The DA VINCI Study: Phase 2 Primary
`Results of VEGF Trap-Eye in Patients with
`Diabetic Macular Edema
`
`Diana V. Do, MD,1 Ursula Schmidt-Erfurth, MD,2 Victor H. Gonzalez, MD,3 Carmelina M. Gordon, MD,4
`Michael Tolentino, MD,5 Alyson J. Berliner, MD, PhD,6 Robert Vitti, MD, MBA,5 Rene Rückert, MD,7
`Rupert Sandbrink, MD, PhD,7,8 David Stein, BS,6 Ke Yang, PhD,6 Karola Beckmann, MSc,7 Jeff S. Heier, MD9
`
`Purpose: To determine whether different doses and dosing regimens of intravitreal vascular endothelial
`growth factor (VEGF) Trap-Eye are superior to focal/grid photocoagulation in eyes with diabetic macular edema
`(DME).
`Design: Multicenter, randomized, double-masked, phase 2 clinical trial.
`Participants: A total of 221 diabetic patients with clinically significant macular edema involving the central
`macula.
`Methods: Patients were assigned to 1 of 5 treatment regimens: 0.5 mg VEGF Trap-Eye every 4 weeks; 2 mg
`VEGF Trap-Eye every 4 weeks; 2 mg VEGF Trap-Eye for 3 initial monthly doses and then every 8 weeks; 2 mg
`VEGF Trap-Eye for 3 initial monthly doses and then on an as-needed (PRN) basis; or macular laser photocoag-
`ulation. Assessments were completed at baseline and every 4 weeks thereafter.
`Main Outcome Measures: Mean change in visual acuity and central retinal thickness (CRT) at 24 weeks.
`Results: Patients in the 4 VEGF Trap-Eye groups experienced mean visual acuity benefits ranging from ⫹8.5
`to ⫹11.4 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters versus only ⫹2.5 letters in the laser
`group (P ⱕ 0.0085 for each VEGF Trap-Eye group vs. laser). Gains from baseline of 0⫹, 10⫹, and 15⫹ letters
`were seen in up to 93%, 64%, and 34% of VEGF Trap-Eye groups versus up to 68%, 32%, and 21% in the laser
`group, respectively. Mean reductions in CRT in the 4 VEGF Trap-Eye groups ranged from ⫺127.3 to ⫺194.5 ␮m
`compared with only ⫺67.9 ␮m in the laser group (P ⫽ 0.0066 for each VEGF Trap-Eye group vs. laser). VEGF
`Trap-Eye was generally well tolerated. Ocular adverse events in patients treated with VEGF Trap-Eye were
`generally consistent with those seen with other intravitreal anti-VEGF agents.
`Conclusions:
`Intravitreal VEGF Trap-Eye produced a statistically significant and clinically relevant improve-
`ment in visual acuity when compared with macular laser photocoagulation in patients with DME.
`Financial Disclosure(s): Proprietary or commercial disclosure may be found after
`the references.
`Ophthalmology 2011;118:1819 –1826 © 2011 by the American Academy of Ophthalmology.
`
`Diabetic macular edema (DME) is the most common
`vision-threatening manifestation of diabetic retinopathy.
`The population-based Wisconsin Epidemiologic Study of Di-
`abetic Retinopathy reported 28% prevalence of DME 20 years
`after the diagnosis of type 1 or type 2 diabetes,1 and the
`10-year incidence of DME varies between 20% and 40%
`depending on age, diabetes type, and severity of diabetes.2
`The prevalence is projected to increase as the prevalence of
`diabetes mellitus increases from 180 million people world-
`wide to 300 million by the year 2025.3
`Phosphorylation of tight junction proteins and disorga-
`nization of the blood–retina– barrier are the key events in
`the pathophysiology of DME,4,5 to which hypoxia-triggered
`vascular endothelial growth factor (VEGF) release contrib-
`utes significantly.6 Intravitreal injection of VEGF has been
`shown to produce all findings of diabetic retinopathy, in-
`cluding microaneurysms, macular edema, and retinal neo-
`
`vascularization.7,8 Correspondingly, intravitreal VEGF lev-
`els are elevated in patients with DME.9 The importance of
`VEGF is underscored by the efficacy of anti-VEGF drugs in
`reducing swelling of the retina and improving vision in
`patients with DME. Recent prospective, randomized studies
`have demonstrated the efficacy of intravitreal injections of
`ranibizumab, a humanized monoclonal antibody that binds
`all isoforms of VEGF-A.10,11 Comparable results were re-
`ported for bevacizumab, the complete antibody with almost
`identical binding sites to VEGF-A as ranibizumab, in inter-
`ventional studies or case series.12,13
`VEGF Trap-Eye (Regeneron Pharmaceuticals, Inc., Tar-
`rytown, New York, NY, and Bayer Healthcare Pharmaceu-
`ticals, Berlin, Germany) is a 115-kDA recombinant fusion
`protein consisting of the VEGF binding domains of human
`VEGF receptors 1 and 2 fused to the Fc domain of human
`immunoglobulin-G1.14 Animal studies have demonstrated
`
`© 2011 by the American Academy of Ophthalmology
`Published by Elsevier Inc.
`
`ISSN 0161-6420/11/$–see front matter
`doi:10.1016/j.ophtha.2011.02.018
`
`1819
`
`Samsung Bioepis Exhibit 1031
`Page 1
`
`

`

`Ophthalmology Volume 118, Number 9, September 2011
`
`that intravitreal VEGF Trap-Eye has theoretic advantages
`over ranibizumab and bevacizumab, including a longer half-
`life in the eye and a higher binding affinity to VEGF-A.15 In
`addition, the fusion protein binds placental growth factors 1
`and 2, which have been shown to contribute to excessive
`vascular permeability and retinal neovascularization.16 A
`phase 1 study showed that a single intravitreal injection of
`VEGF Trap-Eye had biologic activity by improving visual
`acuity and reducing excess retinal thickness in 5 eyes with
`DME.17 On the basis of a sound biological rationale and
`encouraging phase 1 results, a phase 2 multicenter, random-
`ized clinical
`trial was designed to compare intravitreal
`VEGF Trap-Eye with standard macular laser treatment after
`the modified Early Treatment of Diabetic Retinopathy
`Study (ETDRS) protocol.18 The primary purpose of the
`DME and VEGF Trap-Eye: INvestigation of Clinical Im-
`pact (DA VINCI) Study was to determine whether different
`doses and dosing regimens of intravitreal VEGF Trap-Eye
`are superior to standard macular laser treatment over a
`24-week study duration in eyes with DME.
`
`Materials and Methods
`
`The DA VINCI study was designed as a 52-week, multicenter,
`randomized, double-masked, active-controlled phase 2 clinical
`study, performed to assess safety and efficacy of VEGF Trap-Eye
`in comparison with laser photocoagulation. Patients were enrolled
`at 39 sites throughout the United States, Canada, and Austria in
`adherence to the tenets of the Declaration of Helsinki. The protocol
`was approved by the ethics committees at each site, and all
`participants provided written informed consent. Patients were en-
`rolled between December 2008 and June 2009, and the last patient
`completed the 24-week primary end point visit in December 2009.
`
`Participants
`Consecutive qualifying patients presenting to each clinical site
`were considered for inclusion. Eligible participants were aged ⱖ18
`years and diagnosed with type 1 or 2 diabetes mellitus, with DME
`involving the central macula defined as central retinal thickness
`(CRT) ⱖ250 ␮m in the central subfield based on Stratus optical
`coherence tomography (OCT). Participants were required to have
`a best-corrected visual acuity (BCVA) letter score at 4 m of 73 to
`24 (Snellen equivalent: 20/40 –20/320) measured by the ETDRS
`protocol.19 Further, women of childbearing potential were in-
`cluded only if they were willing to not become pregnant and to use
`a reliable form of birth control during the study period.
`Potential participants were excluded if any of the following
`criteria were met in the study eye: history of vitreoretinal surgery;
`panretinal or macular laser photocoagulation or use of intraocular
`or periocular corticosteroids or anti-angiogenic drugs within 3
`months of screening; vision decrease due to causes other than
`DME; proliferative diabetic retinopathy (unless regressed and cur-
`rently inactive); ocular inflammation; cataract or other intraocular
`surgery within 3 months of screening, laser capsulotomy within 2
`months of screening; aphakia; spherical equivalent of ⬎⫺8 di-
`opters; or any concurrent disease that would compromise visual
`acuity or require medical or surgical intervention during the study
`period. In addition, patients were ineligible if any of the following
`criteria were met in either eye: active iris neovascularization, vitreous
`hemorrhage, traction retinal detachment, or preretinal fibrosis involv-
`ing the macula; visually significant vitreomacular traction or epiretinal
`membrane evident biomicroscopically or on OCT; history of idio-
`
`1820
`
`pathic or autoimmune uveitis; structural damage to the center of
`the macula that is likely to preclude improvement in visual acuity
`after the resolution of macular edema; uncontrolled glaucoma or
`previous filtration surgery; infectious blepharitis, keratitis, scleri-
`tis, or conjunctivitis; or current treatment for serious systemic
`infection. Further, the following systemic exclusion criteria were
`imposed: uncontrolled diabetes mellitus; uncontrolled hyperten-
`sion; history of cerebral vascular accident or myocardial infarction
`within 6 months; renal failure requiring dialysis or renal transplant;
`pregnancy or lactation; history of allergy to fluorescein or povi-
`done iodine; only 1 functional eye (even if the eye met all other
`entry criteria); or an ocular condition in the fellow eye with a
`poorer prognosis than the study eye.
`
`Treatment Groups
`Patients were randomly assigned in a 1:1:1:1:1 ratio to 1 of 5
`treatment regimens in 1 eye only: 0.5 mg VEGF Trap-Eye every 4
`weeks (0.5q4); 2 mg VEGF Trap-Eye every 4 weeks (2q4); 2 mg
`VEGF Trap-Eye for 3 initial monthly doses and then every 8
`weeks, (2q8); 2 mg VEGF Trap-Eye for 3 initial monthly doses
`and then on an as-needed (PRN) basis (2 PRN); or macular laser
`treatment by the modified ETDRS protocol.19 Treatment groups
`were assigned on the basis of a predetermined randomization
`scheme. Patients in the laser arm received sham injections at each
`visit. In addition, patients in the 2q8 arm and 2 PRN arm received
`sham injections during visits in which an active dose was not
`given. VEGF Trap-Eye was administered by intravitreal injection
`via a prespecified protocol, using a 30-G needle. Post-treatment
`topical antibiotics were used at the discretion of individual inves-
`tigators. Laser photocoagulation was applied using the modified
`ETDRS technique19 with the baseline treatment applied at week 1.
`After topical anesthesia and placement of a contact lens, all areas
`of diffuse leakage associated with retinal thickening received grid
`therapy using laser wavelengths within the green to yellow spec-
`trum, of 50 ␮m size and 0.05 to 0.1 second duration, spaced
`approximately 2 burn widths apart. Focal laser therapy to leaking
`microaneurysms within the areas of retinal thickening was simi-
`larly applied. All patients in the VEGF Trap-Eye groups received
`sham laser treatment at the week 1 visit, which was administered
`using the above procedure, with the laser remaining in the off
`position.
`
`Retreatment Criteria
`Patients in the VEGF Trap-Eye 2 PRN group were eligible for
`retreatment no more often than once every 4 weeks after the initial
`3-month dosing phase if any of the following criteria were met:
`OCT CRT ⱖ250 ␮m; increase of ⬎50 ␮m CRT compared with
`lowest previous measurement; loss of ⱖ5 letters from the previous
`BCVA measurement with any increase in CRT on OCT; or in-
`crease of ⱖ5 letters in BCVA between current and most recent
`visit. Patients in the laser photocoagulation group were eligible for
`laser retreatment no more often than once every 16 weeks begin-
`ning at week 16 if any of the following criteria were met: thick-
`ening of the retina at or within 500 ␮m of the center of the macula;
`hard exudates at or within 500 ␮m of the center of the macula, if
`associated with thickening of adjacent retina; or a zone or zones of
`retinal thickening ⱖ1 disc area, any part of which is within 1 disc
`diameter of the center of the macula. To maintain participant
`masking, sham injections were performed on visits when an active
`dose was not given, and a sham laser was given to the VEGF
`Trap-Eye groups at week 1. Study drug and sham injections and
`laser and sham laser treatments were performed by an unmasked
`physician who had no other role in the study except to assess
`adverse events (AEs) immediately posttreatment. Sham injections
`
`Samsung Bioepis Exhibit 1031
`Page 2
`
`

`

`Do et al
`
`䡠 VEGF Trap-Eye for Diabetic Macular Edema
`
`followed the active treatment protocol with the exception that no
`needle was attached to the syringe, and the syringe hub was gently
`applied to the sclera to mimic an injection. Sham laser consisted of
`placing a contact lens on the study eye and positioning the patient
`in front of the laser machine for the approximate duration of a laser
`treatment.
`
`Evaluations
`The schedule of study visits and interventions through the primary
`end point visit of 24 weeks is shown in Figure 1. After a screening
`visit to obtain informed consent and determine eligibility, partic-
`ipants attended a baseline visit during which they underwent a
`standardized refraction and determination of BCVA, examination
`of the anterior and posterior segments, determination of intraocular
`pressure (IOP), and OCT using the Stratus OCT with software
`version 3.0 or higher (Carl Zeiss Meditec, Jena, Germany); these
`evaluations were repeated at all postrandomization visits. Partici-
`pants were then randomized to study treatment as described pre-
`viously. Fundus photography and fluorescein angiography were
`performed according to clinic procedures at baseline, week 12, and
`week 24. Patients randomized to VEGF Trap-Eye received the first
`injection at this visit (and patients randomized to laser photoco-
`agulation received a sham injection). One week later, patients
`randomized to laser photocoagulation received the first laser treat-
`ment (and patients randomized to VEGF Trap-Eye received sham
`laser treatment). At each subsequent visit, scheduled every 4
`weeks for 24 weeks, patients received either active or sham VEGF
`Trap-Eye injection. Laser retreatment was administered to patients
`in the laser group no more often than every 16 weeks based on
`retreatment criteria, and patients who met retreatment criteria
`received an active laser retreatment 1 week after the scheduled
`visit at which the need for retreatment was identified. A safety
`assessment was conducted by telephone 3 days after every study
`drug or sham injection. In addition, AEs were solicited at each
`study visit. Laboratory samples for hematology and chemistry
`panel, and hemoglobin A1c were drawn at baseline and weeks 12
`and 24.
`
`End Points
`The primary end point of this trial was the mean change in BCVA
`from baseline to the week 24 visit. Secondary end points included
`
`Figure 1. Study design showing schedule of visits and interventions
`through the primary end point visit of 24 weeks. PRN ⫽ as needed; q ⫽
`every; VEGF ⫽ vascular endothelial growth factor.
`
`the proportion of patients who gained at least 15 ETDRS letters in
`BCVA compared with baseline at week 24, the change from
`baseline in CRT (assessed by OCT) at week 24, and the number of
`focal laser treatments received.
`
`Statistical Analysis
`
`An analysis of covariance model was used for the evaluation of the
`primary end point, including baseline BCVA as a covariate and
`treatment effect as a fixed factor, and comparisons of each VEGF
`Trap-Eye group with the laser treatment group were performed
`using linear contrasts. Hochberg’s method was used to adjust for
`multiple comparisons with an overall type 1 error rate (␣) of 5%.20
`Changes from baseline to week 24 in CRT were evaluated using an
`analysis of covariance model with baseline retinal thickness as a
`covariate. Other secondary end points, as well as demographic,
`baseline, and safety data, were evaluated using summary statistics.
`Efficacy analysis was based on the full analysis data set, which
`included all randomized patients who received any study medica-
`tion, had baseline assessments, and had at least 1 postbaseline
`assessment. Safety analysis was based on the safety data set, which
`included all patients receiving study treatment. Missing data were
`accounted for in the analyses using the last observation carried
`forward approach. A sample size of 200 patients (40 per group)
`was determined to provide 84% power to detect an 8-letter differ-
`ence between each of the 4 VEGF Trap-Eye groups and the laser
`group, assuming a standard deviation of 10 letters per group, with
`a 2-sided t test at an ␣ level 5%/4⫽0.0125.
`
`Results
`
`Subject Disposition and Demographics
`
`Overall, 221 patients with DME were enrolled and randomized, and
`200 completed the study (Table 1, available at http://aaojournal.org).
`Two randomized patients did not receive treatment and 19 patients
`discontinued the study after receiving at least 1 treatment for the
`following reasons: lost to follow-up (6 patients), withdrew consent
`(6 patients), death (3 patients), treatment failures (2 patients), AE
`(1 patient), and protocol deviation (1 patient). Discontinuations
`were evenly distributed among the 5 treatment groups. Demo-
`graphic information and baseline characteristics are given in Table
`2. The groups were generally similar, although the VEGF Trap-
`Eye 2q8 group had higher prevalences of type 1 diabetes and
`history of proliferative diabetic retinopathy (regressed at baseline)
`compared with the other groups. In addition, a history of any
`cardiac disease was twice as common in the VEGF Trap-Eye
`groups compared with the laser group.
`
`Visual Acuity
`
`Baseline values of mean visual acuity by treatment group are given
`in Table 2. Patients in the 4 VEGF Trap-Eye groups experienced
`mean visual acuity gains from baseline to week 24 ranging from
`8.5 to 11.4 letters compared with only 2.5 letters in the laser
`photocoagulation group (Fig 2). The change in BCVA from base-
`line to week 24 was statistically significantly greater in each VEGF
`Trap-Eye group compared with the laser group (P ⫽ 0.0085). The
`study was not powered to detect differences among the VEGF
`Trap-Eye treatment groups, and no statistically significant differ-
`ences were observed.
`At week 24, up to 34% of VEGF Trap-Eye–treated patients
`gained ⱖ15 letters from baseline, up to 64% gained ⱖ10 letters
`
`1821
`
`Samsung Bioepis Exhibit 1031
`Page 3
`
`

`

`Ophthalmology Volume 118, Number 9, September 2011
`
`Table 2. Demographics and Baseline Characteristics
`
`Age (yrs), mean ⫾ SD
`Gender, n (%) female
`Ethnicity, n (%)
`White (non-Hispanic)
`White Hispanic
`Black
`Asian
`Other
`Diabetes, n (%)
`Type 1
`Type 2
`HbA1c, mean ⫾ SD
`Baseline cardiac history, n (%)
`ETDRS BCVA, mean ⫾ SD
`CRT (␮m), mean ⫾ SD
`Diabetic retinopathy Severity score (1–5), n (%)
`None (1)
`Mild (2)
`Moderate (3)
`Severe (4)
`Proliferative (regressed) (5)
`Previous treatment, n (%)
`Laser (focal grid)
`Anti-VEGF (RBZ, BEV, PEG)
`Steroids (TRI, DEX)
`
`Laser
`nⴝ44
`64.0⫾8.1
`17 (38.6%)
`
`30 (68.2%)
`8 (18.2%)
`4 (9.1%)
`1 (2.3%)
`1 (2.3%)
`
`5 (13.6%)
`39 (88.6%)
`7.93⫾1.84
`8 (18.2%)
`57.6⫾12.5
`440.6⫾145.4
`
`1 (2.3%)
`1 (2.3%)
`29 (65.9%)
`12 (27.3%)
`1 (2.3%)
`
`22 (50.0%)
`10 (22.7%)
`12 (27.3%)
`
`0.5q4 (n⫽44)
`62.3⫾10.7
`20 (45.5%)
`
`28 (63.6%)
`13 (29.5%)
`3 (6.8%)
`0
`0
`
`1 (2.3%)
`43 (97.7%)
`8.10⫾1.91
`21 (47.7%)
`59.3⫾11.2
`426.1⫾128.3
`
`0
`2 (4.5%)
`20 (45.5%)
`20 (45.5%)
`2 (4.5%)
`
`21 (47.7%)
`5 (11.4%)
`8 (18.2%)
`
`VEGF Trap-Eye Treatment Groups
`2q4 (n⫽44)
`2q8 (n⫽42)
`62.1⫾10.5
`62.5⫾11.5
`17 (38.6%)
`20 (47.6%)
`
`2PRN (n⫽45)
`60.7⫾8.7
`16 (35.6%)
`
`26 (59.1%)
`15 (34.1%)
`1 (2.3%)
`0
`2 (4.5%)
`
`3 (6.8%)
`41 (93.2%)
`8.08⫾1.94
`15 (34.1%)
`59.9⫾10.1
`456.6⫾135.0
`
`3 (6.8%)
`4 (9.1%)
`25 (56.8%)
`11 (25.0%)
`1 (2.3%)
`
`23 (52.3%)
`10 (22.7%)
`7 (15.9%)
`
`33 (78.6%)
`3 (7.1%)
`2 (4.8%)
`1 (2.4%)
`1 (2.4%)
`
`4 (9.5%)
`38 (90.5%)
`7.85⫾1.72
`18 (42.9%)
`58.8⫾12.2
`434.8⫾111.8
`
`0
`3 (7.1%)
`21 (50.0%)
`11 (26.2%)
`7 (16.7%)
`
`28 (66.7%)
`6 (14.3%)
`10 (23.8%)
`
`28 (62.2%)
`13 (28.9%)
`1 (2.2%)
`2 (4.4%)
`1 (2.2%)
`
`2 (4.4%)
`43 (95.6%)
`7.97⫾1.71
`15 (33.3%)
`59.6⫾11.1
`426.6⫾152.4
`
`0
`5 (11.1%)
`25 (55.6%)
`14 (31.1%)
`1 (2.2%)
`
`26 (57.8%)
`6 (13.3%)
`9 (20.0%)
`
`0.5q4 ⫽ 0.5 mg every 4 weeks; 2q4 ⫽ 2 mg every 4 weeks; 2q8 ⫽ 2 mg for 3 initial doses then every 8 weeks; 2 PRN ⫽ 2 mg for 3 initial doses then as needed;
`BCVA ⫽ best-corrected visual acuity; BEV ⫽ bevacizumab; CRT ⫽ central retinal thickness; DEX ⫽ dexamethasone; ETDRS ⫽ Early Treatment of Diabetic
`Retinopathy Study; HbA1c ⫽ hemoglobin A1c; PEG ⫽ pegaptanib; PRN ⫽ as needed; RBZ ⫽ ranibizumab; TRI ⫽ triamcinolone; SD ⫽ standard deviation;
`VEGF ⫽ vascular endothelial growth factor.
`
`from baseline, and up to 93% of patients gained ⱖ0 letters from
`baseline, compared with only 21%, 32%, and 68% in the laser
`group, respectively (Fig 3). Conversely, 9.1% of patients in the
`laser group and 4.5% of patients treated with 0.5 mg VEGF
`
`Trap-Eye lost ⱖ15 letters at week 24, whereas no patients in any
`of the 2 mg VEGF Trap-Eye groups experienced such vision loss
`at this time point. Figure 4 (available at http://aaojournal.org)
`illustrates BCVA changes for each individual patient in each
`treatment group. Few patients in the VEGF Trap-Eye groups,
`
`Figure 2. Mean changes in BCVA by treatment groups (laser and VEGF
`Trap-Eye). Last observation carried forward analysis; n⫽44 (laser; VEGF
`Trap-Eye 0.5q4, 2q4); n⫽42 (VEGF Trap-Eye 2q8); n⫽45 (VEGF Trap-
`Eye 2PRN). Difference between each treatment versus laser analysis of
`covariance: *P ⬍ 0.0001; ⫹P⫽0.0004; ^P⫽0.0085; †P⫽0.0054. Differ-
`ences among the VEGF-Trap-Eye treatment arms were not significant.
`Treatment groups are defined as follows: 0.5q4 ⫽ 0.5 mg every 4 weeks;
`2q4 ⫽ 2 mg every 4 weeks; 2q8 ⫽ 2 mg for 3 initial doses then every 8
`weeks; 2PRN ⫽ 2 mg for 3 initial doses then as needed. ETDRS ⫽ Early
`Treatment of Diabetic Retinopathy Study; 2 PRN ⫽ as needed; q ⫽ every;
`VEGF ⫽ vascular endothelial growth factor.
`
`1822
`
`Figure 3. Percentage of patients with changes in BCVA at 6 months by
`treatment groups (laser and VEGF-Trap-Eye). Last observation carried
`forward analysis; n⫽44 (laser; VEGF Trap-Eye 0.5q4, 2q4); n⫽42 (VEGF
`Trap-Eye 2q8); n⫽45 (VEGF Trap-Eye 2PRN). Treatment groups are
`defined as follows: 0.5q4 ⫽ 0.5 mg every 4 weeks; 2q4 ⫽ 2 mg every 4
`weeks; 2q8 ⫽ 2 mg for 3 initial doses then every 8 weeks; 2 PRN ⫽ 2 mg
`for 3 initial doses then as needed. BCVA ⫽ best-corrected visual acuity;
`PRN ⫽ as needed; q ⫽ every.
`
`Samsung Bioepis Exhibit 1031
`Page 4
`
`

`

`Do et al
`
`䡠 VEGF Trap-Eye for Diabetic Macular Edema
`
`24, and received a mean of 5.6 (range 1– 6) and 5.5 (range 1– 6)
`injections, respectively. Patients in the VEGF Trap-Eye 2q8 group
`received a mean of 3.8 (range 1– 4) of 4 planned injections.
`Patients in the VEGF Trap-Eye 2 PRN group were scheduled to
`receive 3 monthly injections followed by up to 3 PRN injections
`based on prespecified retreatment criteria. Patients in this group
`received a mean of 1.5 (range 0 –3) of the 3 possible PRN injec-
`tions, for a mean total of 4.4 (range 1– 6) of up to 6 possible
`injections by week 24. Patients in the laser group received laser
`treatment at baseline and were eligible for up to 1 additional laser
`treatment by week 24; patients in this group received a mean of 1.7
`(range 1–3) laser treatments by week 24. According to the proto-
`col, only 2 laser treatments were allowed for patients in the laser
`arm during the first 6 months of the study. However, 1 patient
`received 3 laser treatments during this period.
`
`Safety
`Ocular AEs in patients treated with VEGF Trap-Eye were gener-
`ally consistent with those seen with other intravitreal anti-VEGF
`agents and typical of those seen with intravitreal injections. The
`most frequent ocular AEs are listed in Table 3. Conjunctival
`hemorrhage was the most common, occurring in 18.9% of VEGF
`Trap-Eye–treated eyes and 18.2% of laser-treated eyes. Other
`common AEs included eye pain, ocular hyperemia, and vitreous
`floaters, all of which were seen at approximately equal rates in
`both the VEGF Trap-Eye and laser groups. Two patients had
`endophthalmitis in the study eye, 1 each in the 2q4 and 2 PRN
`arms. One case was culture negative, and the other was positive for
`Staphylococcus epidermidis. One patient in the 0.5q4 arm had a
`diagnosis of uveitis, which was treated as endophthalmitis. Sev-
`enteen patients (9.7%) in the VEGF Trap-Eye groups had AEs of
`increased IOP, none of which were reported as serious. All of these
`events occurred immediately after intravitreal injection, and IOP
`normalized within 1 hour. Topical IOP-lowering medications were
`administered in all but 1 case. One patient in the laser arm had an
`AE of increased IOP that did not require treatment.
`Systemic AEs are given in Table 4. Four patients had serious
`AEs of hypertension (1 in the VEGF Trap-Eye 0.5q4 group and 3
`in the VEGF Trap-Eye 2q4 group), all of whom had a medical
`history of hypertension. Three patients had arterial thromboem-
`
`Figure 5. Mean change in CRT by treatment groups (laser and VEGF-
`Trap-Eye). Last observation carried forward analysis; n⫽44 (laser; VEGF-
`Trap-Eye 0.5q4, 2q4); n⫽42 (VEGF-Trap-Eye 2q8); n⫽45 (VEGF-Trap-
`Eye 2PRN). Difference between each treatment versus laser analysis of
`covariance: *P ⬍ 0.0001; ⫹P⫽0.0066; ^P⫽0.0002; †P ⬍ 0.0001. Differ-
`ences among the VEGF-Trap-Eye treatment arms were not significant.
`PRN ⫽ as needed; q ⫽ every.
`
`particularly the groups receiving 2 mg doses, experienced any loss
`of vision.
`
`Central Retinal Thickness
`Baseline values of mean CRT by group are given in Table 2.
`Reductions in CRT in each group were consistent with the ob-
`served improvements in visual acuity. Patients in the 4 VEGF
`Trap-Eye groups experienced mean reductions in CRT ranging
`from 127.3 to 194.5 ␮m by week 24 compared with only 67.9 ␮m
`in the laser photocoagulation group (Fig 5). The reduction in CRT
`in each VEGF Trap-Eye group was statistically significant when
`compared with the laser group (P ⫽ 0.0066).
`
`Treatment Exposure
`Patients in the VEGF Trap-Eye 0.5q4 and 2q4 treatment groups
`were scheduled to receive a total of 6 monthly injections by week
`
`Table 3. Ocular Adverse Events Occurring in More Than 5% of Subjects and All Serious Ocular Adverse Events by Treatment
`Group, n (%)
`
`Adverse events
`Conjunctival hemorrhage
`IOP increased
`Eye pain
`Ocular hyperemia
`Vitreous floaters
`Serious AEs
`Endophthalmitis
`Uveitis
`Diabetic retinal edema
`Visual acuity reduced
`Vitreous hemorrhage
`Corneal abrasion
`Retinal tear
`
`Laser
`nⴝ44
`
`8 (18.2%)
`1 (2.3%)
`2 (4.5%)
`2 (4.5%)
`2 (4.5%)
`
`0
`0
`1 (2.3%)
`1 (2.3%)
`1 (2.3%)
`0
`0
`
`0.5q4 (n⫽44)
`
`VEGF Trap-Eye Treatment Groups
`2q4 (n⫽44)
`2q8 (n⫽42)
`
`2PRN (n⫽45)
`
`8 (18.2%)
`5 (11.4%)
`3 (6.8%)
`4 (9.1%)
`4 (9.1%)
`
`0
`1 (2.3%)
`0
`0
`0
`0
`0
`
`5 (11.4%)
`6 (13.6%)
`4 (9.1%)
`1 (2.3%)
`2 (4.5%)
`
`1 (2.3%)
`0
`0
`0
`0
`0
`0
`
`11 (26.2%)
`4 (9.5%)
`3 (7.1%)
`3 (7.1%)
`2 (4.8%)
`
`0
`0
`0
`0
`0
`1 (2.4%)
`1 (2.4%)
`
`9 (20.0%)
`2 (4.4%)
`5 (11.1%)
`3 (6.7%)
`1 (2.2%)
`
`1 (2.2%)
`0
`0
`0
`0
`0
`0
`
`All VEGF
`Trap-Eye
`nⴝ175
`
`33 (18.9%)
`17 (9.7%)
`15 (8.6%)
`11 (6.3%)
`9 (5.1%)
`
`2 (1.1%)
`1 (0.6%)
`0
`0
`0
`1 (0.6%)
`1 (0.6%)
`
`0.5q4 ⫽ 0.5 mg every 4 weeks; 2q4 ⫽ 2 mg every 4 weeks; 2q8 ⫽ 2 mg for 3 initial doses then every 8 weeks; 2 PRN ⫽ 2 mg for 3 initial doses then
`as needed; AEs ⫽ adverse events; IOP ⫽ intraocular pressure; PRN ⫽ as needed; VEGF ⫽ vascular endothelial growth factor.
`
`1823
`
`Samsung Bioepis Exhibit 1031
`Page 5
`
`

`

`Ophthalmology Volume 118, Number 9, September 2011
`
`Table 4. Key Systemic Adverse Events and Deaths by Treatment Group, n (%)
`
`Hypertension
`Myocardial infarction
`Cerebrovascular accident
`Death
`
`Laser
`nⴝ44
`
`3 (6.8%)
`0
`0
`0
`
`0.5q4 (n⫽44)
`
`4 (9.1%)
`1 (2.3%)
`1 (2.3%)
`1 (2.3%)
`
`VEGF Trap-Eye treatment groups
`2q4 (n⫽44)
`2q8 (n⫽42)
`
`7 (15.9%)
`1 (2.3%)
`1 (2.3%)
`1 (2.3%)
`
`2 (4.8%)
`0
`0
`1 (2.4%)
`
`2PRN (n⫽45)
`
`4 (8.9%)
`0
`0
`0
`
`All VEGF
`Trap-Eye
`nⴝ175
`
`17 (9.7%)
`2 (1.1%)
`2 (1.1%)
`3 (1.7%)
`
`Treatment groups are defined as follows: 0.5q4 ⫽ 0.5 mg every 4 weeks; 2q4 ⫽ 2 mg every 4 weeks; 2q8 ⫽ 2 mg for 3 initial doses then every 8 weeks;
`2 PRN ⫽ 2 mg for 3 initial doses then as needed. PRN ⫽ as needed; VEGF ⫽ vascular endothelial growth factor.
`
`bolic events. One patient had a cerebral vascular accident in the
`VEGF Trap-Eye 0.5q4 group. One patient had a myocardial in-
`farction in the VEGF Trap-Eye 0.5q4 group. Although the infarc-
`tion was not fatal, it was immediately followed by surgical interven-
`tion, and the patient died of multiorgan failure; in addition to diabetes,
`this patient had a history of coronary artery disease, hypertension, and
`hypercholesterolemia. One patient experienced a cerebrovascular
`event and a silent myocardial infarction on the same day in the VEGF
`Trap-Eye 2q4 group; in addition to diabetes, this patient had a history
`of hypertension and hypercholesterolemia.
`In this study of diabetic patients, there were 3 deaths over the
`first 24 weeks. One patient in the VEGF Trap-Eye 2q8 group, with
`a history of hypertension, seizures, and evidence of impaired renal
`function on baseline laboratory examinations, died of renal failure.
`One patient (described above) in the VEGF Trap-Eye 0.5q4 group,
`with a history of cardiac disease, died of multiorgan failure a few
`days after experiencing a myocardial infarction. One patient in the
`2q4 group, with a history of cardiac disease, chronic obstructive
`pulmonary disease, peripheral vascular disease, kidney disease,
`hypercholesterolemia, and hypertension, experienced “sudden
`death.” Many of the systemic AEs observed may be attributable in
`part to the underlying diabetic morbidity and cardiovascular co-
`morbidities of the patients.
`
`Discussion
`
`In this phase 2 randomized clinical trial, intravitreal VEGF
`Trap-Eye was superior to macular laser treatment by the
`modified ETDRS protocol, the current clinical standard, for
`the treatment of DME over a 24-week period. VEGF Trap-
`Eye resulted in significantly better mean visual acuity out-
`comes (⫹8.5 to ⫹11.4 letters gained) and greater mean
`reductions in retinal thickness (⫺127.3 to ⫺194.5 ␮m)
`compared with laser alone. Moreover, the different doses
`(0.5 or 2 mg) and dosing regimens (given every 4 weeks,
`every 8 weeks, or on a PRN basis) of VEGF Trap-Eye were
`all individually superior to laser and resulted in statistically
`significant increases in visual acuity and reductions in ret-
`inal thickness at week 24. When individual patient out-
`comes are considered, the 2 mg dose of VEGF Trap-Eye
`almost completely eliminated vision loss at all dosing in-
`tervals (Fig 4, available at http://aaojournal.org). In addi-
`tion, there did not seem to be substantial differences among
`the 4 VEGF Trap-Eye groups in terms of functional or
`morphologic outcomes, although the current study was not
`powered to detect differences between VEGF Trap-Eye
`groups.
`
`1824
`
`The current study’s results are consistent with the
`results of prior studies. A recently reported trial compar-
`ing laser, ranibizumab, and triamcinolone alone or in
`combination revealed a mean change of visual acuity of
`approximately ⫹9 letters after 12 months in the ranibi-
`zumab groups with either prompt or deferred laser versus
`⫹3 letters in the laser-only group.11 Similarly, in the
`RESOLVE phase 2 trial, the mean increase of visual
`acuity over 1 year was 7.8 letters with monthly ranibi-
`zumab treatment (Invest Ophthalmol Vis Sci 51[Suppl]:
`5841). Comparable results were also achieved in the
`READ-2 study (⫹7.2 letters after 6 months in the ranibi-
`zumab monotherapy group; ⫺0.4 letters after 6 months in
`the laser group).10 Results from case series with bevaci-
`zumab reflect visual acuity changes of the same magni-
`tude.21 Despite the fact that each of these studies had
`differences in protocol design and study population, they
`are remarkably consistent with each other and with the
`current study’s findings. A possible limitation of this
`study’s findings is that study subjects were allowed to
`have received prior laser treatment up to 3 months before
`screening, and it is not known whether they may have
`perceived a difference between the sham and the true
`laser. However, it is unlikely that this knowledge would
`affect the primary and secondary outcomes of this clini-
`cal trial. These studies in conjunction with this short-term
`study provide evidence in support of the hypothesis that
`anti-VEGF therapy is in general superior to laser therapy
`in diabetic patients with DME. However, the long-term
`consequences of these anti-VEGF therapies for DME in
`diabetic patients remain undefined.
`VEGF Trap-Eye differs from current monoclonal anti-
`bodies and antibody fragments that block VEGF-A in that it
`binds VEGF-A more tightly than its native receptors in a
`strict 1:1 fashion and also binds other VEGF family mem-
`bers, such as placental growth factor. The DA VINCI study
`provides some insight into the potential clinical impact of
`these specific properties because the study design included
`various dosing regimens. In the 2Q8 and 2 PRN arms, the
`treatment interval for VEGF Trap-Eye administration was
`prolonged after the loading phase without a trade-off in
`efficacy, because all VEGF Trap-Eye–treated groups man-
`ifested comparable gains in visual acuity versus baseline.
`The 2Q8 group appeared to have less improv