Update on VEGF Trap-Eye Clinical Trials

A new way to block VEGF

Sumit Sharma, MD • Peter K. Kaiser, MD

Multiple studies have implicated vascular endothelial growth factor in the pathogenesis of neovascular eye diseases, including neovascular age-related macular degeneration, diabetic retinopathy, diabetic macular edema and central retinal vein occlusion (CRVO).^1-6 Currently, the only FDA-approved treatments for AMD targeting the VEGF pathway are pegaptanib sodium (Macugen, Eyetech Pharmaceuticals, Inc), an aptamer that binds VEGF ₁₆₅ and ranibizumab (Lucentis, Genentech), a humanized, affinity-matured Fab fragment that binds all isoforms of VEGF-A; bevacizumab (Avastin, Genentech), a humanized monoclonal antibody with two VEGF-binding domains against all VEGF-A isoforms, is also used off label as an alternative to ranibizumab given its much lower cost.

Intraocular injection of pegaptanib every six weeks reduced the percentage of patients who experience severe vision loss but did not lead to a significant improvement in visual acuity.⁷ In contrast, monthly injections of ranibizumab resulted in a significant improvement in visual acuity in about one-third of patients.^8-9

It is felt that the difference in efficacy between these two drugs is due to the fact that isoforms other than VEGF₁₆₅ are implicated in the pathogenesis of neovascularization in the eye. Although there have been a few small studies evaluating bevacizumab for the treatment of neovascular AMD, there are no completed randomized clinical trials comparing ranibizumab to bevacizumab, but many are currently in progress, including the Comparison of AMD Treatment Trials (CATT), with results expected in 2011.

VEGF TRAP-EYE

VEGF Trap-Eye (Regeneron Pharmaceuticals and Bayer Healthcare AG) is a 110 kDa fusion protein of portions of the extracellular binding domains of VEGF receptors 1 and 2 (VEGFR-1 and VEGFR-2) and the Fc region of human IgG1. Previous studies have found that one of the most potent ways to block VEGF signaling is to prevent VEGF from binding to its receptor by administering decoy VEGF receptors.¹⁰ VEGF Trap-Eye was engineered to have much higher affinity for VEGF-A (~1 pM),¹¹ compared to bevacizumab (500-2,200 pM)^12-14 and ranibizumab (140 pM).¹⁵ This may allow VEGF Trap-eye to be more potent than either drug currently in use.

It is mathematically estimated that VEGF Trap-Eye will maintain significant intravitreal VEGF-binding activity for 10-12 weeks after a single intravitreal injection.¹⁶ Another possible advantage that VEGF Trap-Eye has over ranibizumab is that it blocks all isoforms of VEGF-A as well as placental growth factor (PlGF)-1 and -2. PlGF is a part of an independent angiogenesis cascade (Figures 1 and 2).

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).

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.

Herein, we review the results of phase 2 trials evaluating VEGF Trap-Eye for neovascular AMD and diabetic macular edema, as well as describe trials that are currently in progress.

THE TRIALS

The CLEAR-IT-2 trial was a phase 2, randomized, double-masked, multicenter dose-comparison study of the safety and efficacy of VEGF Trap-Eye in patients with neovascular AMD. Subjects were assigned to one of five treatment groups: monthly intravitreal injections of 0.5 or 2.0 mg of VEGF Trap-Eye for the first 12 weeks (for a total of four mandatory injections) or quarterly dosing with one initial intravitreal injection of 0.5, 2.0 or 4.0 mg of VEGF Trap-Eye followed by a second mandatory injection at week 12. After the 12-week primary outcome, all patients were treated on an as-needed basis for another 40 weeks.

At one year of follow-up, there was a mean improvement of +5.3 letters in best corrected visual acuity for all groups combined (P<0.0001). Patients who received four monthly doses of 0.5 or 2.0 mg followed by as-needed dosing achieved a mean improvement of +5.4 letters (P<.085 vs baseline) and +9.0 letters (P<0.0001 vs baseline) from baseline, respectively. Patients receiving quarterly dosing of 0.5 mg gained +2.6 letters (P=0.344 vs baseline), those receiving quarterly dosing of 2.0 mg gained +5.2 letters (P=0.0412 vs baseline), and those receiving quarterly dosing of 4.0 mg gained +4.2 letters (P=0.0154 vs baseline) at one year. Analysis of retinal imaging studies revealed a statistically significant reduction in central retinal thickness and mean CNV lesion size for all groups.

One hundred seventeen patients originally enrolled in CLEAR-IT-2 were followed in an open-label extension study and received injections of 2.0 mg of VEGF Trap-Eye on an as-needed basis with q8-week monitoring. The mean gain in BCVA from baseline in the original trial of the 117 patients who were followed in the extension study was +7.3 letters (P<0.0001 vs baseline) at three months, +8.4 letters (P<0.0001 vs baseline) at one year, +7.1 letters (P<0.0001 vs baseline) at 18 months, and +6.1 letters (P<0.0001 vs baseline) at two years. Of the patients enrolled in the extension study, 92% lost less than 15 letters, 71% gained 0 or more letters, and 30% gained 15 or more letters of visual acuity after treatment with VEGF Trap-Eye. This compares favorably to the pivotal MARINA/ANCHOR studies, but in CLEAR-IT-2 patients did not require monthly injections, as in the Genentech trials. Over the 21 months of the PRN dosage stage of the phase 2 trial and extension study patients received an average of only 4.6 additional injections of VEGF Trap-Eye, with 9% requiring no additional injections.

Serious adverse events in CLEAR-IT-2 were rare: one patient had culture-negative endophthalmitis, five patients died (one from pre-existing pulmonary hypertension, one from pancreatic cancer, one from pulmonary failure, one from squamous cell lung cancer and one from cerebrovascular accident) and four patients had arterial thromboembolic events (two cerebrovascular accidents and two myocardial infarctions). The most commonly reported adverse events were those related to the intravitreal injection: subconjunctival hemorrhage at the injection site and transient increase in intraocular pressure. Subgroup analysis showed that patients less than 75 years old achieved greater BCVA gains compared to patients older than 75. No other subgroup comparisons achieved statistical significance.

The DME And VEGF Trap-Eye: INvestigation of Clinical Impact (DA VINCI) study was a double masked, randomized, active controlled phase 2 study of the safety, tolerability and biological effect of repeated intravitreal administration of VEGF Trap-Eye in patients with clinically significant DME. Data were presented by Diana Do, MD, at the World Ophthalmology Congress in Berlin, Germany. The primary outcome measure was the change in BCVA at 24 weeks. Two hundred nineteen patients were randomized into one of five groups: the control group received macular laser therapy at week one and as-needed repeat laser therapy as often as every 16 weeks; two groups received doses of 0.5 mg or 2.0 mg every four weeks for 24 weeks; two groups received three initial doses of 2.0 mg every four weeks, followed by either every-eight-week dosing or as-needed dosing.

At the six-month primary analysis, patients had a mean change in vision of +2.5 letters with traditional laser photocoagulation. In contrast, all of the VEGF Trap-Eye arms achieved statistically significant improvements in BCVA over the laser control arm, gaining from +8.5 to +11.4 letters. There was no statistically significant difference in outcomes noted between the VEGF Trap-Eye groups compared to the laser group. There were two cases of endophthalmitis, one growing Staphylococcus epidermidis and one culture negative. The most common adverse events reported were those related to intravitreal injections and were similar to those described above.

TRIALS STILL UNDER WAY

The Double-Masked Study of Efficacy and Safety of Intravitreal VEGF Trap-Eye in Subjects with Wet AMD (VIEW 1 and VIEW 2) studies are the two pivotal, randomized, active controlled, double-masked, phase 3 studies to compare VEGF Trap-Eye dosed 0.5 mg every four weeks, 2.0 mg every four weeks, or 2.0 mg every eight weeks (after three monthly 2.0 mg doses) for one year, compared to ranibizumab 0.5 mg delivered every four weeks for one year.

In the second year of the trial, PRN dosing will be evaluated, but patients will receive a treatment at least once every 12 weeks. The primary outcome is the proportion of subjects who maintain or improve vision at week 52, compared to ranibizumab. VIEW 1 is being performed at 188 sites in the United States and Canada, and VIEW 2 is being performed at 190 sites in Europe, Asia, Japan, Australia and South America. Both trials have completed enrollment with one-year results expected in early 2011.

VEGF Trap-Eye: Investigation of Efficacy and Safety in Central Retinal Vein Occlusion (COPERNICUS and GALILEO) studies are randomized, double-masked, sham controlled phase 3 trials of the efficacy, safety and tolerability of repeated intravitreal administration of VEGF Trap-Eye in subjects with macular edema secondary to CRVO. Both trials consist of two arms: injection of 2.0 mg of VEGF Trap-Eye every four weeks for one year vs sham injections every four weeks for one year.

The primary outcome measure is the improvement of BCVA vs baseline at 24 weeks. All patients are eligible for panretinal photocoagulation at any time during the study if they progress to anterior segment neovascularization. Both trials have reached their enrollment goals of 165 patients and will reach completion in early 2011. COPERNICUS is based at 61 locations in the United States, Canada, India, and South America, while GALILEO is based at 73 sites in Europe, Australia and Asia.

CONCLUSION

Results of the phase 2 AMD and DME trials are expected in the coming year. These results, along with data from the phase 3 studies, should position VEGF Trap-Eye for FDA approval by 2012. RP

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