Drugs (2018) 78:773–780 https://doi.org/10.1007/s40265-018-0914-6 ADIS DRUG EVALUATION Latanoprostene Bunod Ophthalmic Solution 0.024%: A Review in Open-Angle Glaucoma and Ocular Hypertension Sheridan M. Hoy Published online: 14 May 2018 Springer Nature 2018, corrected publication May/2018 Abstract Latanoprostene bunod ophthalmic solution IOP-lowering efﬁcacy seen in APOLLO and LUNAR was 0.024% (hereafter referred to as latanoprostene bunod conﬁrmed in a phase III study (JUPITER) in Japanese TM 0.024%) [Vyzulta ] is a nitric oxide (NO)-donating patients, with IOP reductions observed early (week 4) and prostaglandin F analogue approved in the USA for the maintained over the longer-term (12 months). Latano- 2a reduction of intraocular pressure (IOP) in patients with prostene bunod 0.024% was well tolerated over up to open-angle glaucoma (OAG) or ocular hypertension. It is 12 months in these studies, with most ocular treatment- thought to lower IOP by increasing aqueous humour out- emergent adverse events (TEAEs) being mild to moderate ﬂow through the uveoscleral pathway (mediated by latan- in severity. Thus, current evidence indicates once-daily oprost acid) and increasing the facility of aqueous humour latanoprostene bunod 0.024% is an effective and well tol- outﬂow through the trabecular meshwork pathway (medi- erated treatment option for the reduction of IOP in adults ated by NO). Results from two multinational, phase III with OAG or ocular hypertension. studies (APOLLO and LUNAR) and a pooled analysis of these studies demonstrated the noninferiority of latano- Latanoprostene Bunod Ophthalmic Solution prostene bunod 0.024% to timolol ophthalmic solution 0.024%: clinical considerations 0.5% (hereafter referred to as timolol 0.5%) in terms of IOP-lowering efﬁcacy over 3 months in patients with OAG NO-donating prostaglandin F analogue; instilled 2a or ocular hypertension, with the superiority of latanopros- once daily in the evening tene bunod 0.024% over timolol 0.5% subsequently demonstrated in APOLLO and the pooled analysis. More- Thought to lower IOP via a dual mechanism of action over, there was no apparent loss of IOP-lowering effect in Signiﬁcantly more effective than timolol 0.5% in subsequent safety extension periods of up to 9 months. The lowering IOP in adults The original version of this article was revised due to a retrospective IOP-lowering beneﬁts were maintained over the Open Access request. longer-term (12 months) The manuscript was reviewed by: A. L. Robin, Department of Well tolerated, with most ocular TEAEs being mild Ophthalmology, University of Michigan, Ann Arbor, MI and or moderate in severity Departments of Ophthalmology and International Health, Johns Hopkins University, Baltimore, MD, USA; C. B. Toris, Case Western Reserve University, Cleveland, OH, USA; T. Yamamoto, Department 1 Introduction of Ophthalmology, Gifu University Graduate School of Medicine, Gifu, Japan. Maintaining intraocular pressure (IOP) entails balancing & Sheridan M. Hoy aqueous humour production (in the ciliary body) and out- email@example.com ﬂow (via the trabecular meshwork and uveoscleral path- ways) . Resistance to aqueous humour outﬂow through Springer, Private Bag 65901, Mairangi Bay, Auckland 0754, the trabecular meshwork is increased in patients with New Zealand 774 S. M. Hoy HO primary open-angle glaucoma (OAG), resulting in elevated O IOP, and lowering IOP (by enhancing outﬂow or decreas- O O O ing production) is currently the only proven therapeutic approach to preserving visual function in this patient HO population [1–3]. HO A single topical ophthalmic agent, most commonly a prostaglandin analogue (PGA), is typically used for the initial treatment of primary OAG [1, 4]. However, many patients require treatment with more than one agent HO (preferably agents with differing, but complementary, OH HO N mechanisms of action) to adequately control IOP and thus O O prevent disease progression [1, 3, 4]. Several recently developed agents lower IOP by targeting aqueous humour HO HO outﬂow via the trabecular meshwork pathway [1, 5]. One such agent is the once-daily, nitric oxide (NO)-donating HO OH NO prostaglandin F analogue latanoprostene bunod oph- 2a thalmic solution 0.024% (hereafter referred to as latano- 1 2 TM prostene bunod 0.024%) [Vyzulta ]. Latanoprostene Fig. 1 Chemical structure of latanoprostene bunod and its metabo- bunod is a single molecule with two active metabolites, lism to latanoprost acid (1) and butanediol mononitrate, with the each with its own mechanism of action [1, 5] (Sect. 2.1). subsequent release of nitric oxide (2) and 1,4-butanediol (an inactive This article discusses pharmacological, therapeutic efﬁcacy metabolite). Reproduced from Kawase et al.  with permission and tolerability data relevant to the use of latanoprostene results in several downstream effects, including reduced bunod 0.024% for the reduction of IOP in patients with intracellular calcium levels and Rho-associated protein OAG or ocular hypertension. kinase inhibition, which lead to myosin light chain (MLC)- 2 dephosphorylation [1, 6, 7]. This, in turn, promotes actin cytoskeleton rearrangement, thereby decreasing cell con- 2 Pharmacological Properties tractility and volume, and, thus, improving the facility of aqueous humour outﬂow through the trabecular meshwork 2.1 Mechanism of Action pathway [1, 6, 7]. Following topical administration, latanoprostene bunod is 2.2 Pharmacodynamic Proﬁle hydrolysed (by corneal esterases) to the prostanoid FP receptor agonist latanoprost acid (active metabolite) and The pharmacodynamic properties of latanoprostene bunod butanediol mononitrate, which is further metabolized to have been characterised in vitro and in animal models of 1,4-butanediol and NO (active metabolite)  (Fig. 1). IOP. In human trabecular meshwork cells (HTMCs), latan- Latanoprost acid increases matrix metalloproteinase oprostene bunod (half maximal effective concentration of (MMP)-1, MMP-3 and MMP-9 expression in the ciliary 1.5 lmol/L) signiﬁcantly (p \ 0.05 vs. control) increased muscle, promoting the remodelling of its extracellular cGMP levels in a dose- and sGC-dependent manner . matrix and, subsequently, increased aqueous humour out- Moreover, latanoprostene bunod reduced endothelin-1-in- ﬂow through the uveoscleral pathway . MMPs may also duced MLC-2 phosphorylation (p\ 0.05 vs. endothelin-1) play a minor role in augmenting aqueous humour outﬂow and actin stress ﬁbres (an indicator of cytoskeletal con- facility through the trabecular meshwork pathway by tractility), as well as the localization of vinculin at focal remodelling the extracellular matrix of the trabecular adhesions (an indicator of cell attachment). Equimolar meshwork [1, 6]. concentrations of latanoprost had a minimal effect on these NO is an endogenous signalling molecule known for its parameters . role as a mediator of smooth muscle relaxation and Inducing cell contractility (as seen with endothelin-1 vasodilation . NO synthases are present in various ocular and thrombin) increases HTMC resistance, while decreas- tissues (e.g. trabecular meshwork, Schlemm’s canal, ciliary ing cell contractility decreases HTMC resistance . body) of healthy volunteers, but reduced in these tissues in Latanoprost demonstrated synergy with a NO donor in patients with primary OAG, suggesting reduced NO pro- reducing endothelin-1-induced HTMC resistance; both duction may contribute to elevated IOP . Activation of latanoprost plus the NO donor and latanoprostene bunod the soluble guanylate cyclase (sGC)/cyclic guanosine alone were associated with a signiﬁcantly (p \ 0.05) monophosphate (cGMP)/protein kinase G pathway by NO Latanoprostene Bunod Ophthalmic Solution 0.024%: A Review 775 greater reduction in HTMC resistance than latanoprost patients by 15 min post instillation of latanoprostene alone . bunod 0.024% . Latanoprostene bunod, but not latanoprost, demon- strated an IOP-lowering effect in F-prostanoid receptor knockout mice (a model that is insensitive to PGAs ) 3 Therapeutic Efﬁcacy [data from an abstract] , suggesting that in this model the effect is due to the action of NO on the trabecular The IOP-lowering efﬁcacy of latanoprostene bunod meshwork pathway . Latanoprostene bunod also 0.024% in adults with OAG or ocular hypertension has demonstrated IOP-lowering activity in various ocular been evaluated in several studies, with this section focusing hypertension or glaucoma animal models and lowered IOP on two randomized, double-masked, active comparator- to a greater extent than an equimolar concentration of controlled [timolol ophthalmic solution 0.5% (hereafter latanoprost . referred to as timolol 0.5%)], multinational, phase III studies (APOLLO  and LUNAR ) [Sect. 3.1]. 2.3 Pharmacokinetic Proﬁle Efﬁcacy data from a noncomparative, open-label, multi- centre, phase III study (JUPITER) , which was pri- Following ocular instillation, latanoprostene bunod is marily designed to evaluate safety, are also reviewed (Sect. rapidly hydrolysed [half-life (t ) in rabbit and primate 3.2). Overall, there were no clinical differences between corneal homogenate of 0.05 and 0.40 min compared with elderly patients and other adult patients in terms of efﬁ- 0.28 and 5.2 min for latanoprost] . cacy, according to the US prescribing information . No ocular distribution studies have been conducted in A latanoprostene bunod concentration of 0.024% (in- humans . In a study in monkeys, latanoprostene stilled once daily in the evening) was identiﬁed as the bunod was not detected at any timepoint (consistent with lower of the two most effective concentrations assessed in its rapid hydrolysis) . Following a single topical dose a 4-week, randomized, single-masked, phase II, dose- of latanoprostene bunod 0.012%, maximum concentra- ranging study (VOYAGER)  in adults with OAG or tions (C ) of latanoprost acid in the cornea, aqueous ocular hypertension. Its use resulted in a statistically sig- max humour and iris–ciliary body of rabbits and monkeys niﬁcant (p = 0.005) reduction from baseline in least-squares were reached within 0.5–1 h (which was similar to that mean (LSM) diurnal IOP at day 28 (primary endpoint) seen with an equimolar concentration of latanoprost), compared with latanoprost ophthalmic solution 0.005% suggesting rapid distribution. The t of latanoprost acid (between-group difference of 1.23 mmHg) . The 24-h was 1.8–4.6 h for latanoprostene bunod and 1.1–3.0 h efﬁcacy of latanoprostene bunod 0.024% (instilled once for latanoprost across the two species . As NO has a daily in the evening) compared with timolol 0.5% (instilled short t (& 2 s in extravascular tissue) and is highly twice daily) was assessed in a 4-week, randomized, open- diffusible, it is difﬁcult to measure in vivo ; however, label, crossover, phase II study (CONSTELLATION) in 21 levels of NO’s downstream effector cGMP in the aque- adults with ocular hypertension or early primary OAG . ous humour and iris–ciliary body of rabbits were sig- IOP was measured at baseline and the end of each 4-week niﬁcantly (p \ 0.05) increased from baseline following period in a 24-h sleep laboratory. Latanoprostene bunod the ocular instillation of latanoprostene bunod, but not 0.024% was associated with a signiﬁcant (p B 0.002) latanoprost . reduction from baseline in diurnal and nocturnal IOP, In 22 healthy volunteers who received latanoprostene whereas timolol 0.5% was associated with a signiﬁcant bunod 0.024% once daily (in the morning) for 28 days, (p \ 0.001) reduction from baseline in diurnal IOP only. there were no quantiﬁable plasma concentrations of The reduction in nocturnal IOP was signiﬁcantly (p = latanoprostene bunod [lower limit of quantitation 0.004) higher with latanoprostene bunod 0.024% than (LLOQ) of 10.0 pg/mL) or butanediol mononitrate timolol 0.05%. Moreover, latanoprostene bunod therapy (LLOQ of 200 pg/mL) post instillation on days 1 and 28 resulted in a signiﬁcantly greater diurnal ocular perfusion . Post dose, mean plasma C values of latanoprost pressure compared with baseline (p B 0.006) and nocturnal max acid (LLOQ of 30 pg/mL) were 59.1 and 51.1 pg/mL on ocular perfusion pressure compared with timolol 0.5% (p = the respective days and the mean times to C were 0.01) . max approximately 5 min on both days. Upon reaching the systemic circulation, latanoprost acid is predominately 3.1 APOLLO and LUNAR metabolized via fatty acid b-oxidation in the liver to the 1,2-dinor and 1,2,3,4-tetranor metabolites. Latanoprost APOLLO  and LUNAR  consisted of a 3-month, acid is rapidly eliminated from human plasma, with the active-controlled period followed by a 3-month (LUNAR) plasma concentration dropping below the LLOQ in most or 9-month (APOLLO) open-label safety extension period 776 S. M. Hoy and enrolled patients aged C 18 years with a diagnosis of group difference in the primary endpoint did not exceed the OAG (including pigmentary or pseudoexfoliative OAG) or predeﬁned limit of 0 mmHg at all nine timepoints. In ocular hypertension in one or both eyes. IOP was assessed LUNAR, the superiority criteria were met for all of the at screening and at 8 AM, 12 PM and 4 PM at baseline, timepoints except the 8 AM timepoint at week 2 . with patients required to have an IOP of C 26 mmHg at Sensitivity analyses demonstrated that the results of the C 1 timepoint, C 24 mmHg at C 1 timepoint and primary analyses were robust [12, 13, 17], with the ﬁndings C 22 mmHg at 1 timepoint in the same eye; an IOP of unaffected by prior treatment status [12, 13], patient age B 36 mmHg at all three baseline timepoints in both eyes; (\ 65 vs. C 65 years)  or the concurrent use of and a best-corrected visual acuity (BCVA) of ? 0.7 loga- b-blockers [12, 13]. rithm of the minimum angle of resolution (Snellen equiv- LSM of the mean IOP was signiﬁcantly (p\0.05) lower alent of & 20/100) or better in either eye. The eye with the with latanoprostene bunod 0.024% than timolol 0.5% at all highest IOP was designated the study eye. Patients received timepoints in APOLLO , LUNAR  and the pooled latanoprostene bunod 0.024% (instilled once daily in the analysis , apart from at the 8 AM timepoint at week 2 evening) or timolol 0.5% (instilled twice daily) for in LUNAR (Table 1). Moreover, at all nine timepoints, 12 weeks; those who received IOP-lowering therapy at or signiﬁcantly greater proportions of latanoprostene bunod within 30 days of screening (72%) were required to 0.024% than timolol 0.5% recipients achieved an IOP undergo a B 28-day washout period prior to randomization reduction of C 25% in APOLLO (34.9 vs. 19.5%; p = [12, 13]. During the open-label safety extension period, all 0.001) , LUNAR (31.0 vs. 18.5%; p = 0.007)  and patients received latanoprostene bunod 0.024% . the pooled analysis (32.9 vs. 19.0%; p \ 0.001) , and Patients had a mean duration of exposure to latanoprostene an IOP of B 18 mmHg in APOLLO (22.9 vs. 11.3%; p = bunod 0.024% of 90.3 days during the active-controlled 0.005)  and the pooled analysis (20.2 vs. 11.2%; p = period and 231.9 days during the active-controlled and 0.001) , but not LUNAR (17.7 vs. 11.1%) . In a open-label safety extension periods, and a mean duration of post hoc analysis of pooled data , signiﬁcantly (p \ exposure to timolol 0.5% of 90.4 days . 0.001) more latanoprostene bunod 0.024% than timolol Baseline patient demographics and eye characteristics 0.5% recipients achieved a week 12 IOP of B 18, B 17, were comparable between the latanoprostene bunod B 16, B 15 and B 14 mmHg. 0.024% and timolol 0.5% groups in both APOLLO  Latanoprostene bunod 0.024% was associated with a and LUNAR . Mean baseline diurnal IOP in the latan- signiﬁcantly (p B 0.025) greater mean reduction from oprostene bunod 0.024% and timolol 0.5% groups was 26.7 baseline in mean IOP across the nine timepoints than and 26.5 mmHg in APOLLO  and 26.6 and timolol 0.5% (7.7–9.1 vs. 6.6–8.0 mmHg in APOLLO; 26.4 mmHg in LUNAR . The primary endpoint was 7.5–8.8 vs. 6.6–7.9 mmHg in LUNAR), except for the 8 the study eye IOP at three timepoints (8 AM, 12 PM and 4 AM timepoint at week 2 in LUNAR [12, 13]. PM) at weeks 2, 6 and 12 [12, 13]. The primary objective Mean diurnal IOP was signiﬁcantly lower with latano- was to assess the noninferiority of latanoprostene bunod prostene bunod 0.024% than timolol 0.5% at each visit in 0.024% versus timolol 0.5% in terms of IOP reduction at APOLLO (week 2: 18.2 vs. 19.5 mmHg; week 6: 18.1 vs. each timepoint throughout the 12 weeks of therapy. If 19.3 mmHg; week 12: 18.2 vs. 19.4 mmHg; all p\0.001) noninferiority was established, the secondary objective was  and LUNAR (week 2: 18.6 vs. 19.2 mmHg; week 6: to assess the superiority of latanoprostene bunod 0.024% 18.2 vs. 19.1 mmHg; week 12: 18.1 vs. 19.3 mmHg; all versus timolol 0.5%. Key secondary endpoints were the p B 0.034) . Of note, in a post hoc analysis of pooled proportion of patients achieving an IOP reduction of data, the LSM percentage reduction from baseline to week C 25% and the proportion of patients achieving an IOP of 12 in mean diurnal IOP was signiﬁcantly greater with B 18 mmHg at all nine timepoints. Analyses were con- latanoprostene bunod 0.024% than timolol 0.5% (32.0 vs. ducted in the intent-to-treat population [12, 13]. 27.6%; p \ 0.001) . The IOP-lowering efﬁcacy of latanoprostene bunod In the pooled analysis, the beneﬁcial effects of latano- 0.024% was noninferior to that of timolol 0.5% in prostene bunod 0.024% therapy were maintained during APOLLO , LUNAR  and a pooled analysis of the open-label safety extension periods of APOLLO and these studies, as the upper limit of the 95% CIs for the LUNAR, with no apparent loss of IOP-lowering effect over between-group differences in the primary endpoint did not time . Mean reductions from baseline to months 6, 9 exceed the predeﬁned limits of 1.5 mmHg at all 9 time- and 12 in mean diurnal IOP were 8.6, 8.5 and 8.8 mmHg, points and 1.0 mmHg for C 5 of the 9 timepoints. More- respectively, in patients who received latanoprostene over, in APOLLO  and the pooled analysis , bunod 0.024% during the active-controlled period and 8.5, latanoprostene bunod 0.024% was superior to timolol 8.7 and 8.7 mmHg, respectively, in those who received 0.5%, as the upper limit of the 95% CIs for the between- timolol 0.5% during the active-controlled period (all p \ Latanoprostene Bunod Ophthalmic Solution 0.024%: A Review 777 0.001). The patients who received timolol 0.5% during the active-controlled period showed an additional 1.1–1.2 mmHg reduction in mean diurnal IOP at months 6, 9 and 12 that was signiﬁcant (p B 0.009) versus week 12. During the open-label safety extension periods, the per- centage reductions from baseline (32–34% ) were similar to the percentage reductions reported for therapy with latanoprostene bunod 0.024% at week 12 . 3.2 JUPITER JUPITER  enrolled Japanese patients aged C 20 years with a diagnosis of OAG (including normotensive, pig- mentary or pseudoexfoliative OAG) or ocular hypertension in one or both eyes. Patients were required to have a mean/median IOP of C 15 and B 36 mmHg at 10 AM in one or both eyes, and an IOP of B 36 mmHg in both eyes at baseline; and a corrected visual acuity or BCVA of C 0.5 in both eyes. The eye with the highest IOP was designated the study eye. Patients received latanoprostene bunod 0.024% (instilled once daily in the evening) for 12 months; those receiving IOP-lowering therapy at screening (90%) were required to undergo a 5–28-day washout period prior to baseline. The mean and median duration of exposure to latanoprostene bunod 0.024% was 351.5 and 364.0 days. Mean baseline IOP in the study and fellow treated eyes was 19.6 and 18.7 mmHg. Analyses were conducted in the safety population . The IOP-lowering beneﬁts obtained with latanoprostene bunod 0.024% in APOLLO  and LUNAR  were conﬁrmed in JUPITER , with reductions in IOP seen early and maintained over the longer-term (12 months) in Japanese patients. Signiﬁcant (p \ 0.001) reductions from baseline in mean IOP of 22.0% (4.3 mmHg) in the study eyes (n = 130) and 19.5% (& 3.6 mmHg) in the fellow treated eyes (n = 126) were seen as early as week 4, with signiﬁcant (p \ 0.001) reductions from baseline in this endpoint of[ 22% and[ 20% in the respective eyes seen at every subsequent visit (i.e. every 4 weeks from week 4 to week 52). At week 52, mean IOP in the study eyes and the fellow treated eyes was 14.4 and 14.4 mmHg; the reductions from baseline in mean IOP were 26.3% (5.3 mmHg) and 23.0% (& 4.3 mmHg). The proportions of patients achieving a reduction from baseline in IOP of C 5 mmHg in the study eye were 42.3% at week 4, 48.1% at week 8 and 52.3–64.2% from weeks 12–52 . 4 Tolerability Latanoprostene bunod 0.024% was well tolerated over up to 12 months in adults with OAG or ocular hypertension participating in APOLLO  and LUNAR . In the Table 1 Efﬁcacy of latanoprostene bunod ophthalmic solution 0.024% in adults with open-angle glaucoma or ocular hypertension. Results from two multinational, phase III studies (APOLLO  and LUNAR ) and a pooled analysis  of these studies Study Treatment (no. of pts) LSM of the mean IOP (mmHg) Week 2 Week 6 Week 12 8AM12PM 4PM 8AM12PM 4PM 8AM12PM 4PM APOLLO  LBN 0.024% (284) 18.6**** 18.0**** 18.1**** 18.6*** 17.8**** 17.8**** 18.7*** 17.9**** 17.8**** Timolol 0.5% (133) 19.8 19.4 19.2 19.6 19.1 19.1 19.7 19.2 19.2 LUNAR  LBN 0.024% (278) 19.2 18.5* 18.1* 18.7*** 18.0** 17.9*** 18.7** 17.9**** 17.7**** Timolol 0.5% (136) 19.6 19.2 18.8 19.6 18.9 18.9 19.6 19.2 19.1 Pooled analysis  LBN 0.024% (562) 18.9**** 18.2**** 18.1**** 18.6**** 17.9**** 17.8**** 18.7**** 17.9**** 17.8**** Timolol 0.5% (269) 19.7 19.3 19.0 19.6 19.0 19.0 19.6 19.2 19.1 Noninferiority of LBN 0.024% to timolol 0.5% was established in APOLLO, LUNAR and the pooled analysis; superiority of LBN 0.024% to timolol 0.5% was established in APOLLO and the pooled analysis IOP intraocular pressure, LBN 0.024% latanoprostene bunod ophthalmic solution 0.024%, LSM least-squares mean, pts patients, timolol 0.5% timolol ophthalmic solution 0.5% *p \ 0.05, **p \ 0.01, ***p B 0.005, ****p \ 0.001 vs. timolol 0.5% Primary endpoint 778 S. M. Hoy pooled analysis  of these studies, the overall incidence fellow treated eyes of ﬁve latanoprostene bunod 0.024% of ocular adverse events was comparable with those of recipients (allergic conjunctivitis, conjunctival hyperaemia, other PGAs and no new ocular adverse events were foreign body in the eye, increased IOP, scleritis) and two reported. Overall, there were no clinical differences timolol 0.5% recipients (increased IOP, instillation-site between elderly patients and other adult patients in terms of pain) . There were no serious TEAEs in the study eye safety . in either treatment group; one patient in the latanoprostene In the pooled analysis , 21.6% of 811 latanoprostene bunod 0.024% group experienced a serious ocular TEAE bunod 0.024% recipients (i.e. who received latanoprostene (dislocation of the intraocular lens) in the fellow treated bunod 0.024% during the active-controlled period and/or eye. At least one non-ocular serious TEAE (not considered the open-label safety extension period) and 12.5% of 271 to be related to the study medication) was reported in 2.0% timolol 0.5% recipients (i.e. who received timolol 0.5% of latanoprostene bunod 0.024% recipients and 0.7% of during the active-controlled period) experienced C 1 ocular timolol 0.5% recipients . treatment-emergent adverse event (TEAE) in their study Few patients discontinued treatment because of a TEAE eye. Most of these TEAEs were considered at least possibly (2.1 and 4.5% of patients receiving latanoprostene bunod related to the study medication (80.2 and 86.5% in the 0.024% or timolol 0.5%), according to the pooled analysis latanoprostene bunod 0.024% and timolol 0.5% groups) . Ocular TEAEs led to treatment discontinuation in and mild or moderate in severity (97.0 and 97.3%). Similar 1.4% of latanoprostene bunod 0.024% recipients and 1.5% results were reported for the fellow treated eyes . of timolol 0.5% recipients, with 0.6 and 0.4% of patients TEAEs typical of PGA therapy include conjunctival discontinuing treatment because of non-ocular TEAEs. hyperaemia, eyelash growth and iris hyperpigmentation Two patients in the latanoprostene bunod 0.024% group [14, 17]. The most frequently reported (occurring in C 3% of died (with one death occurring after study exit); neither patients in either the latanoprostene bunod 0.024% or timolol death (cardiac arrest and sepsis) was considered to be 0.5% group) ocular TEAEs in the study eyes of the respective related to the study medication . groups were conjunctival hyperaemia (5.9 and 1.1% of Non-ocular TEAEs occurred in \ 2% of patients in patients), eye irritation (4.6 and 2.6%) and eye pain (3.6 and either treatment group, with the most frequent being 2.2%) . The nature and incidence of the most frequently headache (occurring in ﬁve patients in the latanoprostene reported ocular TEAEs in the fellow treated eyes were gen- bunod 0.024% group and ﬁve patients in the timolol 0.5% erally similar to those in the study eyes. At baseline (i.e. prior group) . None of the non-ocular TEAEs were consid- to initiation of the study medication), the incidence of con- ered deﬁnitely related to the study medication, apart from junctival hyperaemia (which was mostly mild to moderate in one event of dysgeusia in one patient receiving latano- severity) as assessed by the investigator in the study eyes of prostene bunod 0.024% . the latanoprostene bunod 0.024% and timolol 0.5% groups BCVA and vital signs were comparable between the was high (32.6 and 34.3%). The incidence in the latano- latanoprostene bunod 0.024% and timolol 0.5% groups during prostene bunod 0.024% group increased from baseline at the active-controlled period and there were no safety concerns week 2 (49.0% of patients) and was generally stable across in terms of BCVA, ocular signs or vital signs during the open- the remainder of the study (44.2–48.7%), while the incidence label safety extension period . No clinically signiﬁcant in the timolol 0.5% group was generally stable (35.8–38.9%), systemic TEAEs were reported . but increased when patients entered the open-label safety Data from JUPITER showed that latanoprostene bunod extension period and received latanoprostene bunod 0.024% 0.024% was well tolerated over 12 months in Japanese adults (45.2–50.0%). In terms of adverse events of special interest with OAG or ocular hypertension . At least one ocular (eyelid and iris pigmentation, eyelash growth), eyelash TEAE occurred in 58.5% of 130 study eyes and 61.9% of 126 growth considered probably related to the study medication fellow treated eyes, with most considered at least possibly was reported in both eyes of one latanoprostene bunod related to the study medication and all being mild to moderate in 0.024% recipient and iris hyperpigmentation considered def- severity; no severe ocular TEAEs were reported. The most initely related to the study medication was reported in both frequently reported (occurring in C 4.0% of study or fellow eyes of another latanoprostene bunod 0.024% recipient. No treated eyes) TEAEs were conjunctival hyperaemia (occurring adverse events of special interest were reported in patients in 17.7 and 16.7% of eyes), eyelash growth (16.2 and 16.7%), receiving timolol 0.5% . eye irritation (11.5 and 11.9%), eye pain (10.0 and 10.3%) and Severe ocular TEAEs were reported in the study eyes of iris hyperpigmentation (3.8 and 4.0%). Of note, the proportion six latanoprostene bunod 0.024% recipients (allergic con- of study and fellow treated eyes with investigator-assessed junctivitis, blepharospasm, conjunctival hyperaemia, eyelid conjunctival hyperaemia remained low, with only a 2.8% tumour, increased IOP, retinal vein occlusion) and one increase in both the study and fellow treated eye groups at week timolol 0.5% recipient (instillation-site pain) and in the 52 compared with baseline (i.e. prior to initiation of the study Latanoprostene Bunod Ophthalmic Solution 0.024%: A Review 779 medication) values (15.4 and 14.3%). Most cases were mild in primary OAG, with latanoprost the most prescribed PGA in severity. In terms of adverse events of special interest, a clear or the USA . Other agents include a-adrenergic receptor possible iris pigmentation increase from baseline at week 52 agonists (e.g. brimonidine), b-blockers (e.g. timolol) and was reported in 10.0 and 14.6% of 130 study eyes and in 8.8 and carbonic anhydrase inhibitors (e.g. brinzolamide) . 13.6% of 125 fellow treated eyes based on the analysis of iris The NO-donating prostaglandin F analogue latano- 2a photographs. Four patients discontinued JUPITER because of prostene bunod 0.024% is a novel IOP-lowering agent TEAEs, none of which were considered related to the study recently approved in the USA for the reduction of IOP in medication. At least one non-ocular TEAE occurred in 51.5% patients with OAG or ocular hypertension . Following of 130 patients, with nasopharyngitis (32.3%), inﬂuenza ocular instillation, latanoprostene bunod is rapidly metabo- (3.8%), eczema (3.1%) and osteoporosis (2.3%) being the most lised to latanoprost acid and butanediol mononitrate (a NO- frequently reported. None were considered related to latano- donating moiety) [Sect. 2]. It is thought to lower IOP via a prostene bunod 0.024%. There were no safety concerns in terms dual mechanism of action: it increases aqueous humour of vital or ocular signs in JUPITER, and corrected visual acuity outﬂow through the uveoscleral pathway (mediated by appeared to remain generally stable throughout the study . latanoprost acid) and increases the facility of aqueous humour outﬂow through the trabecular meshwork pathway (mediated by NO). The systemic concentrations of latano- 5 Dosage and Administration prostene bunod and its metabolites is negligible (Sect. 2). The IOP-lowering efﬁcacy of the approved 0.024% Latanoprostene bunod 0.024% is approved in the USA for concentration of latanoprostene bunod was noninferior to the reduction of IOP in patients with OAG or ocular that of timolol 0.5% over 3 months in the multinational, hypertension . The recommended dosage is one drop phase III APOLLO and LUNAR studies and in a pooled instilled in the conjunctival sac of the affected eye(s) once analysis of these studies, with the superiority of latano- daily in the evening; this dosage should not be exceeded (as prostene bunod 0.024% over timolol 0.5% subsequently the instillation of PGAs more frequently than once daily demonstrated in APOLLO and the pooled analysis (Sect. has been shown to lessen the IOP-lowering effect). As 3.1). Moreover, at all but the earliest timepoint evaluated in latanoprostene bunod 0.024% contains the preservative LUNAR, mean IOP was signiﬁcantly lower with latano- benzalkonium chloride 0.2 mg/mL, contact lenses should prostene bunod 0.024% than timolol 0.5%. The beneﬁts of be removed prior to its topical administration and not latanoprostene bunod 0.024% therapy seen during the reinserted until 15 min following installation. Latanopros- active-controlled period were maintained during the open- tene bunod 0.024% may be instilled alongside other topical label safety extension periods of APOLLO (9 months) and ophthalmic agents to lower IOP, although the medications LUNAR (3 months), with no apparent loss of IOP-lower- should be administered C 5 min apart . ing effect over time (Sect. 3.1). Results from APOLLO and The use of latanoprostene bunod 0.024% is not recom- LUNAR were conﬁrmed in the phase III JUPITER study in mended in patients aged B 16 years (because of potential Japanese patients (Sect. 3.2). IOP reductions were observed safety concerns related to increased pigmentation follow- early (week 4) and maintained over the longer term ing long-term use) . In general, latanoprostene bunod (12 months) [Sect. 3.2]. It is worth noting that Japanese 0.024% should not be used in patients with active patients are known to have lower IOPs than non-Asian intraocular inﬂammation (as it may exacerbate this condi- patients; indeed, the study and fellow treated eyes in tion) . Local prescribing information should be con- JUPITER had a mean baseline IOP of 19.6 and 18.7 mmHg sulted for detailed information regarding storage (with , whereas the eyes in APOLLO and LUNAR had a unopened bottles requiring refrigeration), use in special mean baseline diurnal IOP of 26.4–26.7 mmHg [12, 13]. patient populations, and other warnings and precautions, Post hoc subgroup analyses (available as an abstract)  including changes to pigmented tissues and eyelashes. of data from APOLLO, LUNAR and JUPITER suggested that latanoprostene bunod 0.024% was effective in lower- ing IOP in patients with a baseline IOP within the normal 6 Current Status of Latanoprostene Bunod range (i.e. B 21 mmHg in APOLLO and LUNAR and 0.024% B 19 mmHg in JUPITER). Studies assessing the efﬁcacy of latanoprostene bunod 0.024% speciﬁcally in patients Several pharmacological options (the most frequently used with normotensive glaucoma, compared with other PGAs initial intervention) are available for lowering IOP, with and over the long term would be of interest. adverse events, cost, the dosing schedule and the degree of Latanoprostene bunod 0.024% was well tolerated over IOP lowering required inﬂuencing the treatment choice up to 12 months in adults with OAG or ocular hyperten- . PGAs are considered ﬁrst-line therapy in patients with sion, with the overall incidence of ocular adverse events 780 S. M. Hoy 2. Abu-Hassan DW, Acott TS, Kelley MJ. The trabecular meshwork: generally comparable with those of other PGAs (Sect. 4). a basic review of form and function. J Ocul Biol. 2014;2(1). http:// Most ocular TEAEs were mild or moderate in severity, fulltextarticles.avensonline.org/JOCB-2334-838-02-0017.html. with conjunctival hyperaemia being the most frequently 3. Aptel F, Chiquet C, Romanet J-P. Intraocular pressure-lowering reported ocular TEAE. The incidence of adverse events of combination therapies with prostaglandin analogues. Drugs. 2012;72(10):1355–71. special interest (eyelid and iris pigmentation, eyelash 4. Hollo´ G, Katsanos A, Boboridis KG, et al. Preservative-free growth) was low (Sect. 4). prostaglandin analogs and prostaglandin/timolol ﬁxed combina- In conclusion, current evidence indicates once-daily tions in the treatment of glaucoma: efﬁcacy, safety and potential latanoprostene bunod 0.024% is an effective and well tol- advantages. Drugs. 2018;78(1):39–64. 5. Lu LJ, Tsai JC, Liu J. Novel pharmacologic candidates for erated treatment option for the reduction of IOP in adults treatment of primary open-angle glaucoma. Yale J Biol Med. with OAG or ocular hypertension. 2017;90(1):111–8. 6. Cavet ME, Vittitow JL, Impagnatiello F, et al. Nitric oxide (NO): an emerging target for the treatment of glaucoma. Invest Oph- Data Selection Latanoprostene bunod: 76 records thalmol Vis Sci. 2014;55(8):5005–15. 7. Cavet ME, DeCory HH. The role of nitric oxide in the intraocular identiﬁed pressure lowering efﬁcacy of latanoprostene bunod: review of nonclinical studies. J Ocul Pharmacol Ther. 2018;34(1–2):52–60. Duplicates removed 15 8. Cavet ME, Vollmer TR, Harrington KL, et al. Regulation of endothelin-1-induced trabecular meshwork cell contractility by lata- Excluded during initial screening (e.g. press releases; 29 noprostene bunod. Invest Ophthalmol Vis Sci. 2015;56(6):4108–16. news reports; not relevant drug/indication; preclinical 9. Saeki T, Tsuruga H, Aihara M, et al. Dose-response proﬁle of PF- study; reviews; case reports; not randomized trial) 03187207 (PF-207) and peak IOP lowering response following Excluded during writing (e.g. reviews; duplicate data; 12 single topical administration to FP receptor knockout mice vs. small patient number; nonrandomized/phase I/II trials) wild type mice [abstract no. 4064]. Invest Ophthalmol Vis Sci. 2009;50(13). Cited efﬁcacy/tolerability articles 6 10. Krauss AH, Impagnatiello F, Toris CB, et al. Ocular hypotensive Cited articles not efﬁcacy/tolerability 14 activity of BOL-303259-X, a nitric oxide donating prostaglandin F2a agonist, in preclinical models. Exp Eye Res. 2011;93(3):250–5. Search Strategy: EMBASE, MEDLINE and PubMed from 1946 11. Bausch & Lomb Inc. VYZULTA (latanoprostene bunod ophthalmic to present. Clinical trial registries/databases and websites were also solution) 0.024%, for topical ophthalmic use: US prescribing searched for relevant data. Key words were Latanoprostene bunod, information. 2017. http://www.fda.gov/. Accessed 30 Jan 2018. BOL-303259-X, Vyzulta, Vesneo, NCX-116. Records were 12. Weinreb RN, Scassellati Sforzolini B, Vittitow J, et al. Latano- limited to those in English language. Searches last updated 30 prostene bunod 0.024% versus timolol maleate 0.5% in subjects April 2018 with open-angle glaucoma or ocular hypertension: the APOLLO study. Ophthalmology. 2016;123(5):965–73. 13. Medeiros FA, Martin KR, Peace J, et al. Comparison of latano- Acknowledgements During the peer review process, the manufac- prostene bunod 0.024% and timolol maleate 0.5% in open-angle turer of latanoprostene bunod 0.024% was also offered an opportunity glaucoma or ocular hypertension: the LUNAR study. Am J to review this article. Changes resulting from comments received Ophthalmol. 2016;168:250–9. were made on the basis of scientiﬁc and editorial merit. 14. Kawase K, Vittitow JL, Weinreb RN, et al. Long-term safety and efﬁcacy of latanoprostene bunod 0.024% in Japanese subjects Compliance with Ethical Standards with open-angle glaucoma or ocular hypertension: the JUPITER study. Adv Ther. 2016;33(9):1612–27. Funding The preparation of this review was not supported by any 15. Weinreb RN, Ong T, Scassellati Sforzolini B, et al. A ran- external funding. domised, controlled comparison of latanoprostene bunod and latanoprost 0.005% in the treatment of ocular hypertension and Conﬂict of interest Sheridan Hoy is a salaried employee of Adis/ open angle glaucoma: the VOYAGER study. Br J Ophthalmol. Springer, is responsible for the article content and declares no rele- 2015;99(6):738–45. vant conﬂicts of interest. 16. Liu JH, Slight JR, Vittitow JL, et al. Efﬁcacy of latanoprostene bunod 0.024% compared with timolol 0.5% in lowering intraocular Open Access This article is distributed under the terms of the pressure over 24 hours. Am J Ophthalmol. 2016;169:249–57. Creative Commons Attribution-NonCommercial 4.0 International 17. Weinreb RN, Liebmann JM, Martin KR, et al. Latanoprostene bunod License (http://creativecommons.org/licenses/by-nc/4.0/), which per- 0.024% in subjects with open-angle glaucoma or ocular hyperten- mits any noncommercial use, duplication, adaptation, distribution and sion: pooled phase 3 study ﬁndings. J Glaucoma. 2018;27(1):7–15. reproduction in any medium or format, as long as you give appro- 18. Kaufman PL. Latanoprostene bunod ophthalmic solution 0.024% priate credit to the original author(s) and the source, provide a link to for IOP lowering in glaucoma and ocular hypertension. Expert the Creative Commons license and indicate if changes were made. Opin Pharmacother. 2017;18(4):433–44. 19. Prum BE Jr, Rosenberg LF, Gedde SJ, et al. Primary open-angle glaucoma Preferred Practice Pattern guidelines. Ophthalmol- References ogy. 2016;123(1):P41–111. 20. Fingeret M, Powell M, Vittitow J. Efﬁcacy of latanoprostene bunod ophthalmic solution 0.024% in eyes with normal intraoc- 1. Liebmann JM, Lee JK. Current therapeutic options and treat- ular pressures [abstract]. In: American Academy of Optometry ments in development for the management of primary open-angle 95th Annual Meeting. 2016. glaucoma. Am J Manag Care. 2017;23(15 Suppl):S279–92.
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Published: May 14, 2018