Approval by the FDA in 2006 of intravitreal (IVT) injections of 0.5 mg ranibizumab, a humanized monoclonal antibody fragment that blocks VEGF, changed the standard-of-care for this blinding disease: based on large pivotal studies, monthly injections of ranibizumab have been shown to provide the best visual outcome and anatomic correction, and on average lead not only to maintenance of vision, but to gains in visual acuity (VA). Because of the marked treatment burden of monthly monitoring visits and injections on the elderly AMD patient population and their caregivers, there has been extensive effort to decrease the frequency of patient visits and injections; however, it has been difficult to replicate the visual gains and anatomic benefit of monthly ranibizumab using such approaches.

SYNOPSIS

VEGF Trap-Eye is a soluble decoy receptor fusion protein created using Trap technology that may have theoretical and mechanistic advantages. Most importantly, the binding affinity to VEGF-A is substantially greater than that of ranibizumab, leading to the mathematical modeling suggestion that it might still be active in the eye for 10 to 12 weeks after a single intravitreal injection, with the binding activity of 2 mg VEGF Trap- Eye at 83 days estimated to be comparable to the activity of 0.5 mg ranibizumab at 30 days (Stewart 2008).

The current application is for the IVT administration of VEGF Trap-Eye for the treatment of wet AMD. The recommended regimen is 2 mg VEGF Trap-Eye administered IVT every 2 months following 3 initial monthly doses.
Based on the primary analysis in two large Phase 3 studies comparing the endpoint of maintenance of vision, this dosing regimen provided efficacy that was numerically similar, statistically non-inferior and clinically equivalent to the current standard of care, ranibizumab 0.5 mg monthly; this dosing regimen also produced similar average gains in vision to monthly ranibizumab in both Phase 3 studies, and similar anatomic benefit. Administration of VEGF Trap-Eye was also associated with a safety profile similar to that of ranibizumab, in terms of both ocular and systemic adverse events (AEs).
As the major safety risks with anti-VEGF therapy in wet AMD are serious ocular AEs related to the IVT injection procedure (e.g., endophthalmitis, retinal detachments, traumatic cataract, and increased intraocular pressure [IOP]), it is anticipated that reducing the number of IVT injections by about half will result in a corresponding decrease in the number of these rare but serious AEs. Moreover, eliminating the need for not only monthly injections but also for mandatory monthly monitoring of patients could substantially reduce the treatment burden on patients, caregivers, and the health care system, without sacrificing patient benefit.

Age-related macular degeneration is the most common degenerative disease of the macula, and is the most common cause of legal blindness in the elderly population of the developed world. Evidence suggests that 10% of individuals aged 65 to 74 years, and 30% of those aged 75 to 85 years, show signs of AMD (Phillips 2009).

The most severe form of AMD is the wet form, so-called because it is marked by abnormal CNV and associated vascular leak and retinal edema.
The new, pathological blood vessels in the retina leak lipids, fluid and blood, leading to edema and retinal thickening that can profoundly impair VA, particularly when the macula is affected. Without treatment, patients can on average lose on the order of one letter a month (corresponding to over 10 letters a year) when evaluated using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual chart (The Early Treatment Diabetic Retinopathy Study Group 1985).

A major paradigm shift occurred in the field with the suggestion that VEGF, a growth factor known to promote both vascular growth and permeability, might be driving the abnormal CNV and retinal edema that leads to vision loss in AMD (Adamis 1994, Aiello 1994).
Since the 1990s, evidence from both animal and clinical studies has accumulated in support of the critical role of VEGF in ocular neovascularization.

Today, anti-VEGF therapy is the standard of care in the treatment of wet AMD. The first anti-VEGF therapy evaluated for clinical efficacy in AMD patients was an RNA-based aptamer known as pegaptanib sodium (Macugen®, Eyetech) that bound and blocked only one isoform of VEGF with relatively low affinity.
Though pegaptanib served as the ground-breaking pioneer both for anti-VEGF therapies and for approaches involving regular IVT injections, its efficacy was modest.
Pegaptanib did not provide vision gains nor did it stabilize vision, but instead it served to slow the rate of ongoing visual deterioration. The next major advance in the field involved the clinical testing of a much broader and higher-affinity VEGF-blocking agent, known as ranibizumab (Lucentis®, Genentech and Novartis). Ranibizumab is an IVT-injected antibody fragment that binds all VEGF- A isoforms (Lowe 2007). Ranibizumab proved highly efficacious in wet AMD when administered monthly.
Data from the MARINA (Rosenfeld 2006) and ANCHOR (Brown 2006) Phase 3 studies showed that monthly ranibizumab resulted not only in maintenance of vision, but also in marked average vision gains.
Approval of monthly IVT injections of ranibizumab by the FDA in 2006 changed the standard-of-care for this blinding disease.

Monthly IVT injections, however, present both a risk and a burden to patients. First, there is the potential for serious risk associated with each IVT injection procedure, including endophthalmitis, retinal detachments, traumatic cataract, and increased IOP.
Second, monthly treatment or even monthly monitoring, which may continue for a patient’s lifetime, is a substantial burden to patients, their caregivers, ophthalmologists and the healthcare system. This burden is more than just an inconvenience. These elderly patients frequently require the assistance of a family member to come to the ophthalmologist.
And this family member is frequently somebody with a full-time job who needs to miss a day of work to help the patient. Thus there are hidden economic and quality-of-life costs associated with monthly visits.

To date, the gold standard treatment for wet AMD, based on the pivotal studies, is monthly injections of ranibizumab. However, because of the safety risks and treatment burden of monthly injections, as well as the cost of this expensive new therapeutic, physicians have been extensively exploring other treatment options.
Physicians have attempted to decrease the safety risk and treatment burden by exploring less frequent dosing strategies, and they have tried to reduce the cost burden by substituting a related, off-label anti-VEGF agent, bevacizumab (Avastin®, Genentech and Roche); bevacizumab is a humanized full-length antibody derived from the same parent antibody as the ranibizumab antibody-fragment, and it is approved for cancer treatment and must be re-aliquotted by compounding pharmacies for use in the eye.
Despite extensive efforts to develop alternative treatment strategies with ranibizumab that would decrease the frequency of patient visits and injections without sacrificing patient benefit, most of these efforts have had difficulty matching the vision gains and anatomic benefit seen with monthly ranibizumab dosing.
Fixed quarterly dosing with ranibizumab failed to stabilize vision from the onset of this dosing regimen (Regillo 2008), while studies testing “as needed” (PRN) ranibizumab, without requiring monthly monitoring visits, also could not stabilize vision (Boyer 2009, Awh 2008).
In addition, though monthly and PRN bevacizumab usage has been widely adopted because of the cost benefit, particularly for patients whose health-care coverage could not cover ranibizumab, definitive data comparing the effectiveness of these regimens to monthly ranibizumab was not available.

To compare the benefit of monthly ranibizumab with bevacizumab, as well as to explore less frequent dosing regimens, the NIH performed the CATT study which compared monthly and PRN regimens of ranibizumab and bevacizumab.
Importantly, in contrast to previous PRN attempts that did not require monthly monitoring, the CATT study mandated monthly monitoring at which time treatment with PRN injection was to be performed if there was any evidence of retinal fluid as judged by Optical Coherance Tomography (OCT).
The primary endpoint was mean change in visual acuity at 1 year. Analysis of the primary endpoint showed that monthly ranibizumab and monthly bevacizumab resulted in numerically similar mean visual acuity gains at 1 year (8.5 letters for monthly ranibizumab vs. 8.0 letters for monthly bevacizumab), and that monthly bevacizumab was noninferior to monthly ranibizumab based on the prespecified non-inferiority criteria.
Ranibizumab given PRN as specified in the protocol (which required an average of 6.9 injections during the first year and yielded a mean change in VA of 6.8 letters) also met the non-inferiority criterion compared to monthly ranibizumab. However, the PRN regimen for Bevacizumab (which required an average of 7.9 injections in the first year and yielded a mean change in VA of 5.9 letters) failed to demonstrate non-inferiority to either of the monthly regimens (Figure 1). With respect to several ways of assessing anatomic correction of the disease and the decrease in retinal swelling and fluid, monthly ranibizumab was significantly better than monthly bevacizumab or either of the PRN regimens; it will be important to understand if differences in these anatomic endpoints will ultimately correlate with longer term problems in vision and/or other aspects of disease control.
The interpretation of these results is therefore complex. However a particular clinical practice might interpret CATT in terms of affecting their usage of ranibizumab versus bevacizumab, or PRN compared to monthly dosing, it is important to note that all of the regimens studied in the CATT trial still required patients to come in for mandatory monthly visits and exams during which difficult treatment decisions had to be made based on anatomic surrogates whose predictive value for clinical outcomes is not completely understood.
Thus, there remains an unmet need for new therapies that will provide efficacy equivalent to monthly ranibizumab treatment but that reduce the burden and risk of monthly injections, and also avoid the burden of mandatory monthly monitoring visits; it would also be desirable to have such therapies that not only provide similar numerical benefit in terms of vision gains, but also provide similar anatomical control of disease activity as heretofore has only been demonstrated by monthly ranibizumab, while also avoiding the need to make “as needed” treatment decisions based on anatomic surrogates whose relevance to ultimate outcome is not completely understood.

The VEGF Trap is a soluble decoy receptor fusion protein that may have theoretical and mechanistic advantages for use in the eye.
The VEGF Trap was created using Trap technology (Economides 2002, Holash 2002) also used to create an Interleukin-1 Trap, rilonacept ARCALYST®, Regeneron), which was recently approved to treat a rare cold-induced auto-inflammatory disease (Arcalyst US package insert) and has been shown in Phase 3 studies to reduce the incidence of gout flares in patients initiating urate lowering therapy (Regeneron, data on file).
In particular, the VEGF Trap was created by fusing DNA sequences encoding the second Ig domain of human VEGF receptor 1 (VEGFR1) to the third Ig domain of human VEGF receptor 2 (VEGFR2), which is in turn fused to the constant region of human IgG1 (Holash 2002); as is also the case with the Interleukin-1 Trap, the VEGF Trap binds to its cognate ligands with substantially higher affinity than do the native receptors from which it was constructed.
Recombinant VEGF Trap protein is expressed in Chinese hamster ovary (CHO) K1 cells, and then purified by a combination of filtration and chromatographic techniques. VEGF Trap-Eye is specially purified and specifically formulated for IVT injection.

NON CLINICAL OVERVIEW AND CLINICAL PHARMACOLOGY

A unique characteristic of VEGF Trap is its high binding affinities to all isoforms of VEGF as well as to the highly related placental growth factor (PlGF); e.g., the equilibrium dissociation constant (KD) for VEGF Trap binding to human VEGF-A165 is 0.5 pM, to human VEGF-A121, is 0.36 pM, and to human PlGF-2 is 39 pM (Holash 2002).
Research with VEGF Trap in several different animal models of ophthalmologic disorders has shown that VEGF Trap can substantially inhibit retinal and choroidal neovascularization, as well as the formation of retinal edema (Section 3.2).

Most importantly, the binding affinity of VEGF Trap to VEGF-A is substantially greater than that of ranibizumab, leading to the mathematical modeling suggestion that because low VEGF Trap concentrations can still provide potent blockade it might still be active in the eye for 10 to 12 weeks after a single intravitreal injection, with the binding activity of 2 mg VEGF Trap-Eye at 83 days estimated to be comparable to that of 0.5 mg ranibizumab at 30 days (Stewart 2008).
Thus, the high-affinity blocking properties of VEGF Trap may allow for an extended dosing interval compared to ranibizumab (Stewart 2008).

In our clinical program we sought to test whether a molecule with these characteristics, VEGF Trap-Eye, would allow for similar efficacy to the standard of care while requiring less frequent IVT dosing.

Early clinical development demonstrated that IVT doses in the range of 0.5 to 2 mg provided maximal clinical benefit in patients suffering from wet AMD, in terms of initially improving visual activity and then maintaining these gains. Greater doses (i.e., 4 mg IVT) did not provide greater effects.
The Phase 2 data as well as modeling data (Stewart, 2008), suggested that the q8 interval may allow sufficient activity to provide maintenance of visual gains.

VEGF Trap is slowly absorbed from the eye into the systemic circulation after IVT administration and is predominately observed in the systemic circulation as an inactive, stable complex with VEGF; however only “free VEGF Trap” is able to bind endogenous VEGF.
It is estimated that after IVT administration of 2 mg to patients, the mean maximum plasma concentration of free VEGF Trap is more than 100-fold lower than the concentration of VEGF Trap required to half-maximally bind systemic VEGF.
Therefore, systemic PD effects using the IVT doses of interest are unlikely. Consistent with this, there was no evidence in early clinical trials that IVT VEGF Trap-Eye was associated with the most sensitive indicator of systemic effects, i.e. induction of increases in blood pressure, in these early studies.

The safety and efficacy of VEGF Trap-Eye were assessed in two similarly-designed, randomized, multi-center, double-masked, active-controlled studies in patients with wet AMD.
A total of 2412 patients were treated and evaluable for efficacy (1817 with VEGF Trap-Eye) in the two studies (VIEW 1 and VIEW 2). In each study, patients were randomly assigned in a 1:1:1:1 ratio to 1 of 4 dosing regimens: 1) ranibizumab administered 0.5 mg every 4 weeks (ranibizumab 0.5 mg Q4); 2) VEGF Trap-Eye administered 2 mg every 4 weeks (VEGF Trap- Eye 2Q4); 3) VEGF Trap-Eye 0.5 mg administered every 4 weeks (VEGF Trap-Eye 0.5Q4); and 4) VEGF Trap-Eye administered 2 mg every 8 weeks following 3 initial monthly doses (VEGF Trap-Eye 2Q8).
Patient ages ranged from 49 to 99 years with a mean of 76 years.

PHASE 3 AMD PROGRAM: VIEW 1 AND VIEW 2

In both studies, the primary efficacy endpoint was the proportion of patients in the Per Protocol Set (PPS) who maintained vision, defined as losing fewer than 15 letters of VA, (measured by ETDRS letter score) at week 52 compared to baseline. The primary analysis was an evaluation of the non-inferiority of VEGF Trap-Eye to ranibizumab with a pre-specified non-inferiority margin of 10%.
Secondary efficacy endpoints included change from baseline to week 52 in best corrected visual acuity (BCVA) letter score, proportion of subjects who gained 15 or more letters from baseline to week 52, change from baseline to week 52 in total National Eye Institute 25-Item Visual Function Questionnaire (NEI-VFQ-25) total score, and change from baseline to week 52 in CNV area. A conditional sequence of testing controlled overall alpha at the 5% level; the every 8 week dosing paradigm was chosen to be last in the conditional sequence as achieving success with this longer-interval dosing regimen was considered to be most challenging.
Aspects of the study design, including the primary analysis and non-inferiority margin, were developed in conjunction with discussions with the FDA as part of a Special Protocol Assessment. Although not in the analysis plan for the study, in a separate communication, the FDA further explained that, whereas the 10% confidence interval would be used to assess non-inferiority, a 5% confidence interval would be used to assess clinical equivalence.

In both pivotal studies (VIEW 1, VIEW 2), all three VEGF Trap-Eye dosing regimens, including the every 8 week dosing regimen, were numerically similar and were consistently shown to be non-inferior to ranibizumab with regard to the pre-specified primary efficacy analysis, i.e., the proportion of subjects maintaining vision after one year of treatment, analyzed for the pre-specified PPS using the last-observation-carried forward (LOCF) approach (VIEW 1: 94.4% for ranibizumab, and 95.9, 95.1, and 95.1% for VEGF Trap-Eye 2Q4, 0.5Q4, and 2Q8, respectively; VIEW 2: 94.4 for ranibizumab and 96.3, 95.6, and 95.6% for VEGF Trap-Eye 2Q4, 0.5Q4, and 2Q8, respectively).
In fact, in each study and for all comparisons, the actual upper limit of the confidence interval (CI) of the difference between ranibizumab and VEGF Trap-Eye (= 3.1%) was substantially below the pre-specified, clinically meaningful non-inferiority margin of 10% and also below 5%. All sensitivity analyses conducted to assess the robustness of these results confirmed the findings of the primary analysis.
The validity of these findings is further supported by the fact that, as is desirable for non-inferiority studies, the active comparator in both pivotal VEGF Trap-Eye studies behaved in a manner entirely consistent with its clinical experience: i.e., the active comparator ranibizumab yielded success rates for the primary efficacy variable (94.4% of all subjects maintained vision in both VIEW 1 and VIEW 2) that were very similar to those obtained in the pivotal studies ANCHOR (Brown 2006) and MARINA (Rosenfeld 2006) that had been used to support the registration of ranibizumab.
The extensive number of secondary and pharmacoynamic variables examined, provide a very robust and compelling picture. Most notably, all VEGF Trap-Eye dosing regimens, including the every 8 week regimen, resulted in similar gains to ranibizumab in the key secondary endpoint of change from baseline to week 52 in change in best corrected visual acuity (BCVA), with mean gains ranging from 7.6 to 10.9 letters in all three regimens across the two studies; the 2 mg VEGF Trap-Eye dosed every 4 weeks demonstrated the largest gain (10.9 letters) and was statistically superior to ranibizumab in VIEW 1, but not in VIEW 2. Similarly, other minor differences seen in VIEW 1 among the three VEGF Trap-Eye dosing regimens were not reproduced in VIEW 2, further suggesting that all three dosing regimens indeed had rather similar efficacy. This conclusion was supported by a pre-specified integrated analysis combining the two studies in which all dosing regimens resulted in 52 week BCVA outcomes within a letter of each other (from 8.3 to 9.3 letters).
In addition to VA outcomes, all 3 VEGF Trap-Eye dosing regimens, including 2 mg VEGF Trap-Eye dosed every 8 weeks, also similarly improved anatomic outcomes as compared to monthly ranibizumab. Consistency was found for both primary and secondary endpoints (i) across all clinical studies designed to assess efficacy of VEGF Trap-Eye, (ii) between analysis sets, i.e. per-protocol set (PPS) versus full-analysis set (FAS), (iii) between original analysis and, where performed, sensitivity analyses and (iv) across all subgroups assessed (e.g. age, gender, race, baseline visual acuity, lesion type, CNV area).

Importantly, these results established that all 3 VEGF Trap-Eye dose regimens, and, in particular, 2 mg VEGF Trap-Eye dosed every 8 weeks, provided efficacy that was clinically equivalent to ranibizumab 0.5 mg dosed every 4 weeks. Moreover, because data from examinations conducted at non-dosing visits in the 2Q8 arm could not be used for clinical decision making (other than for withdrawal of patients) and was only collected for analytic purposes, the results demonstrate that these benefits can be achieved without the need for between- visit monitoring for patients treated with VEGF Trap-Eye 2 mg every 2 months.
Thus, VEGF Trap-Eye 2Q8 can be given on a regular every two month dosing schedule and yield similar vision gains and anatomic disease control as monthly ranibizumab, without the need for intervening monitoring visits, and without the need for making “as needed” treatment decisions based on anatomic surrogates whose relevance to long-term outcomes is not well understood.

VEGF Trap-Eye was well tolerated with an acceptable safety profile and without notable differences compared to ranibizumab 0.5Q4 in ocular or non-ocular treatment emergent AEs (TEAEs).
The most common (>5%) adverse events not related to the underlying disease reported in patients receiving VEGF Trap-Eye were conjunctival hemorrhage, eye pain, cataract, vitreous detachment, vitreous floaters, and increased IOP. Serious adverse reactions related to the injection procedure have occurred in < 0.1% of IVT injections with either VEGF Trap-Eye or ranibizumab and included endophthalmitis, traumatic cataract, and transient increased IOP.
The incidence of SAEs, fatal events, and withdrawals due to AEs was balanced between treatment groups, as was the incidence of adjudicated arterial thromboembolic events based on the definition used by the Anti- Platelet Trialists’ Collaboration (APTC). APTC events (non-fatal myocardial infarctions, non-fatal strokes, and fatal vascular events) are the most clinically important arterial thromboembolic events because they represent irreversible morbidity or mortality.
There was no dose-response across VEGF Trap-Eye groups with regards to APTC events or serious AEs potentially related to systemic VEGF inhibition and the frequencies of these were low across treatment groups and, in the VEGF Trap-Eye groups, consistent with those previously reported for ranibizumab.

All three regimens of VEGF Trap-Eye demonstrated non-inferiority to the current optimal standard of care, i.e. monthly ranibizumab, in two rigorously designed Phase 3 studies.
The data support that all 3 regimens provide essentially the same efficacy as ranibizumab. In clinical studies, VEGF Trap-Eye had an excellent safety profile similar to that of ranibizumab. Therefore, it is reasonable to conclude that the benefit of VEGF Trap-Eye outweighs the potential risks.

RISK/BENEFIT AND CONCLUSION

The 2Q8 regimen for VEGF Trap-Eye has additional potential benefits by allowing substantially less frequent injections compared to monthly dosing regimens and less frequent monitoring compared to PRN regimens that require monthly monitoring.
These additional potential benefits include (i) decreased risk for adverse injection- related events, (ii) eliminated need for interim monitoring visits during which difficult treatment decisions have to be made based on anatomic surrogates whose predictive value for clinical outcomes is not completely understood and thus (iii) decreased burden on the patients, their caregivers and physicians, and the overall healthcare system. These additional potential benefits do not have associated additional risks.
Visual acuity, anatomic endpoints, and functional endpoints at 52 weeks are not compromised by a fixed 2Q8 regimen and there is little reason to believe that interim monitoring visits would meaningfully improve patient safety.

In summary, dosing of VEGF Trap-Eye has a clearly positive benefit / risk balance in patients with wet AMD and the regimen of VEGF Trap-Eye every two months (after 3 initial dosing) provides additional potential benefit over current therapies.
For those instances where it may be clinically warranted, VEGF Trap-Eye may be dosed as frequently as once per month.

Therefore, VEGF Trap-Eye treatment should be initiated with one injection per month for three consecutive months, followed by one injection every 2 months.

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