`
`Retinal Physician - VEGF Trap-Eye for Exudative AMD
`
`Article
`
`VEGF Trap-Eye for Exudative AMD
`
`April 1, 2009
`
`9
`
`VEGF Trap-Eye for Exudative AMD
`
`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
`
`https://www.retinalphysician.com/issues/2009/april-2009/vegf-trap-eye-for-exudative-amd
`
`1/7
`
`Exhibit 2080
`Page 01 of 07
`
`
`
`Retinal Physician - VEGF Trap-Eye for Exudative AMD
`2/7/22, 8:15 AM
`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).
`
`https://www.retinalphysician.com/issues/2009/april-2009/vegf-trap-eye-for-exudative-amd
`
`2/7
`
`Exhibit 2080
`Page 02 of 07
`
`
`
`2/7/22, 8:15 AM
`
`Retinal Physician - VEGF Trap-Eye for Exudative AMD
`
`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
`
`https://www.retinalphysician.com/issues/2009/april-2009/vegf-trap-eye-for-exudative-amd
`
`3/7
`
`Exhibit 2080
`Page 03 of 07
`
`
`
`Retinal Physician - VEGF Trap-Eye for Exudative AMD
`2/7/22, 8:15 AM
`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
`
`https://www.retinalphysician.com/issues/2009/april-2009/vegf-trap-eye-for-exudative-amd
`
`4/7
`
`Exhibit 2080
`Page 04 of 07
`
`
`
`Retinal Physician - VEGF Trap-Eye for Exudative AMD
`2/7/22, 8:15 AM
`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
`
`REFERENCES
`
`1. Gehrs KM, Anderson DH, Johnson LV, Hageman GS. Age-related macular degeneration—emerging
`pathogenetic and therapeutic concepts. Ann Med. 2006;38:450-471.
`2. Schmier JK, Jones ML, Halpern MT. The burden of age-related macular degeneration.
`Pharmacoeconomics. 2006;24:319-334.
`3. AMDAllianceInternational. Impact of AMD-Overview.
`http://www.amdalliance.org/professionals/impactofamd/overview.php. Accessed Feb 19, 2009, 2009.
`4. Kleinman ME, Ambati J. Molecular Mechanisms of Neovascularization in AMD. Retinal Physician. Feb 7,
`2009; http://www.retinalphysician.com/article.aspx?article=101897.
`5. Lotery A, Trump D. Progress in defining the molecular biology of age related macular degeneration. Hum
`Genet. 2007;122:219-236.
`6. Chappelow AV, Kaiser PK. Neovascular age-related macular degeneration: potential therapies. Drugs.
`2008;68:1029-1036.
`7. van Wijngaarden P, Qureshi SH. Inhibitors of vascular endothelial growth factor (VEGF) in the management
`of neovascular age-related macular degeneration: a review of current practice. Clin Exp Optom.
`2008;91:427-437.
`8. Emerson MV, Lauer AK. Emerging therapies for the treatment of neovascular age-related macular
`degeneration and diabetic macular edema. BioDrugs. 2007;21:245-257.
`9. Breen EC. VEGF in biological control. J Cell Biochem. 2007;102:1358-1367.
`10. Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L. VEGF receptor signalling- in control of vascular
`function. Nat Rev Mol Cell Biol. 2006;7:359-371.
`11. Holash J, Davis S, Papadopoulos N, et al. VEGF Trap: a VEGF blocker with potent antitumor effects. Proc
`Natl Acad Sci U S A. 2002;99:11393-11398.
`12. Rudge JS, Holash J, Hylton D, et al. Inaugural Article: VEGF Trap complex formation measures production
`rates of VEGF, providing a biomarker for predicting efficacious angiogenic blockade. Proc Natl Acad Sci U S
`A. 2007;104:18363-18370.
`13. Gerber HP, Hillan KJ, Ryan AM, et al. VEGF is required for growth and survival in neonatal mice.
`Development. 1999;126:1149-1159.
`
`https://www.retinalphysician.com/issues/2009/april-2009/vegf-trap-eye-for-exudative-amd
`
`5/7
`
`Exhibit 2080
`Page 05 of 07
`
`
`
`Retinal Physician - VEGF Trap-Eye for Exudative AMD
`2/7/22, 8:15 AM
`14. Wiegand SJ, Zimmer E, Nork TM, et al. VEGF Trap both prevents experimental choroidal
`neovascularization and causes regression of established lesions in non-human primates. Invest.
`Ophthalmol Vis Sci. 2005;46:(E-Abstr. 1411).
`15. Jain RK, Xu L. alphaPlGF: a new kid on the antiangiogenesis block. Cell. 2007;131:443-445.
`16. Odorisio T, Cianfarani F, Failla CM, Zambruno G. The placenta growth factor in skin angiogenesis. J
`Dermatol Sci. 2006;41:11-19.
`17. 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 pathological conditions. Nat Med.
`2001;7:575-583.
`18. Ziche M, Maglione D, Ribatti D, et al. Placenta growth factor-1 is chemotactic, mitogenic, and angiogenic.
`Lab Invest. 1997;76:517-531.
`19. Rakic JM, Lambert V, Devy L, et al. Placental growth factor, a member of the VEGF family, contributes to the
`development of choroidal neovascularization. Invest Ophthalmol Vis Sci. 2003;44:3186-3193.
`20. Khaliq A, Foreman D, Ahmed A, et al. Increased expression of placenta growth factor in proliferative
`diabetic retinopathy. Lab Invest. 1998;78:109-116.
`21. Mitamura Y, Tashimo A, Ohtsuka K, Mizue Y, Nishihira J. Placenta growth factor and vascular endothelial
`growth factor in the vitreous of patients with proliferative vitreoretinopathy. Clin Experiment Ophthalmol.
`2005;33:226-227.
`22. Economides AN, Carpenter LR, Rudge JS, et al. Cytokine traps: multi-component, high-affinity blockers of
`cytokine action. Nat Med. 2003;9:47-52.
`23. Rudge JS, Thurston G, Davis S, et al. VEGF trap as a novel antiangiogenic treatment currently in clinical
`trials for cancer and eye diseases, and VelociGene-based discovery of the next generation of angiogenesis
`targets. Cold Spring Harbor Symp Quant Biol. 2005;70:411-418.
`24. Kaiser PK. Antivascular endothelial growth factor agents and their development: therapeutic implications in
`ocular diseases. Am J Ophthalmol. 2006;142:660-668.
`25. Konner J, Dupont J. Use of soluble recombinant decoy receptor vascular endothelial growth factor trap
`(VEGF Trap) to inhibit vascular endothelial growth factor activity. Clin Colorectal Cancer. 2004;4(Suppl
`2):S81-S85.
`26. Regeneron/Bayer. Data on file. 2008.
`27. Cursiefen C, Chen L, Borges LP, et al. VEGF-A stimulates lymphangiogenesis and hemangiogenesis in
`inflammatory neovascularization via macrophage recruitment. J Clin Invest. 2004;113:1040-1050.
`28. Stewart MW. Predicted biologic activity of intravitreal bevacizumab. Retina. 2007;27:1196-1200.
`29. Stewart MW, Rosenfeld PJ. Predicted biological activity of intravitreal VEGF Trap. Br J Ophthalmol.
`2008;92:667-668.
`30. Lowe J, Araujo J, Yang J, et al. Ranibizumab inhibits multiple forms of biologically active vascular
`endothelial growth factor in vitro and in vivo. Exp Eye Res. 2007;85:425-430.
`31. Nguyen QD, Hariprasad S, Browning DJ, et al. Interim results from a Phase 1, safety, tolerability, and
`bioactivity study of intravitreal VEGF trap in patients with neovascular age-related macular degeneration: the
`CLEAR-IT 1 study. Paper presented at: Annu Meet Assoc Res Vision Ophthalmol (ARVO), 2007; Fort
`Lauderdale, FL.
`32. Nguyen QD, Shah SM, Browning DJ, et al. Results of a phase I, dose-escalation, safety, tolerability, and
`bioactivity study of intravitreous VEGF Trap in patients with neovascular age-related macular degeneration.
`Paper presented at: Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO);
`April 30-May 4, 2006; Fort Lauderdale, FL.
`33. Heier J. VEGF Trap-Eye for exudative AMD. Paper presented at: Macula 2009; January 16-17, 2009; New
`York, NY.
`34. Regeneron/Bayer. Data on File. 2009.
`35. Do DV, Nguyen QD, Browning DJ, et al. An exploratory study of the safety, tolerability and biological effect
`of a single intravitreal administration of VEGF trap in patients with diabetic macular edema. Paper presented
`https://www.retinalphysician.com/issues/2009/april-2009/vegf-trap-eye-for-exudative-amd
`
`6/7
`
`Exhibit 2080
`Page 06 of 07
`
`
`
`Retinal Physician - VEGF Trap-Eye for Exudative AMD
`2/7/22, 8:15 AM
`at: Association for Research in Vision and Ophthalmology (ARVO); May 6-10, 2007; Fort Lauderdale, FL.
`
`Retinal Physician, Issue: April 2009
`Table of Contents
`Archives
`
`Copyright © 2022, PentaVision, Inc. All rights reserved. Privacy Policy
`
`https://www.retinalphysician.com/issues/2009/april-2009/vegf-trap-eye-for-exudative-amd
`
`7/7
`
`Exhibit 2080
`Page 07 of 07
`
`