One-Year Outcomes of the DA VINCI
`Study of VEGF Trap-Eye in Eyes with
`Diabetic Macular Edema
`
`Diana V. Do, MD,1 Quan Dong Nguyen, MD, MSc,1 David Boyer, MD,2 Ursula Schmidt-Erfurth, MD,3
`David M. Brown, MD,4 Robert Vitti, MD,5 Alyson J. Berliner, MD,5 Bo Gao, PhD,5 Oliver Zeitz, MD,6,7
`Rene Ruckert, MD,6 Thomas Schmelter, PhD,6 Rupert Sandbrink, MD, PhD,6,8 Jeff S. Heier, MD,9 for the
`DA VINCI Study Group*
`
`Purpose: To compare different doses and dosing regimens of Vascular Endothelial Growth Factor (VEGF)
`Trap-Eye with laser photocoagulation in eyes with diabetic macular edema (DME).
`Design: Randomized, double-masked, multicenter, phase 2 clinical trial.
`Participants: Diabetic patients (n ⫽ 221) with center-involved DME.
`Methods: Participants were assigned randomly to 1 of 5 treatment regimens: VEGF Trap-Eye 0.5 mg every
`4 weeks (0.5q4); 2 mg every 4 weeks (2q4); 2 mg every 8 weeks after 3 initial monthly doses (2q8); or 2 mg dosing
`as needed after 3 initial monthly doses (2PRN), or macular laser photocoagulation.
`Main Outcome Measures: The change in best-corrected visual acuity (BCVA) at 24 weeks (the primary end
`point) and at 52 weeks, proportion of eyes that gained 15 letters or more in Early Treatment of Diabetic
`Retinopathy Study (ETDRS) BCVA, and mean changes in central retinal thickness (CRT) from baseline.
`Results: As previously reported, mean improvements in BCVA in the VEGF Trap-Eye groups at week 24
`were 8.6, 11.4, 8.5, and 10.3 letters for 0.5q4, 2q4, 2q8, and 2PRN regimens, respectively, versus 2.5 letters for
`the laser group (P ⱕ 0.0085 versus laser). Mean improvements in BCVA in the VEGF Trap-Eye groups at week
`52 were 11.0, 13.1, 9.7, and 12.0 letters for 0.5q4, 2q4, 2q8, and 2PRN regimens, respectively, versus ⫺1.3
`letters for the laser group (P ⱕ 0.0001 versus laser). Proportions of eyes with gains in BCVA of 15 or more ETDRS
`letters at week 52 in the VEGF Trap-Eye groups were 40.9%, 45.5%, 23.8%, and 42.2% versus 11.4% for laser
`(P ⫽ 0.0031, P ⫽ 0.0007, P ⫽ 0.1608, and P ⫽ 0.0016, respectively, versus laser). Mean reductions in CRT in
`the VEGF Trap-Eye groups at week 52 were ⫺165.4 ␮m, ⫺227.4 ␮m, ⫺187.8 ␮m, and ⫺180.3 ␮m versus ⫺58.4
`␮m for laser (P ⬍ 0.0001 versus laser). Vascular Endothelial Growth Factor Trap-Eye generally was well tolerated.
`The most frequent ocular adverse events with VEGF Trap-Eye were conjunctival hemorrhage, eye pain, ocular
`hyperemia, and increased intraocular pressure, whereas common systemic adverse events included hyperten-
`sion, nausea, and congestive heart failure.
`Conclusions: Significant gains in BCVA from baseline achieved at week 24 were maintained or improved at
`week 52 in all VEGF Trap-Eye groups. Vascular Endothelial Growth Factor Trap-Eye warrants further investigation
`for the treatment of DME.
`Financial Disclosure(s): Proprietary or commercial disclosure may be found after
`Ophthalmology 2012;119:1658 –1665 © 2012 by the American Academy of Ophthalmology.
`
`the references.
`
`Diabetic macular edema (DME) is the most common cause
`of vision loss for patients with diabetes mellitus.1 The
`Wisconsin Epidemiologic Study found that the prevalence
`of macular edema was associated with an increasing dura-
`tion of diabetes.2,3 Worldwide, the prevalence of adult dia-
`betes is anticipated to rise from 4.0% in 1995 to 5.4% by
`2025.4 Given this rising prevalence, it is expected that
`diabetic retinopathy and DME will continue to be common
`and will be important causes of vision impairment.
`The complex pathophysiology of DME has been under
`investigation in recent years. In individuals with diabetic
`retinopathy, fluid can accumulate within the retina as a
`result of a breakdown in the blood–retinal barrier. Hyper-
`glycemia associated with diabetes stimulates an inflamma-
`
`tory response, which causes detrimental effects on the ret-
`inal vasculature.5 Vascular occlusion and ischemia results,
`and can lead to local hypoxia.6 Vascular endothelial growth
`factor (VEGF) and a host of other growth factors are up-
`regulated during hypoxic conditions, and an inflammatory
`cascade of events can ensue.
`Vascular endothelial growth factor is thought to be a key
`factor in the pathogenesis of DME5,7 and is a vasoactive
`cytokine that both induces vascular permeability and stim-
`ulates angiogenesis. It is approximately 50 000-fold more
`potent in inducing permeability than histamine8 –10 and af-
`fects endothelial tight junction proteins. Vascular endothe-
`lial growth factor is known to cause a breakdown of the
`blood–retinal barrier, followed by extracellular fluid accu-
`mulation and retinal edema.11
`
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`
`© 2012 by the American Academy of Ophthalmology
`Published by Elsevier Inc.
`
`ISSN 0161-6420/12/$–see front matter
`doi:10.1016/j.ophtha.2012.02.010
`
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`

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`Do et al
`
`䡠 One-Year Outcomes of VEGF Trap-Eye for DME
`
`Vascular endothelial growth factor concentrations are
`elevated in both the vitreous fluid and aqueous humor of
`patients with active proliferative diabetic retinopathy.12,13
`One study reported that VEGF concentrations in aqueous
`humor were elevated nearly 5-fold in DME eyes compared
`with that of age-matched controls.14 Another study showed
`that the VEGF concentrations in the aqueous humor of eyes
`with DME were 3-fold higher than in the plasma.12 More-
`over, these elevated VEGF levels were correlated signifi-
`cantly with the severity of DME.12 Elevated VEGF concen-
`trations are associated with extensive macular leakage in
`diabetic eyes, and numerous studies have shown that VEGF
`inhibitors are effective for reducing retinal thickness and
`improving visual acuity.15–22
`Vascular Endothelial Growth Factor Trap-Eye is a
`115-kDA recombinant fusion protein comprising the key
`VEGF binding domains of human VEGF receptors 1 and
`2 fused to the Fc domain of human immunoglobulin
`G1.23 Vascular Endothelial Growth Factor Trap-Eye is a
`panisoform VEGF-A inhibitor whose binding affinity to
`VEGF is substantially greater than that of either bevaci-
`ranibizumab,23 leading to a mathematical
`zumab or
`model predicting it could have substantially longer dura-
`tion of action in the eye.24 In addition, VEGF Trap-Eye
`binds placental growth factors 1 and 2, which have been
`shown to contribute to excessive vascular permeability
`and retinal neovascularization.25
`The phase 2 clinical trial DME And VEGF Trap-Eye:
`INvestigation of Clinical Impact (DA VINCI) was designed
`to compare intravitreal VEGF Trap-Eye with macular laser
`photocoagulation. Results at week 24 (primary end point
`data) from the current study have been published previ-
`ously,26 and all VEGF Trap-Eye arms showed significant
`gains in visual acuity compared with laser
`treatment
`(P ⱕ 0.0085) at week 24. Patients in this study continued
`with their assigned dosing regimen and continued follow-up
`to determine if these visual acuity gains were maintained
`through week 52. The 1-year results are reported here.
`
`Patients and Methods
`
`The DA VINCI study was a randomized, double-masked, active-
`controlled multicenter phase 2 clinical trial. Thirty-nine sites in the
`United States, Canada, and Austria participated in the trial, and
`patients were enrolled between December 2008 and June 2009.
`The primary objective was to assess the efficacy of various doses
`and dose intervals of intravitreal VEGF Trap-Eye (aflibercept
`injection) on BCVA. The primary end point was the change in
`BCVA from baseline to week 24. Secondary objectives were to
`assess the effects of intravitreal VEGF Trap-Eye on retinal thick-
`ness assessed by optical coherence tomography (OCT) and to
`assess safety and tolerability of intravitreal VEGF Trap-Eye in
`eyes with DME. Secondary outcomes were the change in BCVA
`from baseline at week 52, the proportion of eyes that gained at
`least 15 ETDRS letters in BCVA compared with baseline at weeks
`24 and 52, the change in central retinal thickness (CRT; central
`subfield on OCT) from baseline to weeks 24 and 52, and the
`number of focal laser treatments given.
`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 tenets of the Declaration of Helsinki. The study was compliant
`with the rules and regulations under the Health Insurance Porta-
`bility and Accountability Act of 1996. All patients provided writ-
`ten informed consent to participate in the study. The DA VINCI
`study is registered with ClinicalTrials.gov (NCT00789477).
`
`Participants
`The study enrolled adult patients 18 years of age or older with type
`1 or 2 diabetes mellitus with clinically significant DME with center
`involvement of the fovea, defined as a central subfield measure-
`ment of 250 ␮m or more on time-domain OCT (Stratus OCT; Carl
`Zeiss Meditec, Jena, Germany). In addition, patients had an ET-
`DRS BCVA letter score at 4 m of 73 to 24(20/40 to 20/320) in the
`study eye.27,28 Patients were excluded if any of the following were
`present in the study eye: history of vitreoretinal surgery, panretinal
`or macular laser photocoagulation within 3 months of screening,
`previous use of intraocular or periocular corticosteroids within 3
`months of screening, or other ocular disorders that could contribute
`to vision loss and could confound the study results. In addition,
`previous treatment with antiangiogenic drugs for either eye
`(pegaptanib sodium, anecortave acetate, bevacizumab, ranibi-
`zumab, etc.) was not allowed within 3 months of screening. Pa-
`tients with uncontrolled diabetes mellitus or hypertension (systolic
`blood pressure ⬎180 mmHg or ⬎160 mmHg on 2 consecutive
`measurements or diastolic blood pressure ⬎100 mmHg on optimal
`medical regimen) also were excluded from the study.
`
`Treatments
`Eyes were assigned randomly using a 1:1:1:1:1 ratio to one of the
`following treatment regimens (Fig 1): (1) 0.5 mg VEGF Trap-Eye
`every 4 weeks (0.5q4); (2) 2 mg VEGF Trap-Eye every 4 weeks
`(2q4); (3) 2 mg VEGF Trap-Eye every 8 weeks after 3 initial
`monthly doses (2q8); (4) 2 mg VEGF Trap-Eye, with dosing as
`needed after 3 initial monthly doses (2PRN); (5) laser photocoag-
`ulation using a modified ETDRS protocol27 at baseline and then as
`needed (but no more frequently than every 16 weeks). Eyes in the
`laser group also received a sham injection every 4 weeks.
`Vascular Endothelial Growth Factor Trap-Eye, provided by
`Regeneron Pharmaceuticals, Inc (Tarrytown, New York), was
`administered by intravitreal injection with a 30-gauge needle using
`standard ophthalmic techniques. Vascular Endothelial Growth
`Factor Trap-Eye was formulated as a sterile liquid to a final
`concentration of either 10 mg/ml or 40 mg/ml VEGF Trap-Eye.
`The injection volume was 50 ␮l (0.05 ml), which provided the
`delivery of 0.5 mg or 2 mg of VEGF-Trap-Eye. Sham injections
`were performed following the identical treatment protocol used for
`the active injections, but only gentle application of the hub of the
`syringe (without the needle) to the sclera was used to mimic an
`injection.
`Laser photocoagulation was performed using the modified ET-
`DRS protocol (baseline treatment at week 1).3,28 After topical
`anesthesia and placement of a contact lens, grid therapy was
`applied to the thickened areas of the retina with diffuse leakage,
`focal therapy, or both being applied to leaking microaneurysms
`within the areas of retinal thickening. Sham laser treatments con-
`sisted 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, while the laser remained in the off position.
`
`Retreatment Criteria
`After the 3 initial monthly doses, eyes assigned to the 2PRN arm
`received an injection of study drug if any one of the following
`criteria were present: a more than 50-␮m increase in CRT com-
`
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`Ophthalmology Volume 119, Number 8, August 2012
`
`Figure 1. Diagram showing study design with interventions and schedule of visits throughout the course of the 12-month study. 0.5q4 ⫽ 0.5 mg every
`4 weeks; 2q4 ⫽ 2 mg every 4 weeks; 2q8 ⫽ 2 mg for 3 initial monthly doses then every 8 weeks; 2PRN ⫽ 2 mg for 3 initial monthly doses then as needed;
`box ⫽ injection; grey ⫽ as needed; oval ⫽ laser; outline ⫽ sham; solid ⫽ active; VEGF ⫽ vascular endothelial growth factor.
`
`pared with the lowest previous measurement; new or persistent
`cystic retinal changes, subretinal fluid, or persistent diffuse edema
`of 250 ␮m or more on OCT; a loss of 5 or more letters of BCVA
`from the best previous measurement in conjunction with any
`increase in CRT; and an increase in BCVA between the current
`and most recent visit of 5 letters or more. Eyes assigned to the
`2PRN arm received sham injections if none of the retreatment
`criteria above were met.
`Eyes in the laser photocoagulation arm of the study received
`their initial laser at week 1 (Fig 1). Starting at week 16, eyes were
`assessed for retreatment according to the following ETDRS crite-
`ria and were retreated if any one of the criteria were met: an
`increase in retinal thickness 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; zone(s) of
`retinal thickening 1 disc area or larger (any part of which was
`within 1 disc diameter of the center of the macula).
`Starting at week 24 (month 6), these same three criteria were
`used to assess eyes in the VEGF Trap-Eye arms for laser rescue.
`Eyes in the VEGF Trap-Eye arms that met the criteria for laser
`rescue received laser 1 week after the scheduled visit, which they
`qualified for laser rescue. Subsequent laser rescue treatments could
`be performed at 16-week intervals.
`
`Masking
`
`Treatments (study drug injection, sham injection, laser or sham
`laser photocoagulation) were performed by an unmasked physi-
`cian. A separate masked physician was assigned to assess adverse
`events (AEs) and retreatment and rescue criteria and to supervise
`the masked assessment of efficacy. Every effort was made to
`ensure that all other study site personnel remained masked to
`treatment assignment to facilitate an unbiased assessment of effi-
`cacy and safety.
`
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`
`Measurements
`Visual acuity was measured using the ETDRS protocol.28 Retinal
`and lesion characteristics of the study eye were evaluated using
`time-domain OCT (Zeiss Stratus OCT equipped with software
`version 3.0 or greater; Carl Zeiss Meditec, Jena, Germany). The
`study eye was evaluated by dilated funduscopic examination,
`fundus photography, and fluorescein angiography. The severity of
`each patient’s diabetic retinopathy was assessed using the Diabetic
`Retinopathy Severity Score.29 Intraocular pressure of the study eye
`was measured using Goldmann applanation tonometry (Haag-
`Streit AG, Köniz, Switzerland) or the Tono-Pen (Reichert Tech-
`nologies, DePew, New York) before dosing and again approxi-
`mately 5 to 10 minutes after dosing. Safety assessments included
`ophthalmic examinations, clinical AEs, laboratory measures, and
`serum samples for potential development of anti-VEGF Trap-Eye
`antibodies.
`
`Concomitant Medications
`Patients were not allowed to receive any treatment for their DME
`in the study eye other than the assigned study treatment with
`VEGF Trap-Eye or laser until week 52 or until the early termina-
`tion visit assessments were completed.
`
`Statistical Analyses
`The full analysis set, which was used for the efficacy analysis,
`included all randomized patients who received any study medica-
`tion and had at least 1 assessment after baseline. The safety
`analysis set, used for all safety and tolerability assessments, in-
`cluded all participants who received any study medication. The last
`observation carried forward approach was used to account for
`missing data. A sample size of 200 patients (40 per group) pro-
`vided 84% power to detect an 8-letter difference between each of
`the 4 VEGF Trap-Eye arms and the laser arm (assuming a standard
`
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`

`Do et al
`
`䡠 One-Year Outcomes of VEGF Trap-Eye for DME
`
`Table 3. Treatment and Exposure Summary for Vascular
`Endothelial Growth Factor Trap-Eye and Laser Treatments over
`the Course of the First 48 Weeks
`
`Mean No. of Vascular
`Endothelial Growth
`Factor Trap-Eye
`Injections (SD)
`
`11.7 (2.49)
`10.8 (2.87)
`7.2 (1.74)
`7.4 (3.19)
`N/A
`
`Mean No. of Laser
`Treatments (SD)
`
`0.8 (0.83)
`0.5 (0.66)
`0.8 (0.86)
`0.7 (0.77)
`2.5 (0.87)
`
`Study Arm
`0.5q4 (n ⫽ 44)
`2q4 (n ⫽ 44)
`2q8 (n ⫽ 42)
`2PRN (n ⫽ 45)
`Laser (n ⫽ 44)
`
`0.5q4 ⫽ 0.5 mg every 4 weeks; 2q4 ⫽ 2 mg every 4 weeks; 2q8 ⫽ 2 mg for
`3 initial monthly doses then every 8 weeks; 2PRN ⫽ 2 mg for 3 initial
`monthly doses then as needed; N/A ⫽ not applicable; SD ⫽ standard
`deviation.
`
`deviation of 10 letters per group, with a 2-sided t test at an ␣ level
`of 5%/4 ⫽ 0.0125). Change from baseline in BCVA and OCT
`were analyzed using analysis of covariance, models with the
`baseline value as covariate and the treatment as fixed factor.
`Hochberg’s procedure was used for the primary analysis to control
`for the multiple comparisons. No adjustments for multiplicity were
`made for the secondary variables. The proportions of patients in
`the VEGF Trap-Eye arms gaining 10 letters or more (15 letters or
`more) were compared with the laser arm using the Fisher exact
`test. Other secondary end points, as well as demographic, baseline,
`and safety data, were evaluated using summary statistics.
`
`Results
`
`Patient Disposition and Demographics
`A total of 221 eyes were randomized, 219 were treated, and 176
`completed the 52-week study (Table 1, available at http://aaojournal.
`org). Forty-three patients discontinued the study after receiving at
`least 1 treatment for the following reasons: lost to follow-up (n ⫽ 11),
`withdrew consent (n ⫽ 11), death (n ⫽ 6), treatment failures (n ⫽ 2),
`AE (n ⫽ 7), protocol deviation (n ⫽ 2), other (n ⫽ 4). Discontinu-
`ations were distributed evenly among all the treatment groups. De-
`mographic information and baseline characteristics are provided in
`Table 2 (available at http://aaojournal.org). The groups generally
`were similar, although the VEGF Trap-Eye 2q8 group had a higher
`prevalence of proliferative diabetic retinopathy (regressed at base-
`line) compared with the other treatment groups. In addition, a
`history of cardiac disease was more common in the VEGF Trap-
`Eye groups compared with the laser group.
`
`Treatment and Exposure Summary
`Over the 52 weeks of the study, the mean number of VEGF
`Trap-Eye injections administered was similar to the number of
`required injections for the group (Table 3). The VEGF Trap-Eye
`groups received an average of less than 1 laser treatment between
`month 6 and month 12 (up to 2 laser treatments were allowed from
`week 24 to week 48). For the laser treatment group, the mean
`number of laser treatments was 2.5 (up to 4 laser treatments were
`allowed from baseline to week 48).
`
`Efficacy
`Treatment with VEGF Trap-Eye produced statistically significant
`improvements in BCVA in all treatment groups compared with
`
`laser at both week 24 (the primary outcome) and week 52 (week
`52, P⬍0.001; Fig 2).27 The ranges of improvement were ⫹8.5
`to ⫹11.4 letters at week 24 and ⫹9.7 to ⫹13.1 letters at week 52.
`No significant differences were observed among the VEGF Trap-
`Eye treatment groups. Waterfall plots displaying BCVA changes
`for individual eyes indicate that few patients in the VEGF Trap-
`Eye groups experienced any loss of vision (Fig 3). At week 52, the
`proportion of eyes that gained 15 letters or more was statistically
`greater (Pⱕ0.001) than that in the laser treatment group in all
`VEGF Trap-Eye groups except 2q8 (Fig 4). The percentages of
`eyes that gained 10 letters or more were 57%, 71%, 45%, 62%,
`and 30%, for the 0.5q4, 2q4, 2q8, 2PRN, and the laser groups,
`respectively.
`Eyes treated with each VEGF Trap-Eye dosing regimen expe-
`rienced statistically significant reductions in CRT compared with
`eyes undergoing laser treatment (week 52, P ⬍ 0.0001; Fig 5). For
`eyes on the VEGF Trap-Eye treatment regimens, CRT continued
`to decrease through week 52.
`For each study eye, baseline diabetic retinopathy severity was
`recorded using the Diabetic Retinopathy Severity Score (Table 2,
`available at http://aaojournal.org). At week 52, 40%, 31%, 64%,
`and 32% of the 0.5q4, 2q4, 2q8, and 2PRN VEGF Trap-Eye
`groups, respectively, had an improvement in their Diabetic Reti-
`nopathy Severity Score compared with 12% in the laser group. In
`addition, eyes treated with VEGF Trap-Eye were less likely to
`have worsening of their Diabetic Retinopathy Severity Score com-
`pared with laser-treated eyes (0%, 13%, 0%, and 14% in the 0.5q4,
`2q4, 2q8, and 2PRN VEGF Trap-Eye groups and 24% in the laser
`group).
`
`Safety
`Vascular Endothelial Growth Factor Trap-Eye was well tolerated,
`and the most common ocular AEs that occurred were typical of
`those associated with intravitreal injections (Table 4, available at
`http://aaojournal.org). The most frequent were conjunctival hem-
`orrhage, eye pain, increased intraocular pressure, ocular hyper-
`emia, cataract, and vitreous floaters. Approximately 11% of pa-
`tients treated with VEGF Trap-Eye experienced an AE of
`increased intraocular pressure immediately after the intravitreal
`injection; however, only 2 of these patients had an increase of
`more than 10 mmHg. Two patients who were randomized to
`
`Figure 2. Graph showing mean changes in best-corrected visual acuity
`letter score by treatment groups (laser and Vascular Endothelial Growth
`Factor [VEGF] Trap-Eye) using last observation carried forward analysis:
`n ⫽ 44 (laser; VEGF Trap-Eye 0.5 mg every 4 weeks [0.5 q4] and 2 mg
`every 4 weeks [2q4]); n ⫽ 42 (VEGF Trap-Eye 2 mg for 3 initial monthly
`doses then every 8 weeks [2q8]); n ⫽ 45 (VEGF Trap-Eye 2 mg for 3 initial
`monthly doses then as needed [2PRN]). Difference between each treat-
`ment versus laser at week 52 was assessed using an analysis of covariance.
`*P ⬍ 0.0001. ETDRS ⫽ Early Treatment Diabetic Retinopathy Study.
`
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`n=44
`
`n=45
`
`Ophthalmology Volume 119, Number 8, August 2012
`
`2q4
`
`2PRN
`
`60
`50
`40
`30
`20
`10
`0
`-10
`-20
`-30
`-40
`-50
`-60
`60
`50
`40
`30
`20
`10
`0
`-10
`-20
`-30
`-40
`-50
`-60
`
`Change from BL in VA
`Change from BL in VA
`
`Change from BL in VA
`
`n=44
`
`n=42
`
`Laser
`
`50
`40
`30
`20
`10
`0
`-10
`-20
`-30
`-40
`-50
`-60
`-70
`
`n=44
`
`0.5q4
`
`2q8
`
`60
`50
`40
`30
`20
`10
`0
`-10
`-20
`-30
`-40
`-50
`-60
`60
`50
`40
`30
`20
`10
`0
`-10
`-20
`-30
`-40
`-50
`-60
`
`Change from BL in VA
`
`Change from BL in VA
`
`Figure 3. Graphs showing individual changes in best-corrected visual acuity (BCVA) letter score by treatment groups (laser and Vascular Endothelial
`Growth Factor Trap-Eye). Each bar corresponds to an individual patient. Dotted line represents median BCVA. 0.5q4 ⫽ 0.5 mg every 4 weeks; 2q4 ⫽ 2 mg
`every 4 weeks; 2q8 ⫽ 2 mg for 3 initial monthly doses then every 8 weeks; 2PRN ⫽ 2 mg for 3 initial monthly doses then as needed; BL ⫽ baseline; PRN ⫽
`as needed; VA ⫽ visual acuity.
`
`VEGF Trap-Eye experienced injection-related endophthalmitis,
`and uveitis developed in 1 patient. Serious nonocular AEs were
`infrequent in all treatment groups (Table 5). The most common
`systemic AEs were hypertension, nausea, and congestive heart
`failure. Because of its limited sample size, this phase 2 study was
`not powered adequately to assess the significance of differences in
`AEs among the treatment arms.
`
`Seven deaths occurred during the study. One patient in the laser
`group died of cardiac arrest. One patient in the 0.5q4 group died of
`multiorgan failure. Three patients in the 2q4 group died: one of
`cerebral infarction, another from non–small-cell lung cancer, and
`the third from sudden death. Two patients in the 2q8 group died:
`one of renal failure and the other of acute coronary syndrome.
`None of the events that led to death in these patients was judged by
`
`Figure 4. Bar graph showing percentage of patients with changes in
`changes in best-corrected visual acuity at 12 months by treatment groups
`(laser and Vascular Endothelial Growth Factor [VEGF] Trap-Eye) using
`last observation carried forward analysis: n ⫽ 44 (laser; VEGF Trap-Eye
`0.5 mg every 4 weeks [0.5q4], 2 mg every 4 weeks [2q4]); n ⫽ 42 (VEGF
`Trap-Eye 2 mg for 3 initial monthly doses then every 8 weeks [2q8]); n ⫽
`45 (VEGF Trap-Eye 2 mg for 3 initial monthly doses then as needed
`[2PRN]). P ⫽ 0.0031, 0.5q4; P ⫽ 0.0007, 2q4; P ⫽ 0.1608, 2q8; P ⫽
`0.0016, 2PRN; all are compared with laser (analysis of covariance).
`
`Figure 5. Graph showing mean change in central retinal thickness (in
`micrometers) by treatment groups (laser and Vascular Endothelial Growth
`Factor [VEGF] Trap-Eye) over the course of 12 months using last obser-
`vation carried forward analysis: n ⫽ 44 (laser; VEGF Trap-Eye 0.5 mg
`every 4 weeks [0.5q4], 2 mg every 4 weeks [2q4]); n ⫽ 42 (VEGF Trap-Eye
`2 mg for 3 initial monthly doses then every 8 weeks [2q8]); n ⫽ 45 (VEGF
`Trap-Eye 2 mg for 3 initial monthly doses then as needed [2PRN]).
`*P ⬍ 0.0001, difference between each treatment versus laser analysis of
`covariance.
`
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`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`Do et al
`
`䡠 One-Year Outcomes of VEGF Trap-Eye for DME
`
`Table 5. Serious Systemic Adverse Events and Deaths by Treatment Group of 4% or More in Any Treatment Arm
`
`Vascular Endothelial Growth Factor Trap-Eye Treatment Groups
`2 mg for 3 Initial
`Monthly Doses
`Then Every
`8 Weeks
`
`2 mg Every
`4 Weeks
`
`2 mg for 3 Initial
`Monthly Doses
`Then as Needed
`
`Macular Laser
`Photocoagulation
`
`0 5 mg Every 4
`Weeks
`
`44
`10 (22.7%)
`
`44
`14 (31.8%)
`
`44
`13 (29.5%)
`
`42
`12 (28.6%)
`
`0
`0
`0
`1 (2.3%)
`0
`0
`0
`0
`0
`
`0
`3 (6.8%)
`0
`1 (2.3%)
`0
`1 (2.3%)
`0
`0
`3 (6.8%)
`
`3 (6.8%)
`2 (4.5%)
`2 (4.5%)
`2 (4.5%)
`2 (4.5%)
`2 (4.5%)
`0
`2 (4.5%)
`0
`
`1 (2.4%)
`0
`0
`0
`1 (2.4%)
`0
`2 (4.8%)
`0
`0
`
`45
`6 (13.3%)
`
`2 (4.4%)
`1 (2.2%)
`3 (6.7%)
`0
`0
`0
`0
`0
`0
`
`All Vascular
`Endothelial
`Growth Factor
`Trap-Eye
`
`175
`45 (25.7%)
`
`6 (3.4%)
`6 (3.4%)
`5 (2.9%)
`3 (1.7%)
`3 (1.7%)
`3 (1.7%)
`2 (1.1%)
`2 (1.1%)
`3 (1.7%)
`
`No. (safety analysis set)
`No. of subjects with at
`least 1 AE, n (%)
`Cardiac failure, congestive
`Cellulitis
`Chest pain
`Cerebrovascular accident
`Hypertension
`Anemia
`Dehydration
`Hyperglycemia
`Myocardial infarction and
`acute myocardial
`infarction
`Deaths*
`
`1 (2.3%)
`
`1 (2.3%)
`
`3 (6.8%)
`
`2 (4.5%)
`
`0
`
`7 (4.0%)
`
`AE ⫽ adverse event.
`*One death occurred after a patient in the 2 mg every 4 weeks group discontinued because of an AE.
`
`the investigators to be related to the study drug or to the study
`procedure.
`
`Discussion
`
`In this phase 2 clinical trial, all VEGF Trap-Eye doses and
`dosing regimens were found to be superior to macular laser
`photocoagulation for the treatment of DME over the course
`of 52 weeks and produced similar results in terms of pre-
`serving and improving visual acuity. Patients who received
`VEGF Trap-Eye benefited from significantly greater in-
`creases in mean visual acuity at 1 year (⫹9.7 to ⫹13.1
`letters of improvement) compared with laser treatment
`alone (⫺1.3 letters change; P⬍0.0001). However, it should
`be noted that this study was not powered adequately to be
`able to discern differences with regard to efficacy among the
`VEGF Trap-Eye treatment groups. In addition, a study of
`longer duration may be able to detect further improvements
`in visual acuity for the laser treatment arm.
`The administration of VEGF Trap-Eye over the course of
`this study generally was consistent with the number of
`treatments that had been planned, indicating good compli-
`ance with the protocol. There were a similar number of
`injections in the 2PRN (7.2) and 2q8 (7.4) groups. These
`numbers are consistent with the number of injections in the
`RESTORE (Efficacy and Safety of Ranibizumab [Intravit-
`real Injections] in Patients with Visual Impairment Due to
`Diabetic Macular Edema) trial for patients treated over 12
`months with ranibizumab or ranibizumab plus laser (7.0 and
`6.8 injections, respectively).22 Longer intervals between
`dosing may provide advantages compared with monthly
`dosing in terms of less frequent monitoring visits and
`a decreased number of injections. Benefits of an extended
`dosing interval may include not only improved safety with
`
`fewer injection-related complications such as endophthal-
`mitis, but also a decreased burden to the patient and their
`caregivers with fewer office visits. This benefit holds par-
`ticularly true for the 2q8 treatment schedule, which could
`reduce the number of visits by half (after the loading phase),
`whereas monthly visits would be needed for determining the
`need for treatment in a PRN schedule.
`The average number of laser treatments administered to
`eyes randomized to VEGF Trap-Eye was fewer than 1 (of a
`maximum of 2 possible lasers), with most patients not
`requiring laser photocoagulation, indicating that the visual
`acuity and anatomic benefits achieved were the result of
`VEGF Trap-Eye and not laser treatment. Eyes that were
`randomized to the laser group received an average of 2.5
`laser treatments (of a maximum of 4 possible lasers), indi-
`cating that nearly the maximum amount of laser was applied
`during the 52-week study period. For comparison, during
`the first year of Protocol I from the Diabetic Retinopathy
`Clinical Research Network (DRCR) study, eyes that were
`randomized to macular laser photocoagulation received a
`median of 3 laser treatments, with 40% of eyes requiring 2,
`1, or 0 additional treatments after the initial laser.30
`A larger proportion of eyes in all the VEGF Trap-Eye
`treatment groups experienced 15-letter or more gains in
`visual acuity at week 52 compared with eyes in the laser
`arm, and these differences were statistically significant for
`0.5q4, 2q4, and PRN treatments. The 2q4 treatment group
`had the highest percentage of eyes with visual acuity im-
`provements at every level (ⱖ0, ⱖ10, and ⱖ15 letters
`gained). The 2q8 group seemed to have less improvement in
`BCVA than in the other 2-mg groups. However, this dif-
`ference was observed during the first 3 months of the study,
`despite the identical 2-mg loading dose, and persisted
`through the end of the study; therefore, this difference in
`visual acuity gains likely is attributable to baseline differ-
`
`1663
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`Regeneron Pharmaceuticals, Inc. Exhibit 2014 Page 6
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
`

`

`Ophthalmology Volume 119, Number 8, August 2012
`
`ences among treatment groups, rather than to the dosing
`interval.
`In this clinical trial, combination treatment of VEGF
`Trap-Eye with laser photocoagulation was not investigated
`formally. Although eyes randomized to VEGF Trap-Eye
`could receive macular laser photocoagulation starting at
`week 24, most study eyes achieved gains in visual acuity
`with VEGF Trap-Eye monotherapy and did not require the
`addition of laser. Similarly, other studies20,21 demonstrated
`that the combination of VEGF inhibitor with laser does not
`seem to provide any additional benefit in visual acuity gains
`or reductions in retinal thickness compared with VEGF
`inhibition alone.
`Significantly greater mean reductions in retinal thickness
`were observed at week 52 for eyes undergoing the VEGF
`Trap-Eye regimens than for those treated with laser alone.
`Retinal thickness continued to decrease for eyes in the
`VEGF Trap-Eye arms after the week 24 primary end point.
`Eyes randomized to VEGF Trap-Eye also were more
`likely to have an improvement in their diabetic retinopathy
`severity scale compared with laser-treated eyes. The bio-
`logic activity of VEGF Trap-Eye not only may treat DME,
`but also it can reduce the severity of diabetic retinopathy.
`This positive effect can be beneficial to patients who are at
`risk for severe vision loss associated with the development
`of proliferative diabetic retinopathy.
`Vascular Endothelial Growth Factor Trap-Eye was well
`tolerated, and the incidence of ocular AEs was low. The rate
`of endophthalmitis was consistent with that observed for
`ranibizumab in the RESOLVE (Safety and Efficacy of
`Ranibizumab in Diabetic Macular Edema With Center In-
`volvement) study (2%).31 Most of the systemic AEs ob-
`served were attributed to the underlying medical conditions
`and cardiovascular comorbidities of these diabetic patients.
`Studies have shown that individuals with diabetes seem to
`have an approximately 2- to 4-fold greater risk for both
`heart disease and stroke.32–34 Most of the dea