1 Mayo Clinic College of
`Medicine, Jacksonville, Florida,
`USA; 2 Bascom Palmer Eye
`Institute, University of Miami
`Miller School of Medicine,
`Miami, Florida, USA
`
`Correspondence to:
`Dr M W Stewart, Department of
`Ophthalmology, 4500 San Pablo
`Rd, Jacksonville, FL 32224,
`USA; stewart.michael@mayo.
`edu
`
`Accepted 11 February 2008
`Published Online First
`20 March 2008
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`Clinical science
`
`Predicted biological activity of intravitreal VEGF Trap
`
`M W Stewart,1 P J Rosenfeld2
`
`ABSTRACT
`Aim: To compare the intravitreal binding activity of VEGF
`Trap with that of ranibizumab against vascular endothelial
`growth factor (VEGF) using a time-dependent and dose-
`dependent mathematical model.
`Methods: Intravitreal half-lives and relative equimolar
`VEGF-binding activities of VEGF Trap and ranibizumab
`were incorporated into a first-order decay model. Time-
`dependent VEGF Trap activities (relative to ranibizumab)
`for different initial doses (0.5, 1.15, 2 and 4 mg) were
`calculated and plotted.
`Results: Seventy-nine days after a single VEGF Trap
`(1.15 mg) injection, the intravitreal VEGF-binding activity
`would be comparable to ranibizumab at 30 days. After
`injection of 0.5, 2 and 4 mg VEGF Trap, the intravitreal
`VEGF-binding activities (comparable to ranibizumab at
`30 days) would occur at 73, 83 and 87 days, respectively
`Conclusion: On the basis of this mathematical model,
`VEGF Trap maintains significant intravitreal VEGF-binding
`activity for 10–12 weeks after a single injection.
`
`(VEGF), a
`Vascular endothelial growth factor
`potent vasoactive cytokine, mediates the patholo-
`gical angiogenesis and hyperpermeability asso-
`ciated with
`several
`chorioretinal
`vascular
`disorders including neovascular age-related macular
`degeneration (AMD). Attempts to stabilise and
`improve the condition of patients with AMD have
`led to the development and subsequent Food and
`Drug Administration (FDA) approval of two drugs
`action: pegaptanib1
`with anti-VEGF
`sodium
`(Macugen, a pegylated aptamer from Eyetech/
`and ranibizumab2 3
`OSI, New York, USA)
`(Lucentis), a recombinant, humanised, antibody
`fragment from Genentech Inc (San Francisco,
`California, USA). In addition, administration of
`intravitreal bevacizumab (Avastin), a full-length,
`recombinant,
`humanised
`antibody
`from
`Genentech and approved for the systemic treat-
`ment of metastatic colon cancer, appears to be
`useful for the treatment of neovascular AMD.4 The
`intravitreal administration of each of these drugs is
`likely to achieve high intraocular concentrations
`with low systemic levels and few adverse effects.
`VEGF Trap, a 110 kDa soluble protein, contains
`extracellular VEGF receptor sequences (VEGFR1
`and VEGFR2) fused to an IgG backbone.5 Although
`its intraocular duration of action is unknown, its
`high VEGF-binding affinity suggests a longer
`period of biological activity than ranibizumab.
`This report presents a time-dependent mathe-
`matical model of intraocular VEGF Trap activity
`relative to ranibizumab.
`
`METHODS AND RESULTS
`VEGF Trap has a very high VEGF-binding af-
`finity (Kd ,1 pmol/l),6 about 140 times that of
`
`laboratory and
`ranibizumab. On the basis of
`clinical data,
`significant biological activity of
`ranibizumab (0.5 mg) persists for 30 days after
`intravitreal administration.7
`If we assume that the intravitreal half-lives of
`antibodies and antibody fragments are propor-
`tional to their molecular masses, then we can
`predict the intravitreal half-life of VEGF Trap in
`primates even though it is not known. We know
`that its molecular mass is 110 kDa, approximately
`half way between that of ranibizumab (48 kDa)
`and that of bevacizumab (148 kDa). As a monkey
`model showed that rhuFab VEGF (a 48 kDa
`antibody fragment) has an intravitreal half-life of
`3.2 days and rhuMab HER2 (a 148 kDa antibody
`similar to bevacizumab) has an intravitreal half-life
`of 5.6 days,8 the half-life of VEGF Trap in a primate
`eye may be reasonably estimated as 4–5 days. In a
`rabbit model, VEGF Trap concentration decreased
`according to first-order kinetics, with a half-life of
`4.79 days
`(unpublished data from Regeneron
`Pharmaceuticals, Tarrytown, New York, USA);
`this value was used for the calculations that
`follow.
`A pharmacokinetic single-compartment rabbit
`model
`showed that
`intravitreal bevacizumab
`concentration decreases according to first-order
`decay.9 Therefore, after a 1.15 mg injection of
`VEGF Trap (1.15 mg VEGF Trap is equimolar to
`0.5 mg ranibizumab), the intravitreal biological
`activity of VEGF Trap, relative to ranibizumab,
`can be calculated according to the following
`equation:
`
`At = Are2kt
`
`where At is the time-dependent VEGF activity, Ar
`is the baseline VEGF activity relative to ranibizu-
`mab, and k is a VEGF Trap time-dependent
`constant. Figure 1 shows this relationship graphi-
`cally. VEGF Trap activity at 79 days equals that of
`ranibizumab at 30 days.
`One treatment arm in the recently completed
`phase 2 VEGF Trap trial used a 4 mg dose. After a
`4 mg VEGF Trap injection, the time-dependent
`intravitreal anti-VEGF activity, relative to 0.5 mg
`ranibizumab, can be calculated according to the
`following:
`
`At = ArCre2kt
`
`where Cr is the molar concentration of injected
`VEGF Trap relative to 0.5 mg ranibizumab. Figure 2
`shows this relationship graphically. On day 87
`after a 4 mg VEGF Trap injection, the relative
`biological activity would be comparable to ranibi-
`zumab at 30 days. Doses of 0.5 mg and 2 mg
`would provide similar biological activities at
`73 days and 83 days, respectively.
`
`Br J Ophthalmol 2008;92:667–668. doi:10.1136/bjo.2007.134874
`
`667
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`Clinical science
`
`Figure 1
`Time-dependent intravitreal
`activity of 1.15 mg VEGF Trap compared
`with that of 0.5 mg ranibizumab. The
`biological activity of VEGF Trap at
`79 days is comparable to that of
`ranibizumab at 30 days.
`
`Figure 2
`Time-dependent intravitreal
`activity of 4 mg VEGF Trap compared
`with that of 0.5 mg ranibizumab. The
`biological activity of VEGF Trap at
`87 days is comparable to that of
`ranibizumab at 30 days.
`
`DISCUSSION
`At 10 weeks after an injection, the intraocular biological
`activity of VEGF Trap is theoretically comparable to the
`activity of ranibizumab at 30 days. This prolonged biological
`activity can be explained by the higher VEGF-binding affinity of
`VEGF Trap and its presumed longer intravitreal half-life when
`compared with ranibizumab. If this theoretical model is correct,
`then the advantages of VEGF Trap will include less frequent
`drug administration, resulting in fewer physician appointments
`and ancillary tests, lower overall cost, less cumulative risk from
`intravitreal injections, and the potential for improved patient
`compliance. However,
`it
`should be appreciated that, by
`increasing the intravitreal dose of VEGF Trap from 1.15 mg to
`4 mg, there is only a marginal increase in the relative biological
`activity from 79 days to 87 days compared with ranibizumab at
`30 days, and this increased dose may not be worth the increase
`in potential systemic adverse events. Consequently, there seems
`to be little advantage to increasing the dose above 1 mg unless a
`much higher initial dose results in greater suppression of VEGF
`and less frequent dosing overall because of the increased initial
`potency of the 4 mg dose.
`A similar analysis comparing the biological activities of
`ranibizumab with bevacizumab showed that the two drugs
`were comparable after 27–38 days.10 This can be explained by
`the lower affinity of bevacizumab for VEGF-A combined with
`longer half-life of bevacizumab compared with ranibizumab. In
`contrast with bevacizumab, VEGF Trap has both a longer
`intravitreal half-life because of its larger size and a much higher
`affinity for VEGF-A than ranibizumab, resulting in the greater
`theoretical duration of biological activity in the eye.
`
`If our assumptions for the half-life and relative biological
`activity of VEGF Trap are correct, then the modelling presented
`in this paper supports less frequent dosing of VEGF Trap
`compared with ranibizumab for the treatment of neovascular
`AMD. This approach will be tested in the upcoming phase 3
`trial with VEGF Trap.
`
`Competing interests: None.
`
`2.
`
`3.
`
`4.
`
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`Gragoudas ES, Adamis AP, Cunningham ET Jr, et al. Pegaptanib for neovascular
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`668
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`Br J Ophthalmol 2008;92:667–668. doi:10.1136/bjo.2007.134874
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`
`Predicted biological activity of intravitreal
`VEGF Trap
` W Stewart and P J Rosenfeld
`
` M
`
`Br J Ophthalmol
`2008
`doi: 10.1136/bjo.2007.134874
`
` 2008 92: 667-668 originally published online March 20,
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