Drugs Aging (2014) 31:395–404 DOI 10.1007/s40266-014-0176-2

ADIS DRUG EVALUATION

Intravitreal Aflibercept (EyleaÒ): A Review of Its Use in Patients with Macular Oedema Secondary to Central Retinal Vein Occlusion Lily P. H. Yang • Kate McKeage

Published online: 17 April 2014 Ó Springer International Publishing Switzerland 2014

Abstract Aflibercept is a fully human, recombinant fusion protein that acts as a soluble decoy receptor for vascular endothelial growth factor (VEGF) family members, including VEGF-A, VEGF-B and placental growth factor (P1GF), thereby inhibiting downstream signalling mediated by these ligands. Aflibercept binds all isoforms of VEGF-A with high affinity, and a markedly higher affinity than that of ranibizumab or bevacizumab. A formulation of aflibercept developed specifically for intravitreal injection (EyleaÒ) is approved for use in several countries for the treatment of patients with macular oedema secondary to central retinal vein occlusion (CRVO). In clinical trials (GALILEO and COPERNICUS) in patients with this condition, intravitreal aflibercept 2 mg every month improved best corrected visual acuity (BCVA), as measured by the proportion of study eyes with a gain of C15 Early Treatment Diabetic Retinopathy Study letters from baseline, significantly more than sham injections at week 24 (primary analysis). The significant improvements achieved with intravitreal aflibercept compared with sham in the first 6 months were maintained in the second 6 months with as-needed (prn) dosing and

The manuscript was reviewed by: D. Boyer, Retina-Vitreous Associates Medical Group, Los Angeles, CA, USA; V. Chong, Oxford Eye Hospital, Oxford University Hospitals, Oxford, UK; M. U. Saeed, The Sutton Eye Unit, Epsom and St Helier’s University Hospitals NHS Trust, London, UK; M. W. Stewart, Department of Ophthalmology, Mayo Clinic, Jacksonville, FL, USA. L. P. H. Yang  K. McKeage (&) Adis, 41 Centorian Drive, Private Bag 65901 Mairangi Bay, North Shore 0754, Auckland, New Zealand e-mail: [email protected]

monthly monitoring. Continued prn dosing with a reduced monitoring frequency was associated with decreased improvements. More data are needed to confirm the optimal monitoring frequency for use with prn dosing, subsequent to initial monthly injections, in order to maintain long-term efficacy. Intravitreal aflibercept was generally well tolerated in clinical trials and there is little potential for systemic drug accumulation. Thus, intravitreal aflibercept is an effective and generally well tolerated agent that extends the options available for the treatment of macular oedema secondary to CRVO.

Intravitreal aflibercept (EyleaÒ) in macular oedema secondary to central retinal vein occlusion: a summary Fully human recombinant fusion protein Binds multiple isoforms of VEGF-A with high affinity, and a markedly higher affinity than that of ranibizumab or bevacizumab Monthly intravitreal injections for 6 months followed by as-needed (prn) injections with monthly monitoring improved outcome measures, including best corrected visual acuity and central retinal vein thickness, more effectively than sham injections The optimal monitoring schedule for use with prn dosing, subsequent to initial monthly injections, is yet to be confirmed Improves vision-related quality of life Generally well tolerated

396

1 Introduction Central retinal vein occlusion (CRVO) results in impaired venous drainage from the eye, leading to increased venous pressure, reduced arterial perfusion and retinal ischaemia [1, 2]. An estimated 2.5 million adults are affected by CRVO worldwide, and the overall prevalence is 0.8 per 1,000 [3]. One result of retinal ischaemia is an increase in the production of vascular endothelial growth factor (VEGF), which can lead to vascular permeability, macular oedema, retinal haemorrhage, capillary nonperfusion and/or neovascularization [1, 2]. Patients with CRVO develop a loss of visual acuity and the visual prognosis is frequently poor. As a result of the role that VEGF plays in the pathology of the condition, VEGF has become an important drug target in treatment strategies [1]. Commonly used intraocular antivascular VEGF (antiVEGF) treatments include ranibizumab, which was developed specifically for intravitreal use and is approved for age-related macular degeneration (AMD), CRVO and diabetic macular oedema (DME), and bevacizumab, a chemotherapy agent that is frequently used off label in eye disorders [4]. Intravitreal aflibercept (EyleaÒ, formerly known as VEGF trap-eye), a formulation of aflibercept developed specifically for intravitreal injection, is the second anti-VEGF agent to be approved by the US FDA for macular oedema secondary to CRVO [5]; it is also approved in this indication in several other countries including the EU [6]. In addition, intravitreal aflibercept is approved for use in patients with neovascular (wet) AMD; reviewed previously in this journal [7]. Intravenous aflibercept is in development for use against various solid tumours and is approved for use in colorectal cancer; however, further discussion of these indications is outside the scope of this review. This article reviews the efficacy and tolerability of intravitreal aflibercept in the treatment of patients with macular oedema secondary to CRVO, and summarizes the pharmacological properties relevant to its use in this condition. 2 Pharmacodynamic Properties The pharmacodynamic properties of aflibercept have been reviewed previously [7]. This section provides a summary of data, with a focus on properties relevant to the use of intraocular aflibercept. Aflibercept is a fully human, recombinant fusion protein that acts as a soluble decoy VEGF receptor [8]. The drug comprises protein sequences from two VEGF receptors (VEGFR-1 and VEGFR-2) fused to the Fc portion of immunoglobulin G1 [8]. Aflibercept binds multiple

L. P. H. Yang, K. McKeage

isoforms of VEGF-A with high affinity, and also binds VEGF-B and placental growth factor (P1GF), thereby inhibiting downstream signaling mediated by these receptors [9]. In vitro, aflibercept bound VEGF-A with an equilibrium dissociation constant (KD) of 0.36 and 0.49 pmol/L for the human VEGF-A121 and -A165 isoforms, respectively [9]. Aflibercept bound human VEGF-A with a markedly faster association rate (77- and 256-fold, respectively) and higher affinity (&100-fold for both) than ranibizumab or bevacizumab [9]. The aflibercept KD values for VEGF-B and P1GF were 1.92 and 38.9 pmol/L, respectively [9]. In contrast, no blocking activity of human PIGF-2 was observed with ranibizumab or bevacizumab in this assay [9]. Based on a mathematical model using intravitreal halflives and relative equimolar VEGF-binding properties, intravitreal aflibercept was predicted to have a markedly longer duration of activity in the eye than ranibizumab, suggestive of the potential for less frequent dosing [10]. Aflibercept concentrations in the range expected to occur in human vitreous following intraocular injection were not harmful to the viability or metabolism of various ocular cells in in vitro studies [11, 12]. In mice with laser-induced choroidal neovascularization (CNV), a single intraocular injection with aflibercept 4.92 lg significantly reduced CNV after 2 weeks compared with controls (p \ 0.0001) [13]. In a phase II study in patients with wet AMD, monthly intravitreal aflibercept 2 mg for 12 weeks, significantly (p \ 0.0001) reduced central retinal thickness (CRT) and improved visual acuity [14]. In phase III trials in patients with macular oedema secondary to CRVO, intravitreal aflibercept 2 mg every 4 weeks effectively reduced CRT (see Sect. 4.2 for full discussion).

3 Pharmacokinetic Properties Pharmacokinetic data on intravitreal aflibercept are limited. This section summarizes data from the manufacturer’s prescribing information based on a study in patients with wet AMD or CRVO [5, 6], and briefly discusses data reported in rabbit studies [15]. Following intravitreal injection, aflibercept is absorbed slowly and is observed in the systemic circulation primarily as an inactive, stable complex with VEGF; only ‘free’ aflibercept is able to bind endogenous VEGF [5, 6]. The mean peak plasma concentration (Cmax) of free aflibercept following intravitreal aflibercept 2 mg per eye in patients with CRVO was low (0.05 lg/mL; range 0–0.081 lg/mL) and was achieved within 1–3 days [5]. Two weeks post-dose, free aflibercept plasma concentrations

Intravitreal Aflibercept: A Review

were undetectable [5]. After repeated 4-weekly intravitreal administration, aflibercept did not accumulate in plasma [5, 6]. The mean Cmax of free aflibercept is thought to be[100fold lower than the concentration of aflibercept required to inhibit the biological activity of systemic VEGF by 50 %; therefore, systemic pharmacodynamic effects are unlikely [5, 6]. As aflibercept is a therapeutic protein, no drug metabolism studies have been performed [5, 6]. The elimination of aflibercept, both free and bound, is expected to be via proteolytic catabolism. Following radiolabelled intravitreal aflibercept injections in rabbits, the mean intravitreal aflibercept half-life was 4.58 days, as determined by integrated positron emission tomography/computed tomography imaging [15]. No studies of intravitreal aflibercept specifically in patients with renal impairment have been conducted. In the VIEW2 study in patients with AMD, in which about 40 % had varying degrees of renal impairment, and in patients with CRVO in the GALILEO study (Sect. 4), there was no evidence of differences in plasma concentrations of free aflibercept between patients with normal renal function and those with mild, moderate or severe renal impairment [5, 6]. Accordingly, no dosage adjustment based on renal function is recommended.

4 Therapeutic Efficacy The clinical efficacy of intravitreal aflibercept in patients with macular oedema secondary to CRVO was evaluated in two randomized, double-masked, sham-controlled, multicentre, phase III trials: the 18-month GALILEO (performed in Europe and Asia Pacific) [16–18] and 2-year COPERNICUS (performed in the US) [19–21]. Data are available for 24 weeks (primary analyses) [16, 19] and 52 weeks [17, 20] for both trials, and 76 weeks for GALILIEO (available in an abstract) [18] and 100 weeks for COPERNICUS [21]. Enrolled patients were treatment naive adults who had centre-involved macular oedema secondary to CRVO, with CRT (as determined by optical coherence tomography) of C250 lm and Early Treatment Diabetic Retinopathy Study (ETDRS) best corrected visual acuity (BCVA) of 20/40 to 20/320 (73–24 letters; i.e. mild to severe visual impairment) in the study eye [16, 19]. Key exclusion criteria included previous vitreoretinal or filtration surgery, or panretinal or macular laser photocoagulation; other causes of decreased visual acuity; a history or presence of AMD, DME or diabetic retinopathy; previous use of intraocular or periocular corticosteroids or antiangiogenic treatment; and uncontrolled glaucoma, hypertension or diabetes [16, 19].

397

Intravitreal aflibercept was administered as a 50 lL injection; sham injections were performed by pressing an empty, needleless syringe to the conjunctival surface to simulate an injection [16, 19]. At any time during the trial and at the investigator’s discretion, patients could receive pan-retinal photocoagulation if they progressed to neovascularization [16, 19]. In both trials, patients received intravitreal aflibercept 2 mg or sham once every 4 weeks during weeks 0–24 [16, 19]. Thereafter, at monthly assessments during weeks 24–52, patients in both groups in COPERNICUS [20] or only the aflibercept group in GALILEO [17] were eligible to receive either intravitreal aflibercept or sham as needed (according to pre-specified criteria); after 52 weeks, all patients were assessed every 8 weeks in GALILEO [18] or quarterly in COPERNICUS [21], and received intravitreal aflibercept as needed (prn). The pre-specified criteria to receive aflibercept after week 24 were: a [50 lm increase in CRT, new or persistent cystic retinal changes or subretinal fluid, persistent diffuse oedema of C250 lm in the central subfield, or a change in visual acuity of C5 letters [17, 20]. Patients not meeting the criteria (or those in the sham group during weeks 24–52 in GALILEO [17]) received a sham injection [17, 20]. The primary endpoint in both trials was the proportion of study eyes with a gain of C15 ETDRS letters in BCVA from baseline to week 24 [16, 19]. Secondary endpoints included CRT, proportion of eyes progressing to ocular neovascularization, and vision-related quality of life as assessed by the National Eye Institute 25-item Visual Function Questionnaire (NEI-VFQ) [16, 19]. At baseline, the mean patient age was 62 years in GALILEO [16] and 66 years in COPERNICUS [19], a little over half of all enrolled patients were male and about three quarters were Caucasian [16, 19]. CRVO was diagnosed within 2 months of enrolment in 53 [16] and 62 % [19] of patients, and 84 [16] and 68 % [19] of study eyes were graded as perfused. Baseline values of key endpoints are presented in Table 1. 4.1 Visual Outcomes 4.1.1 Week 24 Analysis Intravitreal aflibercept treatment for 24 weeks significantly improved visual acuity in both trials in patients with macular oedema secondary to CRVO. In GALILEO [16] and COPERNICUS [19], the proportion of study eyes that gained C15 ETDRS letters in BCVA from baseline to week 24 (primary endpoint) was significantly higher in aflibercept than sham recipients (Table 1). In GALILEO, the unadjusted between-group difference for this endpoint was 38.1 % and the adjusted between-group difference

52

100

Brown et al. [20]

Heier et al. [21]

52

76

Korobelnik et al. [17]

Ogura et al. [18]g 103 68

Sham ? AFL prn

68

Sham AFL ? AFL prn

103

AFL ? AFL prn

73

Sham ? AFL prn

68

114

AFL ? AFL prn

Sham

114 73

AFL ? AFL prn Sham ? AFL prn

103

73

Sham

AFL

114

No. of pts

AFL

Treatmenta

50.9

53.6

48.9

50.7

6.2

13.7

3.8

16.9***

3.3

18.0***

1.5

13.0***

638.7

683.2

672.4

661.7

306.4

389.4

219.3

423.5***

169.3

448.6***

343.3

390.0

413.0 381.8

144.8

457.2**

8.8

5.8

4.4

2.9

15.0

5.3

0.0* 6.8

6.8

0.0*

Disease progressiond (% of eyes)

4.5

7.8*

3.5

7.5*

3.6

6.3

7.5 5.1

0.8 [77.78]

7.2** [77.67]

Vision-related QOL improvemente [BL]

g

f

e

d

c

b

Reported in an abstract

Primary endpoint

Assessed by the National Eye Institute 25-item Visual Function Questionnaire total score

Defined as any neovascularization

Measured with optical coherence tomography

Assessed in terms of letters on the Early Treatment of Diabetic Retinopathy Study chart

* p \ 0.01, ** p B 0.001, *** p \ 0.0001 vs. sham injection a AFL 2 mg or sham was administered once every 4 weeks during weeks 0–24 in both studies. During weeks 24–52, patients in both groups in COPERNICUS and only the aflibercept group in GALILEO were eligible to receive AFL (or sham) as needed (according to pre-specified criteria); after 52 weeks, all patients received AFL as needed (assessed every 8 [GALILEO] or 12 [COPERNICUS] weeks)

29.4

57.3*

32.4

60.2**

22.1f

60.2***f

23.3

49.1**

16.2** 3.8

12.3f 55.3** 30.1

17.3** -4.0

56.1**f

Mean decrease

Mean BL

Mean letters gained

Mean BL

C15 letters gained (% of eyes)

Central retinal thicknessc (lm)

Best-corrected visual acuityb

AFL aflibercept, BL baseline, prn as needed, pts patients, QOL quality of life

24

Holz et al. [16]

GALILEO

24

Time-point (weeks)

Boyer et al. [19]

COPERNICUS

Study

Table 1 Clinical efficacy of aflibercept intravitreal injection in two randomized trials in patients with macular oedema secondary to central retinal vein occlusion

398 L. P. H. Yang, K. McKeage

Intravitreal Aflibercept: A Review

399

COPERNICUS (n = 187)

Patients (%)

Patients (%)

GALILEO (n = 171) 100 90 80 70 60 50 40 30 20 10 0 ≥0

≥10

≥30

100 90 80 70 60 50 40 30 20 10 0

AFL Sham

≥0

≥10

≥15

≥15

≥10

≥5

50

50

45

45

40

40

35

35

Patients (%)

Patients (%)

No. of letters gained

30 25 20 15

30 25 20 15

10

10

5

5

0

0 ≥1

≥10

No. of letters lost Fig. 1 Proportion of patients with vision gain or loss in patients with macular oedema secondary to central retinal vein occlusion in GALILEO [16] and COPERNICUS [19] studies. Intravitreal aflibercept 2 mg or sham injections were administered every 4 weeks for

24 weeks. Last observation carried forward analyses. AFL intravitreal aflibercept 2 mg. *p \ 0.01, **p \ 0.0001 vs. sham (p values indicated where reported). Part of this figure was reproduced from Holz et al. [16], with permission

(adjusted for region and baseline BCVA) was 38.3 % (95 % CI 24.4–52.1; p \ 0.0001) [16]. In COPERNICUS, the unadjusted and adjusted between group differences for this endpoint were 43.8 and 44.8 % (95 % CI 33.0–56.6; p \ 0.001), respectively [19]. An improvement in BCVA with aflibercept was noticeable at the first assessment at week 4 in both trials [16, 19]. Treatment with intravitreal aflibercept was also associated with improvements in other BCVA-related endpoints in both trials [16, 19]. In the aflibercept groups in GALILEO and COPERNICUS, there was a significantly higher mean number of letters gained (Table 1) and a greater proportion of patients gained letters and fewer lost letters relative to sham (Fig. 1). In both studies, during 24 weeks’ treatment, no aflibercept recipient withdrew from the trial because of a lack of efficacy/treatment failure, whereas 5.6 [16] and 5.4 % [19] of sham recipients in each study withdrew for this reason. According to subgroup analyses in both trials, a numerically higher proportion of aflibercept-treated

patients achieved improvements in visual acuity when the time from diagnosis was B2 months compared with [2 months [16, 19]. For example in COPERNICUS, the proportion who gained C15 letters at week 24 in patients treated with aflibercept or sham was 68.8 vs. 15.4 % (treatment difference 53.4 %; 95 % CI 38.4–68.4) among those beginning treatment within 2 months of diagnosis compared with 38.8 vs. 4.8 % (treatment difference 34.0 %; 95 % CI 17.6–50.4) among those starting treatment [2 months after diagnosis [19]. In COPERNICUS, baseline perfusion status did not appear to have any effect on response rates [19]. 4.1.2 Analyses at Later Timepoints As stated previously, during weeks 24–52, the study regimen differed between the two trials. In GALILEO [17], patients in the sham group continued to receive sham and only patients in the aflibercept group were eligible for intravitreal aflibercept prn, whereas in COPERNICUS [20],

400

all patients (regardless of randomization) were eligible for intravitreal aflibercept prn. After week 52, all patients in both trials received aflibercept prn [17, 20]. In GALILEO [17], the median time to the first prn aflibercept injection in the aflibercept ? aflibercept prn group (n = 103) was 83 days and the mean number of injections during weeks 24–52 was 2.5. In COPERNICUS [20], the median time to the first prn aflibercept injection in the aflibercept ? aflibercept prn group (n = 110) and the sham ? aflibercept prn group (n = 60) during weeks 24–52 was 68 and 29 days, respectively, and the mean number of injections was 2.7 and 3.9. During weeks 52–100 in this trial, the mean number of injections was 2.1 and 2.9, respectively, and the mean time between prn injections was 87.1 and 83.3 days [21]. In both trials, the visual acuity improvements reported with aflibercept treatment at week 24 were maintained through to week 52, and improvements continued to significantly favour groups receiving aflibercept ? aflibercept prn versus sham ? sham [17] or sham ? aflibercept prn [20] (Table 1). At 52 weeks, no patients in the aflibercept ? aflibercept prn groups withdrew from either study because of a lack of efficacy [17] or treatment failure [20], compared with 8.5 % in the sham ? sham group in GALILEO [17] and 5.4 % in the sham ? aflibercept prn group in COPERNICUS [20]. While the proportion of study eyes that gained C15 ETDRS letters in BCVA from baseline continued to be significantly higher in patients receiving aflibercept ? aflibercept prn than sham ? aflibercept prn in both trials at week 76 [18] or 100 [21], improvements were diminished compared with earlier timepoints (Table 1). In subgroup analyses, there was generally a numerically greater difference between the aflibercept ? aflibercept prn group and the groups receiving sham ? sham or sham ? aflibercept prn in BCVA endpoints in patients with baseline BCVA B20/200 (vs. those with[20/200) and those who were diagnosed within 2 months (vs. [2 months) [17, 20]. In GALILEO, there was virtually no difference between perfused and nonperfused patients in the aflibercept ? aflibercept prn group in the mean change from baseline BVCA (0.6 letters), but a much larger difference between these subgroups in the sham ? sham group (14.8 letters in favour of the perfused subgroup) [17]. 4.2 Anatomical Outcomes In both trials [16, 19], intravitreal aflibercept improved CRT from baseline to week 24 by a significantly greater extent than sham (Table 1). The adjusted least squares mean between-group difference for this endpoint was -239.4 lm (95 % CI -286.3 to -192.5; p \ 0.0001) in

L. P. H. Yang, K. McKeage

GALILEO [16] and -311.9 lm (95 % CI -389.4 to 234.4; p \ 0.001) in COPERNICUS [19]. At week 24, the difference in the rate of disease progression to neovascularization between aflibercept and sham recipients did not reach significance in GALILEO [16], but was significantly lower in aflibercept recipients in COPERNICUS [19] (Table 1). In GALILEO [16], anterior segment neovascularization developed in two aflibercept and one sham recipient; neovascularization elsewhere developed in one aflibercept and two sham recipients. Of these patients, one aflibercept recipient (with iris neovascularization) and all sham recipients received pan-retinal laser photocoagulation during the 24-week study period [16]. In COPERNICUS [19], no aflibercept-treated eyes progressed to neovascularization and five sham-treated eyes developed anterior segment neovascularization; no aflibercept-treated eyes and four sham-treated eyes required pan-retinal photocoagulation. At week 52, improvements in mean CRT significantly favoured aflibercept ? aflibercept prn versus sham in GALILEO, and in COPERNICUS, the between-group treatment difference between aflibercept ? aflibercept prn and sham ? aflibercept prn group was not significant (Table 1). In GALILEO, six patients in each group developed neovascularization, and these occurred in the anterior segment (4 vs. 1, respectively), elsewhere in the fundus (1 vs. 4), both the anterior segment and elsewhere in the fundus (1 vs. 0) and in the optic disc (0 vs. 1); panretinal photocoagulation was performed for two patients in the aflibercept group and three patients in the sham group [17]. At week 52 in COPERNICUS, no study eyes in the aflibercept ? aflibercept prn group developed neovascularization, which was significantly (p = 0.006) lower than the number of study eyes in the sham ? aflibercept prn group (6.8 %; all were anterior segment neovascularizations and 4 of 5 received pan-retinal photocoagulation) [20]. Between week 52 and 100 in COPERNICUS, six patients in each treatment group developed neovascularization [21]. From baseline to week 100, pan-retinal photocoagulation was required by significantly fewer eyes in the aflibercept ? aflibercept prn group than the sham ? aflibercept prn group (1.8 vs. 8.1 %, respectively; p = 0.0355) [21]. At week 76 in GALILEO [18] and 100 in COPERNICUS [21], the between-group treatment difference with regard to the reduction in mean CRT was not significant (Table 1). 4.3 Vision-Related Quality of Life Intravitreal aflibercept treatment was associated with a significantly greater improvement than sham in vision-

Intravitreal Aflibercept: A Review

related quality of life (as assessed by NEI-VFQ total scores) in both trials at week 24 [16, 19] (Table 1). Improvements continued to be significantly greater with aflibercept ? aflibercept prn than with sham ? sham at week 52 in GALILEO [17], but differences between aflibercept ? aflibercept prn and sham ? aflibercept prn groups were not significantly different at week 52 or 100 in COPERNICUS [20, 21]. With regard to NEI-VFQ subscale scores (near activities, distance activities and vision dependency) at week 24, a significant between-group difference was reported for the near-activities subscore (p = 0.0003) in GALILEO [16], and clinically relevant improvements (C4-point increase [17]) were reported for all subscores in the aflibercept group in COPERNICUS [19].

5 Tolerability Intravitreal aflibercept every 4 weeks was generally well tolerated in the GALILEO [16] and COPERNICUS [19] trials (see Sect. 4 for study design details). Adverse events led to study withdrawal before 24 weeks in no aflibercept recipients compared with 5.6 and 4.1 % of sham recipients in each trial, respectively. 5.1 Ocular Adverse Events During the first 24 weeks of treatment in GALILEO, the proportion of patients experiencing at least one ocular adverse event in the aflibercept and sham groups was 54.8 versus 64.7 % [17]. The most common (incidence [7 %) treatment-emergent adverse events reported for the study eye with aflibercept during this period were eye pain (11.5 vs. 4.4 % with sham) and conjunctival haemorrhage (8.7 vs. 4.4 %) [16]. An increase in intra-ocular pressure, either prior to injection or up to approximately 30 min after the injection, was measured in 9.6 versus 5.9 % of patients, respectively, and in the aflibercept group, 5 (4.8 %) events were considered to be procedure related and 3 (2.9 %) events were considered to be drug related [16]. Importantly, the proportion of patients experiencing increases in intraocular pressure to predefined values (i.e. C10 mm Hg change from baseline, or C21 or C35 mm Hg) was low and similar between treatment groups at all timepoints [16]. From week 24–52 in GALILEO, at least one ocular treatment-emergent adverse event occurred in 69.1 % of patients receiving aflibercept ? aflibercept prn compared with 50.9 % of patients receiving sham ? sham [17]. The most frequently reported ocular treatment-emergent adverse events reported for the study eye during this period were worsening of macular oedema (35.1 vs. 10.5 %,

401

respectively), increased intraocular pressure (13.4 vs. 3.5 %) and reduced visual acuity (11.3 vs. 1.8 %). At least one serious ocular adverse event occurred in two patients (three events) in the aflibercept group (worsening of macular oedema, retinal tear, vitreous detachment) and four patients in the sham group (two cases of glaucoma, worsening of macular oedema, increased intraocular pressure) in the first 24 weeks of GALILEO [16]. There were no reports of endophthalmitis or rhegmatogenous detachment in either treatment group; one case of uveitis in an aflibercept recipient was mild and resolved spontaneously [16]. Most serious ocular adverse events reported during 52 [17] or 76 [18] weeks of treatment were related to the disease or the injection procedure, and no clinically relevant differences between groups with regard to the incidence of serious events were noted [17]. During the first 24 weeks of treatment in COPERNICUS, a similar proportion of patients in the aflibercept and sham groups experienced an ocular adverse event (68.4 vs. 68.9 %) [19]. The most commonly reported (incidence [7 %) ocular events in the aflibercept group were conjunctival haemorrhage (14.9 vs. 17.6 % with sham), eye pain (14.0 vs. 5.4 %) and maculopathy (8.8 vs. 1.4 %) [19, 20]. Conjunctival haemorrhage and most cases of eye pain were attributable to the intravitreal injection [19]. As would be expected, ocular injection-related adverse events were reported in more aflibercept than sham recipients (30.7 vs. 18.9 %). Ocular adverse events that occurred more frequently in the sham group were consistent with complications of CRVO, including visual acuity decrease, retinal haemorrhage, vitreous haemorrhage and iris neovascularization [19]. A drug-related ocular adverse event occurred in only four aflibercept recipients: one case each of endophthalmitis, maculopathy, ocular discomfort and retinal artery occlusion [19]. Throughout 52 [20] and 100 [21] weeks of treatment in COPERNICUS, ocular treatment-emergent adverse events occurred in a similar proportion of patients receiving aflibercept ? aflibercept prn (n = 110) or sham ? aflibercept prn (n = 60): 56.4 vs. 55.0 %, respectively, at week 52, and 87.7 vs. 85.1 %, at week 100. The most common ocular treatment-emergent adverse events occurring during weeks 24–52 included those that occurred most frequently during the initial 6 months of treatment, albeit at a somewhat lower rate: conjunctival haemorrhage (8.2 and 13.3 %, respectively), eye pain (5.5 and 5.0 %) and maculopathy (5.5 and 6.7 %), together with reduced visual acuity (14.5 and 5.0 %), retinal pigment epitheliopathy (2.7 and 8.3 %) and macular oedema (9.1 and 0 %) [20]. Throughout 52 weeks of treatment, an increase in intraocular pressure was recorded in 12.3 and 13.5 % of patients, respectively [20]. During weeks 52–100, ocular treatment-emergent adverse events

402

L. P. H. Yang, K. McKeage

occurring in C10 % of patients receiving aflibercept ? aflibercept prn or sham ? aflibercept prn included reduced visual acuity (16.7 vs. 10.8 %, respectively) and macular oedema (11.4 vs. 2.7 %) [21]. Serious ocular adverse events in the first 24 weeks of COPERNICUS occurred in four aflibercept recipients (one case each of reduced visual acuity, endophthalmitis, retinal artery occlusion and corneal abrasion) compared with 10 sham recipients (most commonly vitreous haemorrhage) [19]. A ocular serious adverse event in patients receiving aflibercept ? aflibercept prn or sham ? aflibercept prn occurred in three and two patients, respectively, during weeks 24–52 [20] and seven and no patients during weeks 52–100 [21]. During weeks 52–100, ocular serious adverse events that occurred in more than one patient included cataract (n = 3) and cystoid macular oedema (n = 2) [21].

patients, respectively) the most common [20]. During weeks 52–100 in COPERNICUS, serious non-ocular adverse events occurred 21.1 versus 25.7 % of patients, respectively, and pneumonia was the only event reported in more than one patient [21]. From baseline to week 100 in COPERNICUS, the incidence of Antiplatelet Trialists’ Collaboration-defined arterial thromboembolic events was 1.8 % (two patients, both nonfatal) and 2.7 % (two patients, both fatal), respectively [21]. No such events occurred in any patients in GALILEO [17]. Where reported, there were no clinically meaningful between-group differences in laboratory values or vital signs [19].

5.2 Non-Ocular Adverse Events

For the treatment of visual impairment due to macular oedema secondary to CRVO, the recommended initial dosing schedule is intravitreal (administered by a qualified physician) aflibercept 2 mg (equivalent to 50 lL) once every 4 weeks (monthly) [5, 6]. It may be possible to gradually increase treatment intervals to maintain a stable visual and anatomical outcome [6]. Local prescribing information should be consulted for full details of administration instructions, as well as contraindications and precautions relating to the use of intravitreal aflibercept.

Non-ocular adverse events during 52 weeks of treatment in GALILEO [16, 17] and 100 weeks in COPERNICUS [19– 21] were mostly mild or moderate in severity. In GALILEO, the incidence of non-ocular adverse events was generally similar in the aflibercept and sham groups in the first 24 weeks (45.2 vs. 54.4 %) and in weeks 24–52 (51.5 vs. 50.9 %) [17]. Nasopharyngitis was the most commonly reported throughout treatment in both groups, with an incidence of 9.3 versus 19.3 %, respectively, from week 24–52. From baseline to week 52 in COPERNICUS, the most frequently reported non-ocular treatment-emergent adverse events in groups receiving aflibercept ? aflibercept prn or sham ? aflibercept prn were hypertension (9.5 and 14.9 %, respectively), nasopharyngitis (6.8 and 7.9 %) and upper respiratory tract infection (5.4 and 7.9 %) [20]. During weeks 52–100, hypertension was the only systemic adverse event that occurred in C10 % of patients (19.3 vs. 16.2 %, respectively) [21]. The incidence of serious non-ocular adverse events was low in both groups of both studies [17, 20, 21]. In GALILEO, serious non-ocular adverse events occurred in a similar proportion of patients in the aflibercept and sham groups in the first 24 weeks (5.8 vs. 7.4 %) and in the aflibercept ? aflibercept prn and the sham ? sham groups during weeks 24–52 (6.2 vs. 8.8 %). In weeks 24–52, these events included pneumonia (one patient each group) and syncope (1 vs. 2 patients, respectively) [17]. In COPERNICUS, serious non-ocular adverse events in groups receiving aflibercept or sham in the first 24 weeks occurred in 5.3 versus 8.1 % of patients, respectively [19]. During weeks 24–52, the incidence of such events in the aflibercept ? aflibercept prn or sham ? aflibercept prn groups was 6.4 versus 8.3 %, with neoplasms (1 vs. 4

6 Dosage and Administration

7 Current Status of Intravitreal Aflibercept in Macular Oedema Secondary to CRVO The introduction of anti-VEGF agents for use in ophthalmology within the last decade has provided much needed options for the treatment of several retinal diseases, including macular oedema secondary to CRVO [22]. In this indication, ranibizumab and bevacizumab are the most commonly used anti-VEGF agents, and while they have not been compared in clinical trials in CRVO, current literature indicates that most physicians consider the two drugs to have similar efficacy in the treatment of exudative AMD [22]. Unlike ranibizumab, bevacizumab is not well studied or indeed approved in CRVO; however, its popularity is most likely attributable to its lower cost [4]. The pharmacology of aflibercept differs from that of ranibizumab and bevacizumab and, thus, clinical performance may also differ [23]; however, head-to-head trials comparing these agents in the treatment of CRVO have not been performed. Unlike ranibizumab and bevacizumab, which are constructed from the mouse anti-human VEGF monoclonal antibody, aflibercept is a recombinant fusion protein comprising portions of VEGF receptors 1 and 2 and

Intravitreal Aflibercept: A Review

the Fc region of human IgG (Sect. 2). In vitro studies demonstrated that aflibercept has a higher binding affinity for VEGF-A than ranibizumab or bevacizumab and, unlike these two agents, aflibercept also binds to VEGF-B and PIGF (Sect. 2). The higher VEGF-binding affinity demonstrated with aflibercept is suggestive of a longer duration of biological activity [10]. Whether the predicted longer duration of activity with aflibercept versus ranibizumab and bevacizumab can lead to a reduced frequency of intravitreal injections remains to be shown and is likely to be an important consideration in treatment selection. Currently in the US, the dosing interval recommended with intravitreal ranibizumab in CRVO is monthly [24], but in ‘real world’ practice, ranibizumab and bevacizumab are frequently administered on a ‘treat-and-extend’ or ‘treatand-observe’ basis to minimize the number of injections and clinic visits [22]. Intravitreal aflibercept is also recommended monthly for initial treatment, but with the proviso that the dosing interval may be increased [6] (Sect. 6). In the GALILEO and COPERNICUS studies, the significant BCVA and CRT improvements achieved with intravitreal aflibercept compared with sham in the first 6 months of the trials were generally maintained with prn aflibercept and monthly monitoring in the second 6 months, but improvements were somewhat diminished after week 52 when prn aflibercept continued but the monitoring frequency was reduced (Sect. 4.1.2). During prn dosing and monthly monitoring in the second 6 months, the mean number of aflibercept injections administered (2.5 and 2.7, in each of the respective studies; Sect 4.1.2) was approximately the same as the number that would have been administered with bimonthly dosing. Of note, bimonthly aflibercept after an initial three monthly doses achieved generally similar efficacy to that of monthly aflibercept or ranibizumab in the pivotal VIEW studies in wet AMD [25]; however no head-to-head comparisons have been performed in patients with CRVO. Also worthy of note, results of an extension of the CRUISE trial in patients with macular oedema secondary to CRVO indicated that prn ranibizumab with monitoring at least every 3 months, subsequent to monthly injections in the first 6 months and prn injections with monthly monitoring in the second 6 months, was associated with worsening of outcome measures [26]. If the efficacy of bimonthly or a ‘treat and extend’ regimen is confirmed with intravitreal aflibercept in patients with macular oedema secondary to CRVO, such a regimen could have cost advantages relative to regimens requiring monthly monitoring. In COPERNICUS, a switch from sham to aflibercept prn at 6 months achieved improvements in visual acuity and CRT; however, the improvement in BCVA at weeks 52 and 100 was greater in the group that had received aflibercept from week 1 (Sect. 4.1.2). These results suggest that when

403

indicated, anti-VEGF treatment in patients with CRVO should commence without delay. The pharmacokinetic properties of aflibercept lead to it forming a stable complex with VEGF in plasma, with little potential to accumulate to toxic concentrations (Sect. 3) [23]. In clinical trials, intravitreal aflibercept injections were generally well tolerated; the most common treatmentrelated adverse events included mild to moderate conjunctival haemorrhage and eye pain (Sect. 5). Intravitreal aflibercept is also being, or has been, investigated in AMD, CRVO, branch retinal vein occlusion, DME and myopic choroidal neovascularization [27]. In conclusion, intravitreal aflibercept is an effective and generally well tolerated agent that extends the options available for the treatment of macular oedema secondary to CRVO. Data selection sources: Relevant medical literature (including published and unpublished data) on aflibercept was identified by searching databases including MEDLINE (from 1946) and EMBASE (from 1996) [searches last updated 31 March 2014], bibliographies from published literature, clinical trial registries/ databases and websites. Additional information was also requested from the company developing the drug. Search terms: aflibercept, macular edema, macular oedema, retinal oedema, retina edema, retina macula edema, papilledema, central retina vein occlusion. Study selection: Studies in patients with macular oedema secondary to central retinal vein occlusion who received aflibercept. When available, large, well-designed, comparative trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Disclosure The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on the article. Changes resulting from comments received were made by the author on the basis of scientific and editorial merit.

References 1. Stewart MW. The expanding role of vascular endothelial growth factor inhibitors in ophthalmology. Mayo Clin Proc. 2012;87(1): 77–88. 2. Figueroa MS, Contreras I. Potential anti-vascular endothelial growth factor therapies for central retinal vein occlusion. Drugs. 2012;72(16):2063–71. 3. Rogers S, McIntosh RL, Cheung N, et al. The prevalence of retinal vein occlusion: pooled data from population studies from the United States, Europe, Asia, and Australia. Ophthalmology. 2010;117(2):313–9. 4. Evoy KE, Abel SR. Aflibercept: newly approved for the treatment of macular edema following central retinal vein occlusion. Ann Pharmacother. 2013;47(6):819–27. 5. Regeneron Pharmaceuticals Inc. EyleaÒ (aflibercept) injection: US prescribing information. 2014. http://www.regeneron.com/ Eylea/eylea-fpi.pdf. Accessed 31 Mar 2014.

404 6. European Medicines Agency. Eylea (aflibercept) solution for intravitreal injection: summary of product characteristics. 4 Sep 2013. http://www.ema.europa.eu/docs/en_GB/document_library/ EPAR_-_Product_Information/human/002392/WC500135815.pdf. Accessed 31 Mar 2014. 7. Frampton JE. Aflibercept for intravitreal injection: in neovascular age-related macular degeneration. Drugs Aging. 2012;29 (10):839–46. 8. Holash J, Davis S, Papadopoulos N, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci USA. 2002;99(17):11393–8. 9. Papadopoulos N, Martin J, Ruan Q, et al. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis. 2012;15(2):171–85. 10. Stewart MW, Rosenfeld PJ. Predicted biological activity of intravitreal VEGF Trap. Br J Ophthalmol. 2008;92(5):667–8. 11. Ammar DA, Mandava N, Kahook MY. The effects of aflibercept on the viability and metabolism of ocular cells in vitro. Retina. 2013;33(5):1056–61. 12. Schnichels S, Hagemann U, Januschowski K, et al. Comparative toxicity and proliferation testing of aflibercept, bevacizumab and ranibizumab on different ocular cells. Br J Ophthalmol. 2013; 97(7):917–23. 13. Saishin Y, Saishin Y, Takahashi K, et al. VEGF-TRAP(R1R2) suppresses choroidal vascularization and VEGF-induced breakdown of the blood-retinal barrier. J Cell Physiol. 2003;195:241–8. 14. Brown DM, Heier JS, Ciulla T, et al. Primary endpoint results of a phase II study of vascular endothelial growth factor trap-eye in wet age-related macular degeneration. Ophthalmology. 2011;118 (6):1089–97. 15. Christoforidis JB, Williams MM, Kothandaraman S, et al. Pharmacokinetic properties of intravitreal I-124-aflibercept in a rabbit model using PET/CT. Curr Eye Res. 2012;37(12):1171–4. 16. Holz FG, Roider J, Ogura Y, et al. VEGF Trap-Eye for macular oedema secondary to central retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J Ophthalmol. 2013;97(3):278–84.

L. P. H. Yang, K. McKeage 17. Korobelnik JF, Holz FG, Roider J, et al. Intravitreal aflibercept injection for macular edema resulting from central retinal vein occlusion: one-year results of the phase 3 GALILEO study. Ophthalmology. 2014;121:202–8. 18. Ogura Y, Korobelnik JF, Roider J, et al. Eighteen-month results of the GALILEO study evaluating intravitreal aflibercept injection (IAI) for macular edema secondary to central retinal vein occlusion (CRVO) [abstract no. 4516]. 2013 Annual Meeting of the Association for Research and Vision in Ophthalmology; 5–9 May 2013; Seattle, WA. 19. Boyer D, Heier J, Brown DM, et al. Vascular endothelial growth factor Trap-Eye for macular edema secondary to central retinal vein occlusion: six-month results of the phase 3 COPERNICUS study. Ophthalmology. 2012;119(5):1024–32. 20. Brown DM, Heier JS, Clark WL, et al. Intravitreal aflibercept injection for macular edema secondary to central retinal vein occlusion: 1-year results from the phase 3 COPERNICUS study. Am J Ophthalmol. 2013;155(3):429–37. 21. Heier JS, Clark WL, Boyer DS, et al. Intravitreal aflibercept injection for macular edema due to central retinal vein occlusion: two-year results from the COPERNICUS study. Ophthalmology. 2014 Mar. doi:10.1016/j.ophtha.2014.01.027. 22. Stewart MW. Aflibercept (VEGF trap-eye): the newest antiVEGF drug. Br J Ophthalmol. 2012;96(9):1157–8. 23. Chong V. Biological, preclinical and clinical characteristics of inhibitors of vascular endothelial growth factors. Ophthalmologica. 2012;227(Suppl 1):2–10. 24. Genetech Inc. LucentisÒ (ranibizumab injection): US prescribing information. Feb 2014. http://www.gene.com/download/pdf/ lucentis_prescribing.pdf. Accessed 31 Mar 2014. 25. Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012;119(12):2537–48. 26. Heier JS, Campochiaro PA, Yau L, et al. Ranibizumab for macular edema due to retinal vein occlusions: long-term followup in the HORIZON trial. Ophtholmology. 2012;119:802–9. 27. US National Institutes of Health. ClinicalTrials.gov. 2014. http:// clinicaltrials.gov/. Accessed 6 Jan 2014.

Intravitreal aflibercept (Eylea(®)): a review of its use in patients with macular oedema secondary to central retinal vein occlusion.

Aflibercept is a fully human, recombinant fusion protein that acts as a soluble decoy receptor for vascular endothelial growth factor (VEGF) family me...
373KB Sizes 0 Downloads 3 Views