be formed as a consequence of VEGF Trap-Eye binding VEGF. Multimeric complexes could potentially aggregate in bodily tissues, causing immunogenic responses.

DRUG EFFECTS IN PRECLINICAL MODELS

Preclinical animal studies have evaluated the efficacy of VEGF TrapEye (R1R2) in several models of neovascularization in the eye, including the suppression of CNV in mice, and suppression of VEGF-induced breakdown of the blood–retinal barrier. Subcutaneous injections or a single intravitreal injection of VEGF Trap-Eye (R1R2) strongly suppressed CNV in mice with laser-induced rupture of Bruch’s membrane.31 Subcutaneous injection of VEGF Trap-Eye (R1R2) also significantly inhibited subretinal neovascularization in transgenic mice that express VEGF in photoreceptors.31 VEGF Trap-Eye blocked angiogenesis in a mouse model of suture-induced inflammatory corneal neovascularization.6 Intravitreal administration of VEGF Trap-Eye prevents the development of grade 4 choroidal neovascular lesions in primates, and markedly reduced proliferative responses of the retina to laser injury in adult cynomolgus monkeys.32 VEGF Trap-Eye administration every 4 weeks via intravitreal injection was also demonstrated to be safe in cynomolgus monkeys after 13 weeks of administration.33

SYSTEMIC AND OCULAR COMPLICATIONS AND TOXICITY

In phase I and II studies, intravitreal injections of VEGF Trap-Eye caused no drug-related systemic adverse events.34,35 In the phase II AMD study there were no drug-related serious adverse events and no systemic adverse events were classified by the investigators as being related to study drug administration.36 There was one reported case of culture-negative endophthalmitis/uveitis in the study eye and one arterial thrombotic event, neither of which was deemed to be drug-related. The most common adverse events were those typically associated with intravitreal injections.

BIOACTIVITY IN HUMAN EYE DISEASES

NEOVASCULAR AMD PHASe I

VEGF Trap-Eye is currently being evaluated for two eye diseases: neovascular (wet) AMD and DME. VEGF Trap-Eye has undergone phase I and II clinical trials in wet AMD, and is presently in phase III clinical testing. The phase I study, known as CLEAR-IT 1 (CLinical Evaluation of Anti-angiogenesis in the Retina Intravitreal Trial), consisted of two parts. It was designed to evaluate the safety, tolerability, and biological effects of intravitreal VEGF-Trap in patients with neovascular AMD. The primary bioactivity measure was the change from baseline in central retinal lesion thickness. Patients were also monitored for ocular and systemic safety. Effects of VEGF Trap-Eye on disease status were followed with best-corrected ETDRS visual acuity (BCVA) using the electronic visual acuity system. Fluorescein angiography assessments were also conducted.

Part 1 was a single, ascending-dose study comprising 21 patients with 6 weeks of observation. VEGF Trap-Eye was injected intravitreally once, with groups of 3–6 patients each receiving single doses of 0.05, 0.15, 0.5, 1, 2, or 4 mg VEGF Trap-Eye.34,35 Inclusion criteria were BCVA of 20/40 (73 letters) or worse. Following a 6-week observation period, patients were redosed at a frequency determined at the discretion of the treating physician under an extension protocol.

For the combined cohorts, a sustained reduction in retinal thickness and an improvement in visual acuity were reported with VEGF TrapEye at the 6-week primary endpoint. BCVA letters improved by a mean

of 4.4 letters and central retinal lesion thickness decreased by −78.8 µm. Furthermore, a potential durability of effect with VEGF Trap-Eye was demonstrated, with patients averaging more than 5 months to the first retreatment in an extension study. The mean time to retreatment was 166 days (median, 127 days; range, 42–470 days) (Table 37.1).34,35

Part 2 of the CLEAR-IT 1 trial was a parallel-group, randomized trial comprising 28 patients who received a single intravitreal dose of 0.15 or 4 mg VEGF Trap-Eye (the range of doses demonstrating clinical activity in part 1) followed by 8 weeks of observation. Patients enrolled and treated in the CLEAR-IT 1 part 2 study had to satisfy the criteria for entry. After 8 weeks postdose, patients were reassessed for retreatment using established criteria.34,35

For part 2 of the CLEAR-IT 1 trial, results have been presented for the first 24 of 28 patients enrolled.34 Both doses reduced retinal thickness at 2 weeks, but the duration of effect was longer in the 4-mg group than in the 0.15-mg group, as evidenced by a significantly greater reduction in retinal thickness in the 4-mg dose group than the 0.15-mg dose group at weeks 4 and 8. Reductions for the 4-mg dose and the 0.15-mg dose were −200 and −72.9 µm at 4 weeks, respectively. Reductions for the 4-mg dose and the 0.15-mg dose were −175 and −67.3 µm at 8 weeks, respectively (P < 0.05 for the 4-mg versus the 0.15-mg group).34 Visual acuity improvements were sustained within the 4-mg dose group through 8 weeks (Figure 37.3).

Fewer patients in the high-dose group required retreatment based on objective criteria at the study’s 8-week endpoint visit. In an extension study, the time to second dose in days for the 0.15-mg group was a

Table 37.1  Decreased retinal thickness and improvement in best corrected visual acuity (BCVA) at 6 weeks

VEGF, vascular endothelial growth factor; CRLT, Central Retinal Lesion Thickness.

Study Week

Figure 37.3  A greater sustained improvement in best corrected visual acuity was seen in the 4 mg dose compared to the 0.15 mg dose.

Diseases Retinal in Mechanisms and Drugs • 4 section

• 37Trapchapter-VEGF Proteins: Fusion

mean of 78 days (median, 64 days; range, 57–141 days), whereas the mean time to retreatment in the 4-mg group was 109 days (median, 69 days; range, 57–242 days). The most common indication for retreatment was new or persistent fluid on optical coherence tomography (OCT: 9/14 patients retreated).34

Overall, in the CLEAR-IT 1 part 1 and part 2 studies, intravitreal injection of up to 4 mg of VEGF Trap-Eye was well tolerated with no ocular inflammation seen.34,35 In part 1, no inflammation or endophthalmitis was observed. There were no serious adverse events, ocular adverse events were mild to moderate in severity, and only one ocular adverse event was considered to be related to the study drug.35 Most adverse events in part 2 were related to the study drug injection procedure. There was no evidence of ocular inflammation. Of the subjects for whom increased intraocular pressure (IOP) was reported, none exceeded 30 mmHg.34

NEOVASCULAR AMD PHASe II

CLINICaL TRIAL

CLEAR-IT 2 was designed based upon the phase I study results showing clinically meaningful improvement in visual acuity with single doses of 0.5, 2.0, and 4.0 mg and sustained clinical activity beyond 1 month. CLEAR-IT 2 was a randomized, phase II, masked, controlled study designed to explore the safety and efficacy of VEGF Trap-Eye for wet AMD at various doses and dosing regimens (n = 159 randomized; n = 157 treated). Patients were randomized into five groups and treated with VEGF Trap-Eye in the study eye at 0.5 and 2.0 mg q 4 weeks and 0.5, 2.0, and 4.0 mg q 12 weeks for 12 weeks, followed by as-needed (pro re nata: PRN) dosing thereafter until week 52.

Inclusion criteria were: (1) males and females 50 or older with subfoveal CNV secondary to AMD; (2) central retinal lesion thickness of 300 m or greater as measured by OCT; (3) ETDRS BCVA of 73–34 letters; (4) a loss of 5 or more ETDRS letters or one or more Snellen line in BCVA over the last 6 months (for previously treated patients with minimally classic or occult lesions); and (5) lesion greatest linear diameter of 5400 m or less (including blood, scars, atrophy, and neovascularization) as assessed by fluorescein angiography, with subretinal hemorrhage making up 50% or less of the total lesion size and sparing the fovea and an area of scar 25% or less of the total lesion.

Patients were monitored for retinal thickness, visual acuity, and safety. The primary endpoint was change in central retinal lesion thickness as determined from a single-line high-resolution posterior-pole OCT scan read at an independent reading center.

A preplanned interim analysis of the first 78 patients who completed 12 weeks of treatment showed that VEGF Trap-Eye met its primary endpoint of a statistically significant mean reduction in retinal thickness after 12 weeks compared with baseline (all groups combined, decrease of 135 m; P < 0.0001). Patients dosed either on a monthly or quarterly schedule achieved significant reductions in retinal thickness as measured by OCT posterior-pole scan versus baseline over the 12-week monitoring period. While results were similar at 8 weeks, monthly dosing was numerically, but not statistically, superior to quarterly dosing at 12 weeks (Figure 37.4).36

The mean change from baseline in visual acuity also demonstrated statistically significant improvement (all groups combined, increase of 5.9 letters; P < 0.0001). All but one patient maintained or improved vision at 12 weeks. In terms of visual acuity, monthly and quarterly dosing did not result in substantially different results at 8 weeks. Monthly dosing was numerically superior to quarterly dosing at 12 weeks, although not statistically significant. Monthly dosing resulted in continued visual acuity improvement through week 12 (range of means, 8.8–10.4 letters gained). Quarterly dosing resulted in substantial improvements at week 8 (range of means, 4.4–5.4 letters gained) and at week 12 (range of the means, 2.8–5.1 letters gained) (Figure 37.5).36

At the interim analysis in the CLEAR-IT 2 study, the most common adverse events were those typically associated with intravitreal injections and appeared to be related to the injection procedure. There was no relationship between VEGF Trap-Eye dose and the occurrence of

Study week

Figure 37.4  These graphs show retinal thickness and visual acuity for all groups combined (mean ± sem). Vascular endothelial growth factor (VEGF) Trap-Eye met its primary endpoint of statistically significant mean reduction in retinal thickness over 12 weeks compared with baseline (all groups combined, decrease of 135 m; P < 0.0001); 65 patients for whom readings were available and interpretable were included in the analysis. Mean change from baseline in visual acuity for all patients included in the interim analysis (n = 78) also demonstrated statistically significant improvement (all groups combined, increase of 5.9 letters,

P < 0.0001). All but one patient maintained or improved vision at 12 weeks. CR/LT, BCVA, best corrected visual acuity.

any particular ocular adverse event. No adverse consequences of increased IOP were reported.36

NEOVASCULAR AMD PHASe III PROGRAM

Based upon the preliminary phase II study results which indicated that doses of 0.5 and 2 mg monthly produced substantial gains in visual acuity and a single 2-mg dose had a sustained improvement in visual acuity as compared to 2 mg monthly for at least 8 weeks, the phase III program was designed to evaluate these dosing schedules as compared to the standard dosing schedule for ranibizumab 0.5 mg monthly. Two identical, noninferiority phase III studies are currently under way to evaluate VEGF Trap-Eye for wet AMD, known as VIEW (VEGF TrapEye: Investigation of Efficacy and Safety in Wet AMD) 1 and VIEW 2. Both will compare VEGF Trap-Eye with the monoclonal antibody fragment ranibizumab using a noninferiority design. Both are randomized, double-masked, active-controlled, efficacy and safety studies with a primary endpoint of the proportion of patients treated with VEGF TrapEye who maintain vision at the end of one year, compared to ranibizumab patients. Visual acuity will be measured via the total number of letters read correctly on the ETDRS chart (2-year study).16

Both studies are double-masked, randomized, controlled-dose and interval-ranging studies of repeated intravitreal VEGF Trap-Eye