A Phase I Study of Intravitreal Vascular
`Endothelial Growth Factor Trap-Eye in
`Patients with Neovascular Age-Related
`Macular Degeneration
`
`Quan Dong Nguyen, MD, MSc,1 Syed Mahmood Shah, MBBS,1 David J. Browning, MD,2
`Henry Hudson, MD,3 Peter Sonkin, MD,4 Seenu M. Hariprasad, MD,5 Peter Kaiser, MD,6
`Jason S. Slakter, MD,7 Julia Haller, MD,1 Diana V. Do, MD,1 William F. Mieler, MD,5 Karen Chu, MS,8
`Ke Yang, PhD,8 Avner Ingerman, MD,8 Robert L. Vitti, MD, MBA,8 Alyson J. Berliner, MD, PhD,8
`Jesse M. Cedarbaum, MD,8 Peter A. Campochiaro, MD1
`
`Purpose: To determine the safety, tolerability, maximum tolerated dose, and bioactivity of an intravitreal
`injection of vascular endothelial growth factor (VEGF) Trap-Eye, a fusion protein of binding domains from human
`VEGF receptors 1 and 2 with human immunoglobulin-G Fc that binds VEGF family members, in patients with
`neovascular age-related macular degeneration (AMD).
`Design: Dose-escalation, multicenter, interventional clinical trial.
`Participants: Twenty-one patients (13 female, 8 male) with neovascular AMD (NVAMD) and lesions ⱕ12 disc
`areas in size and ⱖ50% active choroidal neovascularization (CNV) with best-corrected visual acuity (BCVA)
`ⱕ20/40 received a single intraocular injection of 0.05 mg (n ⫽ 3), 0.15 mg (n ⫽ 3), 0.5 mg (n ⫽ 3), 1 mg (n⫽ 6),
`2 mg (n⫽ 3), or 4 mg (n⫽ 3) of VEGF Trap-Eye.
`Methods: Safety assessments included eye examinations, vital signs, and laboratory tests. Measures of
`bioactivity included changes from baseline in BCVA, optical coherence tomography (OCT), and fluorescein
`angiography. The primary end point was 6 weeks and patients were followed up for 12 weeks.
`Main Outcome Measure: Safety assessments.
`Results: There were no serious adverse events and no identifiable intraocular inflammation. The mean
`decrease in excess foveal thickness for all patients was 104.5 ␮m at 6 weeks, and the mean increase in visual
`acuity was 4.43 letters. In the 2 highest dose groups combined (2 and 4 mg), the mean increase in BCVA was
`13.5 letters, with 3 of 6 patients demonstrating improvement of ⱖ3 lines and 3 patients requiring no adjunctive
`treatment of any type for 12 weeks. Some showed elimination of fluorescein leakage and reduction in area of
`CNV.
`Conclusions:
`injection of up to 4 mg of VEGF Trap-Eye in patients with NVAMD was well
`Intravitreal
`tolerated with no evidence of ocular inflammation. Although the number of patients in each cohort was small,
`there was evidence of bioactivity, because several patients, especially those receiving 2 or 4 mg of VEGF
`Trap-Eye, showed substantial improvement in BCVA associated with reductions in foveal thickness. Phase III
`trials to investigate the efficacy of intraocular VEGF Trap-Eye in patients with NVAMD are under way.
`Financial Disclosure(s): Proprietary or commercial disclosure may be found after
`the references.
`Ophthalmology 2009;116:2141–2148 © 2009 by the American Academy of Ophthalmology.
`
`Age-related macular degeneration (AMD) is the most
`common cause of severe vision loss in patients aged more
`than 60 years in developed countries.1 Patients with non-
`neovascular AMD are at risk for development of choroi-
`dal neovascularization (CNV) and thereby converting to
`neovascular AMD (NVAMD). Patients with NVAMD ac-
`count for only approximately 10% of patients with AMD, but
`they account for the majority of severe vision loss.1
`The pathogenic events underlying conversion from non-
`neovascular to NVAMD are uncertain, but studies in animal
`
`models suggest that increased expression of vascular endo-
`thelial growth factor (VEGF) is likely to play a critical role.
`Inhibition of VEGF receptor signaling by systemic admin-
`istration of kinase inhibitors2 or blockade of VEGF by
`intraocular injection of an anti-VEGF antibody fragment3
`significantly suppresses CNV in animal models. These data
`suggest that VEGF is an important therapeutic target for
`treatment of CNV. This concept has been confirmed in
`clinical trials testing the effects of VEGF antagonists in
`patients with NVAMD. Intraocular injections of pegaptanib
`
`© 2009 by the American Academy of Ophthalmology
`Published by Elsevier Inc.
`
`ISSN 0161-6420/09/$–see front matter
`doi:10.1016/j.ophtha.2009.04.030
`
`2141
`
`0001
`
`CELLTRION - EXHIBIT 1005
`
`

`

`Ophthalmology Volume 116, Number 11, November 2009
`
`(Macugen, OSI Pharmaceuticals, Melville, NY), an aptamer
`that specifically binds VEGF165, every 6 weeks for 1 year in
`patients with NVAMD reduced the percentage of patients
`who experienced severe loss of vision (ⱖ15 letters) from
`45% in the sham injection group to 30% but did not lead to
`significant improvement in vision.4 Monthly intraocular in-
`jections of ranibizumab (Lucentis, Genentech, San Francisco,
`CA), a Fab fragment of an antibody that binds all isoforms of
`VEGF-A, reduced the percentage of patients who had severe
`loss of vision to 5% and caused significant improvement in
`visual acuity (VA) in 34% to 40%.5,6 It is not certain why
`ranibizumab is so superior to pegaptanib, but one possibility is
`that other isoforms of VEGF in addition to VEGF165 play an
`important role in the pathogenesis of CNV.
`There are a number of gene products that share homol-
`ogy with VEGF-A and have similar activities because they
`activate VEGF receptor 1 or 2. The genes that code for
`VEGF-A and these other proteins, VEGF-B, C, and D, and
`placental growth factors 1 and 2, constitute the VEGF gene
`family. The role of VEGF family members other than
`VEGF-A in ocular neovascularization has not been com-
`pletely elucidated, but there is evidence to suggest that
`placental growth factor 1 participates.7
`VEGF Trap is a recombinant protein in which the bind-
`ing domains of VEGF receptors 1 and 2 are combined with
`the Fc portion of immunoglobulin-G. The receptor portion
`of the molecule has a high affinity for all VEGF-A isoforms
`(Kd⬍1 pM), placental growth factors 1 and 2, and VEGF-B.8
`Therefore, VEGF Trap is distinguished from ranibizumab
`by its higher binding affinity for all VEGF-A isoforms and
`its ability to inhibit other VEGF family members. A ran-
`domized, multicenter, placebo-controlled clinical trial in-
`vestigating the effect of intravenous VEGF Trap in patients
`with NVAMD showed elimination of approximately 60% of
`excess retinal thickness after either single or multiple infu-
`sions.9 The maximum tolerated dose of intravenous VEGF
`Trap in this study population was 1.0 mg/kg; at 3 mg/kg,
`hypertension and proteinuria, which are class effects of
`
`systemic anti-VEGF therapy, were noted. Thus, alternative
`routes of delivery to increase therapeutic window and to
`decrease adverse events, were investigated.
`Intravitreal administration of VEGF Trap strongly sup-
`pressed laser-induced CNV in mice10 and primates (Wie-
`gand et al. ARVO abstract 1411, 2005). These findings led
`to the development of a formulation for intraocular delivery,
`VEGF Trap-Eye, a formulation using ultra-purified VEGF
`Trap with a combination and concentration of buffers com-
`patible with ocular tissues. In primate toxicology studies,
`there were no systemic safety signals after intraocular in-
`jections of VEGF Trap-Eye, and there was an excellent
`ocular safety profile based on ocular examinations, color
`photography, fluorescein angiography (FA), electroretinog-
`raphy, and postmortem microscopic examination of ocular
`tissues.11 The only abnormality identified was mild, revers-
`ible inflammation in the anterior chamber and vitreous in
`some primates after intraocular injection, clearing the way
`for the Phase 1 clinical trial reported.
`
`Materials and Methods
`
`Study Design
`
`The study was conducted at 5 study sites in compliance with the
`Declaration of Helsinki, US Code 21 of Federal Regulations, and
`the Harmonized Tripartite Guidelines for Good Clinical Practice
`(1996) and was reviewed and approved by the Western Institu-
`tional Review Board. A dose-escalation design was used to inves-
`tigate 6 doses of VEGF Trap-Eye (0.05, 0.15, 0.5, 1, 2, and 4 mg)
`in patients with subfoveal CNV due to NVAMD. There was a
`2-week waiting period after dosing the last patient in each cohort
`and dosing the first patient in the next cohort to watch for safety
`signals. Six weeks after injection of VEGF Trap-Eye, patients
`returned to standard care and were able to receive any treatment
`judged to be indicated by the investigator. Patients were monitored
`for 12 weeks after intravitreal VEGF Trap-Eye administration as
`part of the active phase of the study but were monitored for safety
`with eye examinations every 3 months for 1 year.
`
`Table 2. Baseline Characteristics of the Study Population
`
`Parameters
`
`Age
`BCVA*
`Snellen equivalent
`Foveal thickness† (automated, fast macular scans)
`
`78 yrs
`
`Mean
`
`39.3
`⬃20/160
`375 ␮m
`
`552 ␮m
`
`Range
`
`67–88 yrs
`0–72
`20/40 to ⬎20/800
`259 – 616 ␮m
`(normal ⫽ 179 ␮m)
`332–1021 ␮m
`(normal ⫽ 270 ␮m)
`
`Foveal ⫹ lesion thickness (manual, posterior pole scans)
`
`No. of prior treatments in study eye (PDT ⫾ steroids,
`pegaptanib, or investigational small interfering RNA)
`Lesion type
`
`Gender
`Study eye
`
`None: 10 patients
`ⱖ1: 11 patients
`Classic: 3 (14%)
`Occult: 8 (38%)
`Minimally classic: 6 (29%)
`Predominantly classic: 4 (19%)
`13 female : 8 male
`11 left : 10 right
`
`BCVA ⫽ best-corrected visual acuity; PDT ⫽ photodynamic therapy; VA ⫽ visual acuity.
`*Early Treatment Diabetic Retinopathy Study letters read as measured by electronic VA.
`†Scans were gradable in 20 of 21 patients.
`
`2142
`
`0002
`
`

`

`Nguyen et al
`
`䡠 VEGF Trap-Eye in Patients with Neovascular AMD
`
`Study Population
`The main inclusion criteria for the study were as follows: (1) male
`or female (any ethnicity), 50 years of age or older; (2) diagnosis of
`NVAMD in the study eye with leaking subfoveal CNV ⱕ12 disc
`areas (measured according to the protocol of the Macular Photo-
`coagulation Study);12 (3) best-corrected visual acuity (BCVA) of
`20/40 or worse; and 4) central subfield thickness ⱖ250 ␮m mea-
`sured by optical coherence tomography (OCT). Other inclusion
`criteria and exclusion criteria are listed in Table 1 (available at
`http://aaojournal.org).
`
`Intravitreal Administration of Vascular
`Endothelial Growth Factor Trap-Eye
`and Study Activities
`A sterile lid speculum was inserted, topical anesthesia was applied,
`and the conjunctiva was irrigated with 5% povidone iodine. After
`additional local anesthesia, a 30-gauge needle was inserted through
`the pars plana and 100 ␮l containing a prespecified amount of
`VEGF Trap-Eye was injected into the vitreous cavity. Funduscopic
`examination was done to confirm retinal perfusion, and the patients
`were observed for 1 hour or until intraocular pressure returned to
`
`normal. Patients were closely monitored for safety and tolerability
`using the following assessments and procedures: BCVA; slit-lamp
`biomicroscopy;
`indirect ophthalmoscopy;
`tonometry; adverse
`events reporting; vital signs; physical examinations; serum elec-
`trolytes; creatinine; quantitative protein determination in 24-hour
`urine specimens; and measurement of serum neutralizing antibod-
`ies directed against VEGF Trap-Eye. Stereoscopic color fundus
`photographs and FA were performed at baseline and week 6.
`Optical coherence tomography was performed at each study visit.
`
`Optical Coherence Tomography
`
`The Digital Angiographic Reading Center (DARC, New York,
`NY) analyzed fluorescein angiograms, and the DARC/Digital OCT
`Reading Center (Cleveland, OH) analyzed OCT scans. All images
`were evaluated with the grader masked with respect to treatment
`group. Optical coherence tomography was performed using
`StratusOCT (Carl Zeiss Meditec, Dublin, CA). The Digital OCT
`Reading Center provided detailed instruction in the protocol for
`image acquisition. Standard protocol (6-mm fast macular thickness
`map and 6⫻6-mm cross-hair) was used. Foveal thickness (in
`micrometers, defined as the mean height of the neurosensory retina
`in a central 1-mm diameter area) and total macular volume (in
`
`Figure 1. Color fundus photographs, fluorescein angiograms, and OCT at baseline and 6 weeks (Day 43) after intravitreous injection of 1 mg (Patient 1),
`2 mg (Patient 2), or 4 mg (Patient 3) of vascular endothelial growth factor Trap-Eye. OCT ⫽ optical coherence tomography.
`
`2143
`
`0003
`
`

`

`Ophthalmology Volume 116, Number 11, November 2009
`
`cubic millimeters) were automatically computed by the StratusOCT
`software version 4.0. The median baseline central retinal/lesion
`thickness was measured by masked graders.
`
`Fluorescein Angiography
`High-resolution digital FA was performed using a Zeiss FF4
`fundus camera (Carl Zeiss, Oberkochen, Germany) attached to a
`Medical Research Professionals (Boston, MA) capture station. A
`modified FA acquisition protocol was used for image acquisition,
`and compliance was monitored by a site visit. Digital images of FA
`were then sent to the DARC for analyses.
`
`Data Analysis
`Analyses of biological activity included central retinal/lesion
`thickness, foveal thickness as assessed by OCT, CNV area and
`
`total lesion size assessed by FA, and VA. The primary analyses
`included assessment of change from baseline in bioeffect variables
`at Day 43. Mean changes from baseline at each visit were dis-
`played. Analyses were also performed by pooled dose groups of
`low (0.05, 0.15, and 0.5 mg), intermediate (1.0 mg), and high (2.0
`and 4.0 mg) doses to show the bioeffect at different dose levels.
`The number of patients who needed additional treatments after the
`primary end point was determined and evaluated with regard to
`their bioeffect. All data including images were made available to
`the investigators.
`
`Results
`
`The baseline characteristics of the 21 patients included in the study
`are listed in Table 2. Although the majority of the patients had
`
`Figure 2. Changes in foveal thickness or combined foveal and lesion thickness after a single injection of VEGF Trap-Eye. Patients received a single
`intraocular injection of 1 of 6 doses of VEGF Trap-Eye and at several time points after injection had Fast Macular OCT scans to measure central subfield
`foveal thickness (A, B) and posterior pole scans to measure combined foveal and lesion thickness (C, D). Data are shown for 20 of 21 study patients who
`had gradable scans. The mean change from baseline in foveal thickness for all patients was substantially reduced 1 week (Day 8) after injection, was
`maximally reduced by 2 weeks (Day 15), and remained stable between 2 and 6 weeks (Day 43) (A). Stratification into low- (0.05, 0.15, and 0.5 mg),
`intermediate- (1.0 mg), and high- (2.0 and 4.0 mg) dose groups of VEGF Trap-Eye showed minimal effect in the low-dose group, whereas the intermediate
`and high-dose groups showed substantial and comparable reductions in foveal thickness (B). The mean change from baseline in combined foveal and lesion
`thickness was similar to that for foveal thickness between baseline and 2 weeks (Day 15) but regressed somewhat between 2 and 6 weeks (Day 43) (C).
`The mean reduction from baseline in lesion and foveal thickness was greater in the intermediate- and high-dose groups compared with the low-dose group
`(D). OCT ⫽ optical coherence tomography; VEGF ⫽ vascular endothelial growth factor.
`
`2144
`
`0004
`
`

`

`Nguyen et al
`
`䡠 VEGF Trap-Eye in Patients with Neovascular AMD
`
`received prior treatments for their NVAMD, an effort was made to
`determine the presence of classic or occult CNV within lesions.
`
`Safety
`There were no ocular serious adverse events or evidence of in-
`flammation. There were also no systemic serious adverse events or
`changes in laboratory values. There was no dose-limiting toxicity,
`and a maximum tolerated dose was not identified.
`
`Fluorescein Angiography and Optical Coherence
`Tomography
`Many of the patients in this study had advanced disease with
`substantial subretinal fibrosis and a poor visual prognosis but had
`active CNV in addition to subretinal fibrosis, allowing some as-
`sessments of drug effects. Because of advanced disease, not all
`fluorescein angiograms were able to be assessed for changes in
`lesion characteristics or size. Figure 1 shows fluorescein angio-
`grams and OCT scans at baseline and 6 weeks after intravitreous
`injection of VEGF Trap-Eye in 3 patients. One patient (Patient 1)
`had 20/400 vision due to a large CNV lesion that showed substan-
`tial leakage during the late phase of the angiogram and moderate
`thickening of the overlying retina on OCT (Fig 1, column 1). Six
`weeks after injection of 0.5 mg of VEGF Trap-Eye, BCVA was
`20/320 and there was less filling of the CNV, as illustrated by areas
`of relative hypofluorescence, reduced leakage shown by less fuzzi-
`ness of most regions of the lesion, and decreased macular thick-
`ening on OCT (Fig 1, column 2). Another patient (Patient 2) had
`BCVA of 20/400 and showed a small region of classic CNV
`associated with a larger temporal arc of occult CNV and substan-
`tial leakage, as illustrated by fuzziness during the late phase of the
`angiogram and a pocket of intraretinal fluid on OCT (Fig 1,
`column 3). Six weeks after injection of 1 mg of VEGF Trap-Eye,
`BCVA was 20/250, the small area of classic CNV stained but did
`not leak, and the occult CNV was indiscernible, suggesting pos-
`sible regression (Fig 1, column 4). The pocket of intraretinal fluid
`seen on the baseline OCT scan was eliminated. At baseline, a third
`patient (Patient 3) had BCVA of 20/800 due to a large lesion
`containing central subretinal fibrosis surrounded by active CNV
`associated with subretinal hemorrhage (Fig 1, column 5). There
`was staining of the fibrosis and leakage from the surrounding
`CNV, which appeared fuzzy during the late phase of the angio-
`gram, and the OCT showed subretinal and intraretinal fluid. Six
`weeks after injection of 4 mg of VEGF Trap-Eye, BCVA was
`20/320, the subretinal fibrosis was more defined on the color
`photograph and still stained during FA, but the surrounding CNV
`was gone, suggesting regression or contraction. There was no
`leakage, and OCT showed resolution of subretinal fluid and min-
`imal intraretinal fluid (Fig 1, column 6).
`
`Changes in Optical Coherence Tomography
`Measurements
`The OCT scans from 20 patients were analyzed by the reading
`center; by mistake 1 patient did not receive an OCT at baseline and
`therefore could not be included in the analysis. The mean decrease
`in foveal thickness at 6 weeks for all patients across all 6 doses of
`VEGF Trap-Eye was 104.5 ␮m (Fig 2A). Patients were divided
`into those receiving low (0.05, 0.15, and 0.5 mg), intermediate (1.0
`mg), and high (2.0 and 4.0 mg) doses of VEGF Trap-Eye. Patients
`injected with 1.0 mg or greater of VEGF Trap-Eye showed a
`substantially greater reduction in foveal thickness compared with
`those injected with 0.5 mg or less (Fig 2B).
`Posterior pole scans measure thickness in the CNV complex,
`subretinal fluid, and retinal thickness. The reduction in this com-
`
`bined measure of lesion and foveal thickness after injection of
`VEGF Trap-Eye was similar to but somewhat less than that for
`foveal thickness.
`As was true for foveal thickness, the reduction in combined
`foveal and lesion thickness was greater for those patients injected
`with 1.0 mg or more of VEGF Trap-Eye compared with those
`injected with 0.5 mg or less (Fig 2D).
`
`Changes in Visual Acuity
`Ninety-five percent of patients injected with any dose of VEGF
`Trap-Eye showed stable or improved vision at 6 weeks, and the
`mean increase in VA was 4.7 letters (Fig 3A). Only 1 patient
`showed a reduction in BCVA 6 weeks after injection of VEGF
`
`Figure 3. Change in BCVA from baseline after a single intraocular
`injection of VEGF Trap-Eye. Patients received a single intraocular injec-
`tion of 1 of 6 doses of VEGF Trap-Eye and at several time points after
`injection had BCVA measured by the Early Treatment Diabetic Retinop-
`athy Study protocol. A, The mean (⫾ standard error of the mean) change
`in number of letters read at 4 m (not change in Early Treatment Diabetic
`Retinopathy Study VA score) for all patients showed an improvement of
`approximately 1 line at 6 weeks (Day 43). B, Stratification into low- (0.05,
`0.15, and 0.5 mg), intermediate- (1.0 mg), and high- (2.0 and 4.0 mg) dose
`groups of VEGF Trap-Eye showed negligible change in the low-dose group,
`1 letter in the intermediate and 13.5 letters in the high-dose group.
`BCVA ⫽ best-corrected visual acuity; ETDRS ⫽ Early Treatment Dia-
`betic Retinopathy Study; VA ⫽ visual acuity; VEGF ⫽ vascular endothe-
`lial growth factor.
`
`2145
`
`0005
`
`

`

`Ophthalmology Volume 116, Number 11, November 2009
`
`Trap-Eye; that patient received a 1.0 mg injection and had a
`reduction of 18 letters. Patients in the low and intermediate dose
`groups had a mean increase in VA of 1 letter. Patients in the
`high-dose group had a mean increase in VA of 13.5 letters with 3
`of the 6 patients improved by 3 or more lines (Fig 3B).
`
`Need for Additional Treatment 6 Weeks after Injection
`of Vascular Endothelial Growth Factor Trap-Eye
`Nine of 21 patients received other treatment in the study eye 6
`weeks after injection of VEGF Trap-Eye, and 1 patient received
`
`Figure 4. Changes in foveal thickness and BCVA at all time points to 12 weeks (Day 85) in patients treated with 2 or 4 mg of VEGF Trap-Eye. A, B,
`Change from baseline in central subfield foveal thickness and combined foveal and lesion size thickness, respectively, in 3 patients who showed no
`evidence of recurrent leakage at 6 weeks (Day 43). Relative stability is demonstrated between 1 and 12 weeks (Day 85) after a single injection. C, Change
`from baseline in BCVA measured as number of letters read at 4 m in 3patients who showed no evidence of recurrent leakage at 6 weeks (Day 15). Relative
`stability is demonstrated between 1 and 12 weeks (Day 85) after a single injection. D, E, Change from baseline in central subfield thickness combined
`foveal and lesion size thickness, respectively, in 3 patients who showed recurrent leakage at 6 (Day 43) weeks and required an intraocular injection of
`bevacizumab. F, Change from baseline in BCVA in 3 patients who showed recurrent leakage at 6 (Day 43) weeks and required an intraocular injection
`of bevacizumab. BCVA ⫽ best-corrected visual acuity; VEGF ⫽ vascular endothelial growth factor.
`
`2146
`
`0006
`
`

`

`Nguyen et al
`
`䡠 VEGF Trap-Eye in Patients with Neovascular AMD
`
`additional treatment at 4 weeks. Among the 6 patients injected
`with 2 or 4 mg of VEGF Trap-Eye, 3 had no evidence of leakage
`and no increase in foveal and combined lesion thickness at 6 weeks
`(Fig 4A, B), whereas 3 showed leakage and an increase in foveal
`and combined lesion thickness between 4 and 6 weeks and thus
`received an intraocular injection of 1.25 mg of bevacizumab (Fig
`4D, E). The 3 patients who did not require treatment at 6 weeks
`were still stable with regard to foveal and combined lesion thick-
`ness (Fig 4A, B) and VA (Fig 4C) at 12 weeks. One of the patients
`in the high-dose VEGF Trap-Eye group who required additional
`treatment at 6 weeks showed improvement in VA from baseline of
`20 letters despite the need for additional treatment, and this benefit
`was maintained 6 weeks after the injection of bevacizumab (Fig 4F).
`
`Discussion
`
`Intravenous infusions of VEGF Trap showed evidence of
`biologic activity in patients with NVAMD by reducing
`excess foveal thickness and halting progression of CNV, but
`infusions of 3 mg/kg were complicated by hypertension.9 In
`this study, VEGF Trap specifically formulated for intraoc-
`ular injection, VEGF Trap-Eye, was investigated in patients
`with NVAMD. After a single intraocular injection of doses
`ranging from 0.05 to 4 mg of VEGF Trap-Eye, there were
`no ocular or systemic serious adverse events and none of the
`patients showed any hypertension or proteinuria. There was
`no intraocular inflammation or other significant problems in
`the eye. Thus, a single intraocular injection of up to 4 mg of
`VEGF Trap-Eye appears safe and well tolerated.
`Optical coherence tomography is an outstanding tool for
`assessing effects of drugs on CNV because it provides an
`objective measure of the amount of fluid within or under the
`retina. Excess foveal thickness is a measure of excess fluid
`within the retina, and it was substantially reduced in a
`dose-dependent manner after intraocular injection of VEGF
`Trap-Eye. There were modest effects after single injections
`of 0.05 to 0.5 mg and substantial effects after single injec-
`tions of 1.0 to 4.0 mg. Foveal thickness is completely
`objective because it is calculated by the software, but it
`suffers from errors in recognizing correct retinal borders
`and does not take into account the thickness of CNV lesions
`and subretinal fluid. Masked grading of combined thickness
`of CNV lesions and overlying retina takes into account fluid
`beneath the retina, as well as fluid within the retina, and this
`parameter was also reduced in a dose-dependent manner by
`injections of VEGF Trap-Eye. This improvement in ana-
`tomic outcome measures was accompanied by evidence of
`functional improvement in VA, which was also most prom-
`inent after injections of 1.0 mg or more of VEGF Trap-Eye.
`Four of 6 patients treated with 2.0 or 4.0 mg of VEGF
`Trap-Eye improved by 3 or more lines on an Early Treat-
`ment Diabetic Retinopathy Study VA chart. Despite the
`lack of a placebo control group, the magnitude of these
`improvements in VA, their dose-dependency, and their cor-
`relation with anatomic improvement all strongly indicate
`that they represent true VEGF Trap-Eye–related effects and
`not random changes.
`Patients were evaluated for the need for adjunctive treat-
`ments 6 weeks after injection of VEGF Trap-Eye. Three of
`6 patients who had received 2 or 4 mg showed no evidence
`
`of recurrent leakage or increase in foveal thickness between
`2 and 6 weeks. These patients continued to show no leakage
`and maintained gains in VA at 12 weeks after injection,
`suggesting that a single injection of 2 or 4 mg may have
`persistent effects for 3 months in some patients.
`Many of the patients had substantial subretinal fibrosis,
`making grading of FAs difficult, but as exemplified in
`Figure 1, some patients who received 1 mg or more of
`VEGF Trap-Eye showed marked reduction in fluorescein
`leakage correlating with decreased central retinal thickening
`on OCT. Reduced leakage indicating resorption of intrareti-
`nal and subretinal fluid is a well-recognized class effect of
`VEGF antagonists in patients with NVAMD.5 In addition,
`some patients (see Patients 2 and 3 in Fig 1) showed areas
`of CNV seen at baseline that were no longer distinguishable
`at 6 weeks after injection of VEGF Trap-Eye, suggesting the
`possibility of regression of CNV. Although the results are
`preliminary and must be confirmed, they raise the possibil-
`ity that VEGF family members other than VEGF-A may
`contribute to survival of endothelial cells in CNV in patients
`with NVAMD and that by blocking multiple VEGF family
`members, partial regression of CNV may occur. Partial
`regression may delay the recurrence of leakage, therefore
`prolonging the therapeutic effects of the drug. In diseases
`other than AMD, such as pathologic myopia and ocular
`histoplasmosis, endothelial cells in CNV may show greater
`dependence on VEGF-A for survival than is the case in
`patients with NVAMD, because partial regression of CNV
`was seen after systemic infusions of bevacizumab.13 In that
`setting, partial regression of CNV was also associated with
`prolonged leakage-free periods.
`In conclusion, the results of this study are encouraging
`and intriguing, and they raise many questions. How often
`does intraocular injection of VEGF Trap-Eye cause par-
`tial regression of CNV in patients with NVAMD and how
`strongly is it correlated with prolonged leakage-free pe-
`riods? Can repeated injections of VEGF Trap-Eye pro-
`mote further regression CNV? What is an appropriate
`interval between injections? Will repeated injections re-
`sult in retinal toxicity? What are the long-term effects of
`VEGF Trap-Eye on VA in patients with NVAMD? These
`questions and others are being addressed in ongoing
`clinical trials.
`
`References
`
`1. Klein R, Klein BE, Linton KP, DeMets DL. The Beaver Dam
`Eye Study: the relation of age-related maculopathy to smok-
`ing. Am J Epidemiol 1993;137:190 –200.
`2. Kwak N, Okamoto N, Wood JM, Campochiaro PA. VEGF is
`major stimulator in model of choroidal neovascularization.
`Invest Ophthalmol Vis Sci 2000;41:3158 – 64.
`3. Kryzstolik MG, Afshari MA, Adamis AP, et al. Prevention of
`experimental choroidal neovascularization with intravitreal
`anti-vascular endothelial growth factor antibody fragment.
`Arch Ophthalmol 2002;120:338 – 46.
`4. Gragoudas ES, Adamis AP, Cunningham ET Jr, et al, VEGF
`Inhibition Study in Ocular Neovascularization Clinical Trial
`Group. Pegaptanib for neovascular age-related macular degen-
`eration. N Engl J Med 2004;351:2805–16.
`
`2147
`
`0007
`
`

`

`Ophthalmology Volume 116, Number 11, November 2009
`
`5. Rosenfeld PJ, Brown DM, Heier JS, et al, MARINA Study
`Group. Ranibizumab for neovascular age-related macular de-
`generation. N Engl J Med 2006;355:1419 –31.
`6. Brown DM, Kaiser PK, Michels M, et al, ANCHOR Study
`Group. Ranibizumab versus verteporfin for neovascular
`age-related macular degeneration. N Engl J Med 2006;355:
`1432– 44.
`7. Carmeliet P, Moons L, Luttun A, et al. Synergism between
`vascular endothelial growth factor and placental growth factor
`contributes to angiogenesis and plasma extravasation in patho-
`logical conditions. Nat Med 2001;7:575– 83.
`8. Holash J, Davis S, Papadoupoulos N, et al. VEGF-Trap: a
`VEGF blocker with potent antitumor effects. Proc Natl Acad
`Sci U S A2002;99:11393– 8.
`9. Nguyen QD, Shah SM, Hafiz G, et al, CLEAR-AMD 1 Study
`Group. A phase 1 trial of intravenously administered vascular
`endothelial growth factor Trap for treatment in patients with
`
`choroidal neovascularization due to age-related macular
`degeneration. Ophthalmology 2006;113:1522–32.
`10. Saishin Y, Saishin Y, Takahashi K, et al. VEGF-TRAP(R1R2)
`suppresses choroidal neovascularization and VEGF-induced
`breakdown of the blood-retinal barrier. J Cell Physiol 2003;
`195:241– 8.
`11. Zimmer E, Christian BJ, Miller PE, et al. Safety evaluation of
`intravitreal administration of VEGF trap in Cynomolgus monkeys
`for 13 weeks. Invest Ophthalmol Vis Sci 2006;47:E-Abstract 1751.
`12. Macular Photocoagulation Study Group. Argon laser photo-
`coagulation for neovascular maculopathy: five year results
`from randomized clinical trials. Arch Ophthalmol 1991;109:
`1109 –14.
`13. Nguyen QD, Shah SM, Hafiz G, et al. Intravenous bevaci-
`zumab causes regression of choroidal neovascularization sec-
`ondary to diseases other than age-related macular degenera-
`tion. Am J Ophthalmol 2008;145:257– 66.
`
`Footnotes and Financial Disclosures
`
`Originally received: January 20, 2009.
`Final revision: April 12, 2009.
`Accepted: April 15, 2009.
`Manuscript no. 2009-85.
`Available online: August 22, 2009.
`1 Johns Hopkins Wilmer Eye Institute, Baltimore, Maryland.
`2 Charlotte Eye, Ear, Nose, and Throat Associates, Charlotte, North Carolina.
`3 Retina Center, PC, Tucson, Arizona.
`4 Retina-Vitreous Associates, PC, Nashville, Tennessee.
`5 University of Chicago, Chicago, Illinois.
`6 Cleveland Clinic Foundation, Cleveland, Ohio.
`7 Vitreous Retina Macula Consultants of New York, New York.
`8 Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
`Financial Disclosure(s):
`The author(s) have made the following disclosure(s):
`QDN is a recipient of a K23 Career Development Award (EY 13552) from the
`National Eye Institute. PAC is the George S. and Dolores Dore Eccles
`
`Professor of Ophthalmology and Neuroscience. QDN is on the Steering
`Committee for the phase 3 studies of VEGF Trap-Eye for NVAMD.
`PAC is on the Safety and Data Monitoring Board for the Regeneron
`Phase 3 trial of VEGF Trap-Eye for NVAMD, but was not during the
`time frame of this study. QDN and the Johns Hopkins University have
`received research funding from Regeneron to support the studies of
`VEGF Trap-Eye in retinal vascular diseases. KC, KY, AI, RV, and JC
`were employees of Regeneron during the conduct of the study, which
`has a commercial interest in VEGF Trap-Eye. JSS received research
`grant support and travel reimbursement from Regeneron.
`
`Presented in part at: the Meeting of the American Academy of Ophthal-
`mology, November 2006, Las Vegas, Nevada.
`
`Correspondence:
`Peter A. Campochiaro, MD, Maumenee 719, The Wilmer Eye Institute,
`The Johns Hopkins University School of Medicine, 600 North Wolfe
`Street, Baltimore, MD 21287-9277. E-mail: pcampo@jhmi.edu.
`
`2148
`
`0008
`
`

`

`Nguyen et al
`
`䡠 VEGF Trap-Eye in Patients with Neovascular AMD
`
`Table 1. Additional Inclusion and Exclusion Criteria
`
`Inclusion Criteria
`(1) Patients eligible for a standard therapy were recommended to have it and could only participate if they refused standard therapy.
`(2) For men and women of childbearing potential, willingness to use adequate contraception from screening to 12 weeks after the last dose of
`VEGF Trap or pegaptanib sodi