Primary Endpoint Results of a Phase II
`Study of Vascular Endothelial Growth
`Factor Trap-Eye in Wet Age-related
`Macular Degeneration
`
`David M. Brown, MD,1 Jeffrey S. Heier, MD,2 Thomas Ciulla, MD,3 Matthew Benz, MD,1
`Prema Abraham, MD,4 George Yancopoulos, MD, PhD,5 Neil Stahl, PhD,5 Avner Ingerman, MD,5
`Robert Vitti, MD, MBA,5 Alyson J. Berliner, MD, PhD,5 Ke Yang, PhD,5 Quan Dong Nguyen, MD, MSc,6
`for the CLEAR-IT 2 Investigators
`
`Objective: To evaluate the biologic effects and safety of vascular endothelial growth factor (VEGF) Trap-Eye
`during a 12-week fixed-dosing period in patients with neovascular (wet) age-related macular degeneration (AMD).
`Design: Multicenter, prospective, randomized, double-masked clinical trial with initial 12-week fixed dosing
`period. Data were analyzed to week 16.
`Participants: We included 159 patients with subfoveal choroidal neovascularization secondary to wet AMD.
`Methods: Patients were randomized 1:1:1:1:1 to VEGF Trap-Eye during the fixed-dosing phase (day 1 to
`week 12): 0.5 or 2 mg every 4 weeks (0.5 mg q4wk, 2 mg q4wk) on day 1 and at weeks 4, 8, and 12; or 0.5, 2,
`or 4 mg every 12 weeks (0.5 mg q12wk, 2 mg q12wk, or 4 mg q12wk) on day 1 and at week 12.
`Main Outcome Measures: The primary endpoint was change from baseline in central retinal/lesion thick-
`ness (CR/LT) at week 12; secondary outcomes included change in best-corrected visual acuity (BCVA), propor-
`tion of patients with a gain of ⱖ15 letters, proportion of patients with a loss of ⬎15 letters, and safety.
`Results: At week 12, treatment with VEGF Trap-Eye resulted in a significant mean decrease in CR/LT of 119
`␮m from baseline in all groups combined (P⬍0.0001). The reduction in CR/LT with the 2 mg q4wk and 0.5mg
`q4wk regimens was significantly greater than each of the quarterly dosing regimens. The BCVA increased
`significantly by a mean of 5.7 letters at 12 weeks in the combined group (P⬍0.0001), with the greatest mean gain
`of ⬎8 letters in the monthly dosing groups. At 8 weeks, BCVA improvements were similar with 2 mg q4wk and
`2 mg q12wk dosing. After the last required dose at week 12, CR/LT and visual acuity were maintained or further
`improved at week 16 in all treatment groups. Ocular adverse events were mild and consistent with safety profiles
`reported for other intraocular anti-VEGF treatments.
`Conclusions: Repeated monthly intravitreal dosing of VEGF Trap-Eye over 12 weeks demonstrated signif-
`icant reductions in retinal thickness and improvements in visual acuity, and was well-tolerated in patients with
`neovascular AMD.
`Financial Disclosure(s): Proprietary or commercial disclosure may be found after
`Ophthalmology 2011;118:1089 –1097 © 2011 by the American Academy of Ophthalmology.
`
`the references.
`
`Age-related macular degeneration (AMD) is a leading cause of
`vision loss among older adults in Western countries.1,2 The
`vast majority of patients with AMD have the dry form of the
`disease, but severe vision loss occurs most frequently in pa-
`tients who develop choroidal neovascularization (CNV).3 Neo-
`vascular AMD is characterized by the growth of anomalous
`vessels originating from the choroidal vascular network, which
`causes hemorrhage and leakage in the subretinal and intrareti-
`nal spaces resulting in metamorphopsia and decreased vision.
`The pathophysiology of ocular neovascularization is
`complex, but vascular endothelial growth factor (VEGF)-A
`is an important stimulus for both the growth of new blood
`vessels and increased vascular leakage resulting in retinal
`edema as seen in animal models and human AMD.4 –7 The
`mammalian VEGF family also includes VEGF-B, VEGF-C,
`
`VEGF-D, and placental growth factor (PlGF), but the mem-
`bers predominantly involved in ocular neovascularization
`are VEGF-A and PlGF.8,9 Of at least the 4 major isoforms
`of human VEGF-A, VEGF165 is the most abundantly ex-
`pressed, although the other isoforms are also biologically
`active.8,10 The biological activities of VEGF-A are medi-
`ated through 2 receptor tyrosine kinases, VEGF receptor
`(VEGFR)1 and VEGFR2. Found predominantly on the sur-
`face of vascular endothelial cells, VEGFR2 plays a key role
`in mediating endothelial cell survival, migration, and pro-
`liferation, both during normal development as well as in a
`variety of pathophysiologic conditions. Initially discovered
`as a vascular permeability factor, VEGF–A also decreases
`barrier functions of the endothelium, resulting in increased
`extravasation of water and macromolecules.10,11 Vascular
`
`© 2011 by the American Academy of Ophthalmology
`Published by Elsevier Inc.
`
`ISSN 0161-6420/11/$–see front matter
`doi:10.1016/j.ophtha.2011.02.039
`
`1089
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`Ophthalmology Volume 118, Number 6, June 2011
`
`endothelial growth factor-A is a potent promoter of vascular
`permeability (approximately 50 000 times more potent than
`histamine), and the onset of this effect is very rapid.
`Vascular endothelial growth factor increases permeabil-
`ity of the pathologic choroidal vessels, leading to extrava-
`sation of fluid into and under the retina. The resulting
`increase in central retinal thickness is responsible in part for
`the decrease in central visual acuity. Although not always
`correlative with visual acuity, the change in central retinal
`thickness, as measured by optical coherence tomography,
`has become one of the established means of monitoring the
`disease and its response to treatment.
`The related angiogenic factor, PlGF, binds to VEGFR1
`and collaborates with VEGF-A in promoting angiogenesis
`and vascular permeability, particularly in pathologic condi-
`tions.9,12,13 The mechanism of action of PlGF has not yet
`been fully elucidated,11,14 but it has been shown that PlGF
`ligation of VEGFR1 promotes leukocyte chemotaxis,13 and
`that PlGF may play a role in recruiting inflammatory cells
`into the diseased retina, leading to release of VEGFs and
`other inflammatory mediators, perpetuating the cycle of
`angiogenesis and inflammation.15
`Most current anti-VEGF treatments target VEGF-A. Of
`the currently approved anti-VEGF agents for ocular disease,
`pegaptanib is specific for VEGF165,16 and ranibizumab tar-
`gets multiple VEGF-A isoforms and their degradation prod-
`ucts.17 Bevacizumab, a full-length humanized monoclonal
`anti-VEGF antibody that is used off-label to treat AMD, is
`derived from the same mouse antibody as ranibizumab and
`is also directed against all isoforms of VEGF-A.18,19
`Vascular endothelial growth factor Trap-Eye (VEGF
`Trap-Eye) is a fully human, soluble recombinant decoy
`VEGFR that is biologically engineered to contain key bind-
`ing domains of VEGFR1 and VEGFR2 fused to the constant
`Fc region of IgG1.20 Unlike currently available anti-VEGF
`agents, VEGF Trap-Eye inhibits PlGF in addition to all
`isoforms of VEGF-A.20 Because the binding affinity of
`VEGF Trap-Eye for VEGF-A isoforms (KD, 0.5–1 pmol/L)
`and PlGF (KD, 39 –392 pmol/L) is higher than that of native
`receptors (KD of 10 –30 pmol/L for VEGFR1 and 100-300
`pmol/L for VEGFR2), it effectively blocks VEGF binding
`and activation of these receptors, even when VEGF Trap-
`Eye is present at low concentrations. The binding affinity of
`anti-VEGF monoclonal antibodies by contrast is many fold
`lower (KD, 0.1–10 nmol/L).21,22 Tight binding of VEGF
`Trap-Eye to all VEGF-A isoforms and PlGF could theoret-
`ically offer a differential impact on visual acuity. As shown
`in modeling studies, high-affinity blockade of VEGF-A and
`PlGF activity with VEGF Trap-Eye may increase the dura-
`tion of effect, thus allowing an extended dosing interval.23
`VEGF Trap-Eye also forms a stable, inert 1:1 complex with
`VEGF dimers, unlike the rapidly cleared multimeric im-
`mune complexes formed with an antibody.24
`Preclinical studies support a therapeutic role for VEGF
`Trap-Eye in multiple vascular eye diseases, including wet
`AMD. Blockade of VEGF with VEGF Trap-Eye inhibited
`CNV, suppressed VEGF-induced breakdown of the blood-
`retinal barrier, and promoted regression of newly formed
`and established blood vessels (Invest Ophthalmol Vis Sci
`5307 [Suppl]:46,2005; Invest Ophthalmol Vis Sci 1411
`
`1090
`
`[Suppl]:46,2005; and Invest Ophthalmol Vis Sci 5300
`[Suppl]:46,2005).25 Primate studies showed VEGF Trap-
`Eye rapidly reversed vascular leakage in retinal injury mod-
`els and had a favorable ocular safety profile (Invest Oph-
`thalmol Vis Sci 1751 [Suppl]:47,2006).
`The clinical activity of VEGF Trap-Eye was initially
`demonstrated in a 6-week, sequential, single ascending-
`dose, phase 1 study (CLinical Evaluation of Anti-angiogenesis
`in the Retina Intravitreal Trial [CLEAR-IT 1]) in patients
`with neovascular AMD (Invest Ophthalmol Vis Sci 1751
`[Suppl]:47,2006). After receiving single intravitreal injec-
`tions of VEGF Trap-Eye (0.05– 4 mg), patients showed a
`dose-dependent improvement in visual acuity, which corre-
`lated with anatomic improvement. At 6 weeks, an overall
`mean decrease in foveal thickness of 104.5 ␮m and mean
`increase in visual acuity of 4.4 letters was reported for all
`groups combined. In the 2 highest dose groups (2 and 4 mg)
`combined, best-corrected visual acuity (BCVA) increased
`by a mean of 13.5 letters, and by 6 weeks, vision had
`stabilized or improved in 95% of patients. Anatomic benefits
`and visual gains were maintained out to 12 weeks in 3 of 6
`patients who received single administrations of higher doses.
`Based on these encouraging results from CLEAR-IT 1, a dose-
`and interval-ranging phase 2 study (CLinical Evaluation of
`Anti-angiogenesis in the Retina Intravitreal Trial [CLEAR-IT
`2]) was designed to investigate the safety and biologic effects
`of VEGF Trap-Eye after repeated dosing. The study consisted
`of a fixed-dosing phase during which patients received 1 of 5
`regimens of VEGF Trap-Eye for 12 weeks, followed by as-
`needed (PRN) dosing from weeks 16 through 52. The details
`of the PRN dosing phase are presented in the accompanying
`article.26 The primary endpoint and results from the fixed-
`dosing period are presented herein.
`
`Materials and Methods
`
`Study Design
`The primary objectives of the study were to assess the effect of
`intravitreal VEGF Trap-Eye on central retinal/lesion thickness
`(CR/LT) and to assess the ocular and systemic safety and tolera-
`bility of repeated doses of VEGF Trap-Eye in patients with CNV
`associated with wet AMD. A key secondary objective was to
`assess the effect of VEGF Trap-Eye on BCVA.
`The CLEAR-IT 2 was a prospective, double-masked, random-
`ized study conducted at 33 sites in the United States. Patients were
`enrolled between May 2006 and April 2007. Five groups of ap-
`proximately 30 patients each were randomized in a balanced ratio
`to receive an intravitreal injection of VEGF Trap-Eye 0.5 or 2 mg
`every 4 weeks, (0.5 mg q4wk or 2 mg q4wk) on day 1 and at weeks
`4, 8, and 12 for a total of 4 treatments or 0.5, 2, or 4 mg every 12
`weeks (0.5 mg q12wk, 2 mg q12wk, or 4 mg q12wk) on day 1 and
`week 12 for a total of 2 treatments (Fig 1). The PRN dosing phase
`began at week 16 and continued through week 52.26 The primary
`endpoint (change in CR/LT) and BCVA were assessed at week 12
`(after 1 or 3 doses in the quarterly and monthly dosing groups,
`respectively) and the results of the fixed dosing phase were as-
`sessed at week 16 (after 2 or 4 doses in the quarterly and monthly
`dose groups, respectively). Although the primary endpoint of the
`study was at week 12, results at week 16 were evaluated to assess
`the impact of the final fixed dose from each dose group on
`anatomic outcomes and BCVA.
`
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`Brown et al
`
`䡠 Fixed Dosing with VEGF Trap-Eye for Neovascular AMD
`
`Figure 1. Study design. During the fixed-dosing phase of the CLEAR-IT 2 study, patients were randomized in equal ratios to receive 1 of 5 different
`regimens of VEGF Trap-Eye for 12 weeks: 0.5 or 2 mg every 4 weeks, or 0.5, 2, or 4 mg every 12 weeks. The primary endpoint, change from baseline in
`CR/LT, and a key secondary endpoint, BCVA, was measured at 12 weeks. BCVA ⫽ best-corrected visual acuity; CLEAR-IT ⫽ CLinical Evaluation of
`Anti-angiogenesis in the Retina Intravitreal Trial; CR/LT ⫽ central retinal/lesion thickness; ETDRS ⫽ Early Treatment of Diabetic Retinopathy Study;
`VEGF ⫽ vascular endothelial growth factor.
`
`The study protocol was approved by the institutional review
`board or ethics committee at every institution and was conducted
`according to the recommendations of Good Clinical Practice and
`the Declaration of Helsinki. The study was compliant with the
`rules and regulations under the Health Insurance Portability and
`Accountability Act of 1996. All patients provided written informed
`consent to participate in the study. The CLEAR-IT 2 study is
`registered with ClinicalTrials.gov (NCT00320788).
`
`Study Population
`Patients eligible for the study were ⱖ50 years old, had a diagnosis of
`subfoveal CNV secondary to wet AMD, and met the following
`inclusion criteria: CR/LT ⱖ300 ␮m, Early Treatment of Diabetic
`Retinopathy Study (ETDRS) BCVA letter score of 73 to 34 letters
`(20/40–20/200), loss of ⱖ5 ETDRS letters in BCVA over the pre-
`ceding 6 months for previously treated patients with minimally classic
`or occult lesions, linear diameter of lesion ⱕ5400 ␮m by fluorescein
`angiography, subretinal hemorrhage (if present) sparing the fovea and
`comprising ⱕ50% of total lesion, area of scar ⱕ25% of total lesion,
`and sufficient clarity of ocular media to allow retinal photography.
`Exclusion criteria were vitreous hemorrhage in preceding 4
`weeks; aphakia or pseudophakia with absence of a posterior cap-
`sule (unless as a result of a yttrium aluminum garnet capsulotomy);
`significant subfoveal atrophy or scarring; active ocular inflamma-
`tion; corneal transplant; previous uveitis in either eye; or history of
`macular hole of grade 3 or higher. Patients who had previously
`received any of the following treatments in the study eye were
`excluded: Subfoveal thermal laser therapy, any operative interven-
`tion for AMD, extrafoveal laser coagulation treatment or photo-
`dynamic therapy in preceding 12 weeks, pegaptanib sodium in
`preceding 8 weeks, systemic or intravitreal treatment with VEGF
`Trap-Eye, ranibizumab, or bevacizumab at any time, juxtascleral
`steroids, anecortave acetate, or intravitreal triamcinolone acetonide
`or other steroids in preceding 24 weeks. Additional reasons for
`exclusion were other causes of CNV in either eye; active ocular
`infection; congenital lid anomalies that might interfere with intra-
`vitreal administration; any retinal disease other than CNV in either
`eye; previous trabeculectomy or pars plana vitrectomy; cup-to-disc
`
`ratio ⱖ0.8, intraocular pressure ⬎25 or receipt of ⬎2 agents for
`treatment of glaucoma; allergy to povidone iodine, fluorescein, or
`recombinant proteins; absolute neutrophil count ⬍1000 cells/mm3;
`human immunodeficiency virus positivity, active systemic infec-
`tion requiring antibiotics; proteinuria ⬎1⫹ or urine protein:creati-
`nine ratio ⱖ1 on 2 repeated determinations within 1 week; New
`York Heart Association class III or IV; symptomatic cardiovascular or
`peripheral vascular disease, malignancy other than basal cell carci-
`noma in preceding 2 years; and any other conditions or laboratory
`abnormalities that could interfere with disease assessment or patient
`participation in the study. The use of standard agents or other anti-
`VEGF agents was not permitted before week 16.
`
`Endpoints and Assessments
`The 12-week assessment measured anatomic and visual changes
`after administration of 3 doses of VEGF Trap-Eye in the monthly
`dose group and 1 dose in the quarterly dosing group. All assess-
`ments at week 12 were performed before the planned injection.
`Results at week 16 were evaluated to assess the impact of the final
`fixed dose at week 12 from each dose group on these parameters.
`One eye was designated as the study eye, with all evaluations
`performed on that eye. Criteria, in descending order, for selection of
`the study eye in cases of bilateral exudative AMD were worse visual
`acuity, clearer ocular media, and nondominant eye. If these factors
`were similar in both eyes, the right eye was chosen as the study eye.
`The primary efficacy endpoint was change in CR/LT from
`baseline at 12 weeks, as assessed by Stratus (software version 4.0
`or higher) optical coherence tomography scans (Carl Zeiss Med-
`itec, Inc., Dublin, CA) read at a masked independent central
`reading center (Digital Optical Coherence Tomography Reading
`Center [DOCTR], Cleveland, OH). The CR/LT was defined as the
`distance between the inner limiting membrane and the inner border
`of the retinal pigment epithelium/choriocapillaris complex, includ-
`ing any subretinal fluid and thickness of any observable choroidal
`neovascular membrane or scar tissue in the central 1 mm of the
`posterior pole scan. A posterior pole scan was obtained, consisting
`of a high-resolution 7-mm scan from a single scan line from the
`meridian of the optic disc margin, declined at a 5-degree angle
`
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`Ophthalmology Volume 118, Number 6, June 2011
`
`Table 1. Patient Disposition
`
`No. of Patients
`
`0.5 q4
`
`2 q4
`
`0.5 q12
`
`2 q12
`
`4 q12
`
`Screened
`Randomized
`Treated
`Completed week 12
`Withdrawn by week 12
`
`32
`32
`31
`1
`
`32
`31
`31
`
`32
`32
`31
`1
`
`32
`31
`29
`2
`
`31
`31
`30
`1
`
`All patients
`
`301
`159
`157
`152 (96.8%)
`5 (3.2%)
`
`0.5q4 ⫽ 0.5 mg every 4 weeks; 2q4 ⫽ 2 mg every 4 weeks; 0.5q12 ⫽ 0.5 mg every 12 weeks; 2q12 ⫽ 2 mg every 12
`weeks; 4q12 ⫽ 4 mg every 12 weeks.
`
`through the presumed foveal center. The placement of the scan line
`was based on anatomic landmarks as visualized by a trained,
`certified operator to offer better registration.
`Key secondary endpoints included the change in BCVA as
`measured by ETDRS letter score at 12 weeks and the proportions
`of patients with avoidance of moderate vision loss (loss of ⱕ15
`letters), stabilization, or improvement in visual acuity (gain of ⱖ0
`letters), and significant vision gain (gain of ⱖ15 letters) at 12
`weeks. Certified examiners assessed BCVA using the ETDRS
`protocol (at 4 m). Examiners were masked to treatment assignment
`and performed no other study assessments. Safety was monitored
`with reporting of adverse events (AEs) and serious AEs, clinical
`laboratory tests, vital signs, and ophthalmic examination.
`
`Statistical Analyses
`Efficacy analyses were performed on the full analysis set, which
`included all enrolled patients who underwent baseline and ⱖ1
`postbaseline assessment. The last observation carried-forward
`method was used to impute missing data. The safety analysis set
`included all patients who received study treatment. The primary
`analysis was a paired comparison t test of the change in CR/LT
`from baseline to week 12 for all groups combined. If this was
`significant, an analysis of covariance was done on the 5 individual
`groups. A similar analysis was done for BCVA measurements.
`Results are presented for all 5 treatment groups combined as well
`as for the individual groups.
`
`Results
`
`Disposition
`Patient disposition is shown in Table 1. Among the 159 patients
`who were randomized, 157 received treatment. Two patients, 1
`each in the 2-mg monthly and 2-mg quarterly groups, were with-
`drawn before receiving treatment. Of the 157 patients who re-
`ceived treatment, 152 (96.8%) completed the 12-week visit, and 5
`patients were withdrawn. Reasons for withdrawal were death (n ⫽
`1, 4q12 group), AE (n ⫽ 1, 2q12 group), inability to attend visits
`(n ⫽ 1, 2q12 group), investigator decision (n ⫽ 1, 0.5q12 group),
`and subject request (n ⫽ 1, 0.5q4 group).
`
`Baseline Characteristics
`The study population was representative of the exudative AMD
`population in the United States. The mean age of patients overall
`was 78.2 years (range, 53–94) and a majority were women (62%).
`The duration of disease ranged from 0 to 67 months, with a mean
`of 3.9 months, and 20 patients had received previous treatment
`(photodynamic therapy [n ⫽5], focal laser photocoagulation [n ⫽
`
`1092
`
`4], intravitreal pegaptanib sodium [n ⫽ 3], intravitreal triamcino-
`lone [n ⫽ 1], and combination [n ⫽ 7]). All CNV lesion types
`were represented in the following distribution: Predominantly clas-
`sic (38.2%), minimally classic (23.6%), and occult-no-classic
`(38.2%; Table 2). Of note, the baseline CR/LT was thicker (507
`␮m) in the 4 mg q12wk arm (Table 3).
`
`Primary Endpoint: Change in Central Retinal
`Lesion Thickness
`At week 12, treatment with VEGF Trap-Eye resulted in a signif-
`icant decrease in mean CR/LT of 119 ␮m from baseline in all
`treatment groups combined (P⬍0.0001; Fig 2A). A significant
`mean improvement from baseline was observed as early as week 1
`(⫺103 ␮m for all treatment groups combined; P ⫽ 0.04). The
`significant reduction in CR/LT was observed in each treatment
`group at week 12, with monthly dosing with 0.5 or 2 mg providing
`a more profound and consistent effect (Fig 2B). At 12 weeks, the
`mean reductions in CR/LT with the 0.5 mg q4 wk (⫺153.5 ␮m;
`standard deviation [SD] ⫽ 113.3) and 2 mg q4wk (⫺169.2 ␮m;
`SD ⫽ 138.5) regimens were significantly greater than mean re-
`ductions with each of the quarterly dosing regimens (0.5 mg q4:
`P ⫽ 0.0022, P⬍0.0001, and P ⫽ 0.0255; 2 mg q4: P ⫽ 0.0010,
`P⬍0.0001, and P ⫽ 0.0129 versus 0.5 mg q12, 2 mg q12, and 4
`mg q12, respectively).
`
`Changes in Best-corrected Visual Acuity
`At week 12, BCVA, as measured by ETDRS letters score, showed
`a significant mean increase from baseline of 5.7 letters in all
`
`Table 2. Baseline Demographic and Clinical Characteristics
`
`Characteristic
`
`All Treated Patients (n ⴝ 157)
`
`Age, years (mean [range])
`Gender (%M:%F)
`Disease duration, mos (mean [range])
`Previous treatment
`Lesion size (mean ⫾ SD) in disc
`area
`Lesion type (n [%])
`Predominantly classic
`Minimally classic
`Occult lesions
`Disease status (mean [range])
`Central retinal/lesion thickness
`Foveal thickness
`Best corrected visual acuity
`(ETDRS letters)
`
`78.2 (53-94)
`38:62
`3.9 (0–67)
`20 (12.7%)
`3.11 ⫾ 2.12
`
`60 (38.2)
`37 (23.6)
`60 (38.2)
`
`456 ␮m (186–1316 ␮m)
`327 ␮m (116–1081 ␮m)
`56 (27–83)
`
`ETDRS ⫽ Early Treatment of Diabetic Retinopathy Study; F⫽ Female;
`M ⫽ Male; SD ⫽ standard deviation.
`
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`䡠 Fixed Dosing with VEGF Trap-Eye for Neovascular AMD
`
`Table 3. Baseline Disease Status by Treatment Group
`
`0.5q4 (n ⴝ 32)
`
`2q4 (n ⴝ 31)
`
`0.5q12 (n ⴝ 2)
`
`2q12 (n ⴝ 31)
`
`4q12 (n ⴝ 31)
`
`All groups (n ⴝ 157)
`
`CR/LT (␮m)
`Foveal Thickness (␮m)
`BCVA (ETDRS letters)
`
`434 (282–710)
`329 (212–509)
`54 (27–76)
`
`453 (232–960)
`307 (171–524)
`58 (32–83)
`
`442 (186–762)
`319 (116–559)
`56 (30–72)
`
`447 (265–948)
`334 (186–762)
`57 (32–72)
`
`507 (240–1316)
`360 (177–1081)
`53 (28–80)
`
`456 (186–1316)
`327 (116–1081)
`56 (27–83)
`
`BCVA ⫽ best-corrected visual acuity; CR/LT ⫽ central retinal/lesion thickness; ETDRS ⫽ Early Treatment of Diabetic Retinopathy Study; 0.5q4 ⫽ 0.5
`mg every 4 weeks; 2q4 ⫽ 2 mg every 4 weeks; 0.5q12 ⫽ 0.5 mg every 12 weeks; 2q12 ⫽ 2 mg every 12 weeks; 4q12 ⫽ 4 mg every 12 weeks.
`Values are presented as mean (range).
`
`treatment groups combined (P⬍0.0001; Fig 3A). A significant
`gain in BCVA was noted as early as week 1 (mean gain of 3
`letters). Each treatment group showed an improvement in visual
`acuity at week 12 (Fig 3B). Mean increases were similar among all
`treatment groups at week 8 (Pⱖ0.25 for all pairwise comparisons,
`analysis of covariance), after which in the monthly treatment
`groups of 0.5 mg q4wk and 2 mg q4wk, vision continued to
`improve, with a mean gain of 8.8 (SD ⫽ 9.2) and 8.3 (SD ⫽ 10.1)
`letters, respectively, at week 12. Of note, the mean improvement in
`
`visual acuity at 8 weeks was similar after administration of a single
`2-mg dose (quarterly dose group) or 2 monthly 2-mg doses.
`
`Frequency of Changes in Best-corrected Visual
`Acuity
`After 12 weeks, 98% of patients in all treatment groups combined
`(range, 94%–100% in the individual dose groups) avoided vision
`
`Figure 2. Mean change from baseline in central retinal/lesion thickness
`(CR/LT) for (A) all groups combined and (B) individual dosing groups.
`Change in CR/LT from baseline at 12 weeks was the primary study
`endpoint; in the combined treatment group, a significant decrease of 119
`␮m was observed at week 12. *P⬍0.0001 versus baseline. All treatment
`groups demonstrated a significant reduction in CR/LT from baseline at
`week 12, with the greatest reductions in the monthly dosing groups. The
`last-observation-carried-forward method was used to impute missing data.
`CR/LT ⫽ central retinal/lesion thickness; 0.5q4 ⫽ 0.5 mg every 4 weeks;
`2q4 ⫽ 2 mg every 4 weeks; 0.5q12 ⫽ 0.5 mg every 12 weeks; 2q12 ⫽ 2 mg
`every 12 weeks; 4q12 ⫽ 4 mg every 12 weeks.
`
`Figure 3. Mean change from baseline in best-corrected visual acuity
`(BCVA) for (A) all groups combined and (B) individual dosing groups.
`The combined treatment group showed a significant gain of 5.7 letters
`(P⬍0.0001 versus baseline). The BCVA was improved in all treatment
`groups at week 12, but the greatest improvements were observed in the
`monthly dosing groups. The last observation-carried-forward method was
`used to impute missing data. BCVA ⫽ best corrected visual acuity;
`ETDRS ⫽ Early Treatment of Diabetic Retinopathy Study; 0.5q4 ⫽ 0.5
`mg every 4 weeks; 2q4 ⫽ 2 mg every 4 weeks; 0.5q12 ⫽ 0.5 mg every 12
`weeks; 2q12 ⫽ 2 mg every 12 weeks; 4q12 ⫽ 4 mg every 12 weeks.
`
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`Ophthalmology Volume 118, Number 6, June 2011
`
`Figure 4. Visual acuity changes at weeks 12 and 16. The proportions of patients who avoided moderate vision loss (loss of ⱖ15 letters) or had significant
`vision gain (gain of ⱖ15 letters) in the combined treatment group and individual dosing groups are shown. At both 12 and 16 weeks, only 2% of patients
`in the combined treatment group experienced a loss of ⱖ15 letters, whereas 19% of patients showed a significant gain in vision at 12 weeks; in individual
`treatment groups, the proportions of patients showing a significant gain in vision remained steady or increased at week 16. 0.5q4 ⫽ 0.5 mg every 4 weeks;
`2q4 ⫽ 2 mg every 4 weeks; 0.5q12 ⫽ 0.5 mg every 12 weeks; 2q12 ⫽ 2 mg every 12 weeks; 4q12 ⫽ 4 mg every 12 weeks. Decreases in visual acuity were
`due to retinal pigment epitheliopathy as reported by the investigators (n ⫽ 1), subretinal hemorrhage (n ⫽ 1), retinal hemorrhage (n ⫽ 1), and
`unexplained (n ⫽ 6).
`
`loss of ⱖ15 letters (Fig 4). Overall, 4 patients (2.5%) experienced
`vision loss of ⱖ15 letters, including 2 patients in the 0.5 mg q12wk
`group, 1 patient in the 2 mg q4wk group, and 1 patient in the 4 mg
`q12wk group. In all treatment groups combined, the proportion of
`patients experiencing a clinically significant gain in vision (ⱖ15
`letters) was 19% at week 12. Again, the frequency of clinically
`significant vision gain was highest in the 2 mg q4wk group (26%
`at 12 weeks).
`By week 12, monthly dosing reduced the proportion of patients
`with vision of ⱕ20/200, and all dose regimens of VEGF Trap-Eye
`(Fig 5) increased the proportion of patients with ⱖ20/40 vision.
`The proportion of patients with ⱕ20/200 vision was higher in the
`quarterly treatment groups than in the monthly treatment groups at
`week 12; none of the patients in the 2 mg q4wk group had
`ⱕ20/200 vision (data not shown). Conversely, a lower proportion
`of patients who received quarterly doses achieved ⱖ20/40 vision;
`
`Figure 5. Snellen equivalent of ⱖ20/40 vision. All treatment groups
`showed an increase from baseline in the proportion of patients with
`ⱖ20/40 vision at week 12. The last-observation-carried-forward method
`was used to impute missing data. BL ⫽ baseline; 0.5q4 ⫽ 0.5 mg every 4
`weeks; 2q4 ⫽ 2 mg every 4 weeks; 0.5q12 ⫽ 0.5 mg every 12 weeks; 2q12 ⫽
`2 mg every 12 weeks; 4q12 ⫽ 4 mg every 12 weeks.
`
`1094
`
`the 2 mg q4wk dose group again had the highest proportion of
`patients (58%) with ⱖ20/40 vision.
`
`Results at 16 Weeks (Fixed-Dose Phase)
`Although the primary endpoint was assessed at week 12, the data
`collected at week 16 were indicative of the response to the last
`mandatory injection of the fixed-dosing phase at week 12. In the
`treatment groups combined, a further decrease in CR/LT was noted
`from a mean of ⫺119 ␮m at week 12 to a mean of ⫺160 ␮m at
`week 16 (Fig 2A). In the monthly treatment groups, CR/LT de-
`creased continuously from baseline to week 16; in the quarterly
`treatment group, the reduction in CR/LT was attenuated by week
`12 but was noted again at 16 weeks (after administration of the
`second dose at week 12).
`In addition, the BCVA improved from week 12 to week 16 in
`the combined treatment group and in most individual treatment
`groups (Fig 3B). In the combined treatment group, the BCVA
`improved further, from a mean of 5.7 letters at week 12 to a mean
`of 6.6 letters at week 16. The 0.5-mg and 2-mg monthly dose
`groups showed a continuing and consistent improvement in BCVA
`to week 16. In the quarterly dose groups, the BCVA, which had
`declined by week 12, showed mixed results at week 16, with
`improved acuity in the 0.5- and 4-mg dose groups, but with
`worsened vision in the 2-mg dose group. The proportion of pa-
`tients experiencing a gain of ⱖ15 letters continued to increase
`between weeks 12 and 16 for the overall group (from 19% to 23%)
`and in both monthly dose groups (from 19% to 25% in the 0.5 mg
`q4wk group and from 26% to 39% in the 2 mg q4wk group; Fig 4).
`
`Safety
`The mean total dose administered to each group was consistent
`with the anticipated amount based on the dosing schedule. The
`highest total exposure was in the 2 mg q4wk group, which received
`a mean total of 5.74 mg through week 12. All patients in the
`quarterly dosing groups, and 90.6% and 90.3% in the 0.5 mg q4wk
`
`Exhibit 2094
`Page 06 of 09
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`Brown et al
`
`䡠 Fixed Dosing with VEGF Trap-Eye for Neovascular AMD
`
`Table 4. Adverse Events in the Study Eye (Frequency ⱖ5% in
`All Groups Combined*) at Week 16
`
`Adverse Event
`
`Number (n)
`
`Percent (%)
`
`Conjunctival hemorrhage
`Increased IOP (transient postinjection)
`Refraction disorder
`Retinal hemorrhage
`Eye pain
`Vitreous detachment
`Detachment of retinal pigment
`epithelium
`Visual acuity reduced (patient-
`reported)
`
`42
`22
`16
`14
`12
`11
`9
`
`9
`
`26.8
`14.0
`10.2
`8.9
`7.6
`7.0
`5.7
`
`5.7
`
`IOP ⫽ intraocular pressure.
`*Patients receiving treatment with vascular endothelial growth factor
`Trap-Eye (n ⫽ 157).
`
`and 2 mg q4wk dose groups, respectively, received the required
`doses.
`Most AEs were related to the injection procedure and no ocular
`serious AEs, clinically significant ocular inflammation, or endo-
`phthalmitis was reported in any study eyes during the first 16
`weeks of the study. The ocular AEs that occurred through week 16
`were mild and were similar to those reported for other intravitre-
`ally administered anti-VEGF compounds. An ocular AE was re-
`ported in 70.7% of patients in the treatment groups combined
`(Table 4). In general, fewer patients in the 0.5 mg q12wk and 2 mg
`q12wk groups (62.5% and 74.2%, respectively) reported an ocular
`AE compared with the 0.5 mg q4wk, 2 mg q4wk, and 4 mg q12wk
`groups (68.8%, 67.8%, and 80.7%, respectively).
`Systemic serious AEs were observed in 12 patients. One case of
`angina pectoris (2 mg q4wk group), 2 cases of congestive heart
`failure (0.5 mg q4wk and 2 mg q4wk groups), and 2 cases of
`coronary artery diseases (2 mg q4wk and 4 mg q12wk groups)
`were reported during the treatment period. One death occurred
`during this part of the study from preexisting pulmonary hyper-
`tension. There did not seem to be any relationship between the
`VEGF Trap-Eye dose and the occurrence of any particular AE.
`
`Discussion
`
`During the 12-week fixed-dosing period of this phase 2
`study, intravitreally administered VEGF Trap-Eye demon-
`strated significant anatomic and visual improvements from
`baseline at week 12 after repeated monthly dosing. Treat-
`ment with VEGF Trap-Eye 0.5 mg and 2 mg dosed every 4
`weeks resulted in the greatest improvements in both mea-
`sures at the 12-week endpoint. The CR/LT decreased by a
`mean of ⫺153.5 and ⫺169.2 ␮m from baseline, and BCVA
`mean letter score improved by 8.8 and 8.3 letters with 0.5-
`and 2-mg monthly dosing, respectively. In this index study,
`60% of patients had occult or minimally classic lesions and
`40% had predominantly classic lesions. In the pivotal trials
`of ranibizumab, the improvement in BCVA at 12 weeks
`after fixed monthly dosing was 10.0 and 6.8 letters with 0.5
`and 0.3 mg ranibizumab, respectively, in patients with pre-
`dominantly classic lesions27 and 5.9 and 5.1 letters with 0.5
`mg and 0.3 mg ranibizumab, respectively, in patients with
`minimally classic or occult lesions.28 Although our smaller
`
`study did not compare VEGF Trap-Eye directly with ranibi-
`zumab and cross-trial comparisons must be made with cau-
`tion, the improvements in BCVA with VEGF Trap-Eye are
`of similar magnitude to those noted at 12 weeks after fixed
`dosing with ranibizumab in the larger pivotal trials.27-29
`Both monthly dose groups continued to show anatomic
`and vision i