCs have been increasingly used in the last 10 years. They have several advantages such as improved adherence, fewer side effects and lower costs. Tafluprost is a preservative-free prostaglandin analog, which appears to have a similar therapeutic efficacy when compared to other prostaglandin analogs. However, its improved adverse effect profile seems to be beneficial in patients with sensitivities to preservatives. The preservative-free TTFC has no market authorization yet. Only one Phase III trial was published so far, but results are promising in terms of efficacy, tolerability and safety. Though at present there is only little information and no long-term clinical experience available, the ingredients in tafluprost have been extensively used since 2008. For timolol, clinical data for > 40 years are available. This strongly indicates that the TTFC will have a role in the treatment of open-angle glaucoma and ocular hypertension.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.