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`Retinal Physician - VEGF Trap-Eye for Exudative AMD
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`Article
`
`VEGF Trap-Eye for Exudative AMD
`
`April 1, 2009
`
`9
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`VEGF Trap-Eye for Exudative AMD
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`BY JEFFREY S. HEIER, MD
`
`The vascular endothelial growth factor (VEGF) family is a group of molecules that direct both normal and
`pathological processes in the body. Certain members of the family and their receptors have been implicated in the
`angiogenesis underlying pathological disease processes, including the development of eye diseases such as
`neovascular (wet) age-related macular degeneration (AMD). Despite recent therapeutic advances, wet AMD
`1
`continues to be debilitating and rapidly progressive, often having a dramatic impact on the lives of patients, as
`2
`well as their caregivers. It is the leading cause of vision loss in adults aged 50 years and older in many regions,
`3
`including North America and Europe.
`
`Endothelial growth and angiogenesis, caused by vascular endothelial growth factors, hypoxia, wound healing, and
`4,5
`inflammation, are believed to contribute to wet AMD development.
` Blocking VEGF activities has become a
`6,7
`mainstay therapy for treating eye diseases that have angiogenesis at their etiological core.
` Although highly
`effective at delaying disease progression, current therapies do not always prevent loss of visual acuity or
`consistently improve lost vision. Moreover, treatment often requires frequent office visits and intravitreal
`6,8
`injections.
`
`THE VEGF FAMILY AND ITS BIOLOGICAL FUNCTION
`
`Vascular endothelial growth factor has been implicated as a primary player in angiogenesis. The first molecule
`discovered in this growth factor family was VEGF-A. Other family members found in mammalian species include
`9,10
`placental growth factor (PlGF), VEGF-B, VEGF-C, and VEGF-D,
` but VEGF-A and PlGF are believed to be the
`11,12
`predominant factors involved in angiogenesis.
` There is evidence that VEGF-A has physiological roles in
`13,14
`promoting angiogenesis during development, injury,
` and promoting vascular permeability and thereby wound
`9,10
`healing. However, this latter effect can increase leakage in diseases such as wet AMD.
` PlGF has been
`15,16
`described as promoting pathological angiogenesis, but its role is less understood than that of VEGF-A.
`Several recent studies using animal models have implicated PlGF purely in disease-related angiogenesis (such as
`17-21
`ischemia, inflammation, wound healing, and cancer).
`
`9,10
`There are 2 primary receptors in the VEGF family, VEGFR1 and VEGFR2.
` VEGFR2 is best characterized in
`terms of its role in angiogenesis: VEGF-A binds to VEGFR2 to stimulate angiogenesis. Although its precise role
`continues to be investigated, recent research suggests a role for PlGF in promoting pathologic angiogenesis as
`well. PlGF binds to the VEGFR1, potentially stimulating angiogenesis directly through a signaling pathway through
`this receptor. Alternatively, the role of PlGF may be to compete with VEGF-A for VEGFR1, allowing VEGF-A to
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`Retinal Physician - VEGF Trap-Eye for Exudative AMD
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`bind to VEGFR2 and stimulate angiogenesis. PlGF may also serve as a chemoattractant for inflammatory cells
`stimulating the VEGFR1 on monocytes, increasing their migration and stimulating production of VEGF and other
`inflammatory mediators. A third receptor, VEGFR3, regulates the development of lymphatic endothelial cells.
`9
`
`Jeffrey S. Heier, MD, is a vitreoretinal surgeon at Ophthalmic Consultants of Boston and president of the Center
`for Eye Research and Education in Boston. He reports moderate financial interest in Regeneron. Writing
`assistance was provided by Alisa G Woods, PhD and Euro RSCG Life through funding from Regeneron
`Pharmaceuticals, Inc. and BayerHealthcare.
`
`VEGF TRAP-EYE DESIGN
`
`Regeneron's VEGF Trap-Eye is a cytokine trap — a soluble fusion protein currently being evaluated to treat retinal
`diseases. Traps include 2 extracellular cytokine receptor domains and a human Fc region of immunoglobulin G
`(IgG).
` Because VEGF Trap-Eye is biologically engineered, specific properties of different naturally occurring
`22
`component molecules were selected for their therapeutic potential. VEGF Trap-Eye includes specific extracellular
` As seen in Figures 1
`components of VEGF receptors 1 and 2 fused to the constant region (Fc) of IgG1.
`11,23-25
`and 2, this results in 2 identical arms, each constructed from select pieces of both VEGFR1 and VEGFR2. These
`components were selected based on their high affinity for both VEGF-A and PlGF. VEGF Trap-Eye contains all-
`human amino acid sequences, giving it a low potential for immunogenicity in humans.
` VEGF Trap-Eye binds
`11
`both VEGF-A and PlGF, and it does so with higher affinity than they do to their native receptors. VEGF Trap-Eye
`uniquely binds both ends of activated dimerized VEGF or PlGF between its arms, preventing it from binding to the
`native receptors or cross-linking, which is possible due to the binding properties of monoclonal
`antibodies.
` VEGF Trap-Eye has been developed exclusively for ophthalmic use. The ophthalmic
`6,11,23,26,27
`formulation is specifically purified and formulated as an iso-osmotic solution to avoid irritation of the eye.
`
`Figure 1. A key binding domain of VEGFR1 and a key binding domain of VEGFR2 (left) are fused for tight
`binding affinity for both VEGF-A isomers and PlGF (center). Two dual-domain arms are used for one VEGF
`Trap-Eye molecule to mimic the natural receptor pairing necessary for growth factor signaling (right).
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`Retinal Physician - VEGF Trap-Eye for Exudative AMD
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`Figure 2. The Fc portion of IgG1 (left) is fused to the two dual-domain arms (center) resulting in the
`engineered molecule of VEGF Trap-Eye (right). This exemplifies how a molecule can be designed to
`possess specific properties of different naturally-occurring molecules with a goal of optimizing
`therapeutic activity.
`
`VEGF TRAP-EYE MECHANISM OF ACTION
`
`VEGF Trap-Eye was developed in an effort to address the unmet need for wet AMD treatments that produce
`sustainable improvements in visual acuity and/or reduced injection frequency. Based on its unique binding
`properties (which are distinct from VEGF antibodies/antibody fragments), predictive modeling studies indicate that
`VEGF Trap-Eye should have a longer duration of activity than currently available treatments.
` Each arm of
`28,29
`VEGF Trap-Eye binds to the binding interface on each pole of the active VEGF or PlGF dimer. This forms a stable
`and inert 1:1 complex with the growth factor,
` uniquely binding the dimer on both sides. The Trap is aptly named,
`12
`since the molecule isolates (or traps) the dimer, forming inert complexes with the growth factor
` that do not
`12
`interact with more than 1 VEGF Trap molecule. This blocks and effectively arrests the VEGF angiogenesis
`cascade. It also prevents the creation of multimeric complexes that might aggregate and cause immune responses
`in body tissues. VEGF Trap-Eye binds VEGF more tightly than native receptors, blocking cell-surface receptor
`activation.
` VEGF antibodies and their fragments bind with lower affinity, allowing VEGF dimers to occasionally
`23
`interact with other molecules, including their receptors.
` VEGF Trap-Eye has undergone phase 1 and phase 2
`6,30
`clinical trials in wet AMD, and is currently in phase 3 testing.
`
`PHASE 1 STUDY IN WET AMD
`
`CLEAR-IT 1 (CLinical Evaluation of Anti-angiogenesis in the Retina Intravitreal Trial) evaluated safety, tolerability,
`and biologic activity of intravitreal VEGF Trap-Eye in patients with wet AMD. Safety was the primary endpoint. The
`primary efficacy measure was the change from baseline in central retinal lesion thickness, determined by an
`independent optical coherence tomography (OCT) reading center. Best-corrected visual acuity (BCVA), as graded
`on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, was conducted using the Electronic Visual
`Acuity (EVA) system.
`31,32
`
`Part 1 (N=21) was a single, ascending-dose 6-week study. One intravitreal VEGF Trap-Eye injection was given
`(0.05, 0.15, 0.5. 1, 2, or 4 mg), which reduced retinal thickness and improved visual acuity for the combined
`experimental groups vs baseline. BCVA scores improved by a mean of 4.4 letters and central retinal lesion
`thickness diminished by 78.8 μm. The effects of VEGF Trap-Eye appeared durable; patients averaged >5 months
`before retreatment was necessary in an extension study, with a mean time to retreatment of 166 days.
` Part 2
`31,32
`was a parallel-group, randomized, 8-week trial (N=28), examining 1 intravitreal VEGF Trap-Eye injection (0.15 or 4
`mg). Both doses diminished retinal thickness at 2 weeks, with a significantly greater reduction in retinal thickness
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`Retinal Physician - VEGF Trap-Eye for Exudative AMD
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`in the 4-mg group at weeks 4 and 8. The 4-mg dose significantly improved visual acuity at 4, 6, and 8 weeks. In
`both parts of this study, intravitreal injection of up to 4 mg of VEGF Trap-Eye was well tolerated, with no clinically
`significant intraocular inflammation.
` In part 1, no inflammation or endophthalmitis was observed. No serious
`31,32
`ocular adverse events occurred, ocular adverse events were mild to moderate in severity, and only 1 ocular
`adverse event was related to the study drug.
` Most adverse events in Part 2 were related to the injection
`32
`procedure. No ocular inflammation was evident. In subjects with increased intraocular pressure, none exceeded
`30 mm Hg.
`31
`
`PHASE 2 STUDY IN WET AMD
`
`CLEAR-IT 2 was designed based upon results of CLEAR-IT 1. This was a randomized, controlled, doseand
`33
`interval-ranging study of intravitreal VEGF Trap-Eye in patients with wet AMD. Patients were randomized into 5
`groups (N=159 randomized, N=157 treated) and treated with VEGF Trap-Eye in the study eye at 0.5 mg and 2.0
`mg q4 weeks, and 0.5, 2.0, and 4.0 mg q12 weeks for 12 weeks, followed by as-needed (prn) dosing through
`week 52. Retinal thickness, visual acuity, and safety were measured. The primary endpoint was change in central
`retinal lesion thickness as determined from Stratus OCT scans read at an independent reading center.
`
`Treatment with VEGF Trap-Eye induced clinically meaningful and durable vision improvement over 1 year. At 12
`weeks, VEGF Trap-Eye significantly improved visual acuity, with a mean of +5.7 letters gained for all groups
`combined. At 12 weeks there was also significantly reduced retinal thickness, with a mean reduction of 119 μm for
`all groups combined. There was a 5.3 mean letter gain in visual acuity vs baseline (P<.0001) and a mean
`decrease in retinal thickness of 130 μm vs baseline (P<.0001) for all dose-groups combined at week 52. During
`the prn dosing period from week 12 to week 52, patients from all dose groups combined received, on average,
`only 2 additional injections.
`
`Patients receiving 4 monthly doses of VEGF Trap-Eye, either 2.0 or 0.5 mg, for 12 weeks followed by prn dosing
`thereafter, achieved mean improvements in visual acuity vs baseline of 9.0 letters (P<.0001) and 5.4 letters
`(P=.085), respectively, and mean decreases in retinal thickness vs baseline of 143 μm (P<.0001) and 125 μm
`(P<0.0001) at week 52, respectively. During the subsequent prn dosing phase, patients initially dosed on a 2.0 mg
`monthly schedule received, on average, only 1.6 additional injections, and those initially dosed on a 0.5 mg
`monthly schedule received, on average, 2.5 injections.
`
`While prn dosing following a fixed quarterly dosing regimen (with dosing at baseline and week 12) also yielded
`improvements in visual acuity and retinal thickness vs baseline at week 52, the results generally were not as
`robust as those obtained with initial fixed monthly dosing.
`
`On fluorescein angiography, VEGF Trap-Eye was associated with a reduction in the size of the total active
`choroidal neovascularization. In addition, all groups showed either stabilization or a reduction in total lesion size,
`with the 2.0 mg q4 week group reaching a statistically significant reduction.
`
`VEGF Trap-Eye was generally well tolerated and there were no drug-related serious adverse events. There was 1
`reported case of culture-negative endophthalmitis/uveitis in the study eye and 1 arterial thrombotic event, neither
`of which was deemed to be drug-related. The most common adverse events were those typically associated with
`intravitreal injections.
`
`PHASE 3 STUDIES IN WET AMD
`
`Two identical, noninferiority Phase 3 studies called VIEW 1 and VIEW 2 (VEGF Trap-Eye: Investigation of Efficacy
`and Safety in Wet AMD)
` are currently under way to examine the effects of VEGF Trap-Eye in wet AMD. These
`34
`trials have been designed to evaluate VEGF Trap-Eye vs the standard dosing schedule for the monoclonal
`antibody fragment ranibizumab, 0.5 mg monthly. Four treatment groups will be followed for 52 weeks: 3 VEGF
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`Trap-Eye treatment groups, 0.5 mg q 4 weeks, 2.0 mg q 4 weeks, and 2.0 mg q 8 weeks will be compared with
`ranibizumab 0.5 mg q 4 weeks. VIEW 1 and 2 are randomized, double-masked, active-controlled efficacy and
`safety studies with a primary endpoint of the prevention of moderate vision loss at the end of 1 year. Visual acuity
`will be assessed using total number of letters read correctly on the ETDRS chart.
`
`SUMMARY AND KEY POINTS
`
`VEGF Trap-Eye is a promising investigational compound in development for the treatment of eye diseases
`characterized by the pathologic production of VEGF, including wet AMD and diabetic macular edema. It is a fully
`human fusion protein of VEGFR1 and VEGFR2. It uniquely blocks all forms of VEGF-A, as well as PlGF, each arm
`binding to each pole of an active growth factor dimer. This forms a stable and inert 1:1 complex. Its high affinity
`allows it to bind growth factors more tightly than naturally occurring VEGF receptors or antibodies, perhaps leading
`to more complete blockade of VEGF signaling and potentially an increased duration of efficacy. To date, VEGF
`Trap-Eye has demonstrated encouraging efficacy and safety in phase 1 and 2 clinical trials in the treatment of wet
`AMD and in a phase 1 study for diabetic macular edema.
` A phase 2 dose-ranging study comparing various
`35
`doses of VEGF Trap-Eye for DME administered at various dosing intervals to focal laser treatment is currently
`ongoing (the DA VINCI study).
` Phase 3 studies for the treatment of exudative AMD (VIEW1 and VIEW2) are
`34
`currently in progress and will further explore whether VEGF Trap-Eye will provide a sustainable improvement in
`clinical effect with prolonged dosing intervals. RP
`
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`at: Association for Research in Vision and Ophthalmology (ARVO); May 6-10, 2007; Fort Lauderdale, FL.
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`Retinal Physician, Issue: April 2009
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