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Pharmacology: Pharmacodynamics: Mechanism of Action: Aflibercept acts as a soluble decoy receptor that binds VEGF-A and PlGF with higher affinity than their natural receptors, and thereby can inhibit the binding and activation of these cognate VEGF receptors.
Pharmacodynamic Effects: Neovascular (wet) age-related macular degeneration: The ALTAIR study enrolled patients with treatment wet AMD, showing similar outcomes to the VIEW studies using 3 initial monthly Aflibercept (Eylea) 2 mg injections, followed by one injection after 2 months, and then continued with a treat-and-extend regimen with variable treatment intervals (2-week or 4-week adjustments) up to a maximum 16 week interval according to pre-specified criteria. At week 52, there were mean decreases in central retinal thickness (CRT) on OCT of -134.4 and -126.1 microns for the 2-week adjustment group and the 4-week adjustment group, respectively. The proportion of patients without fluid on OCT at week 52 was 68.3% and 69.1% in the 2- and 4-week adjustment groups, respectively.
In patients with polypoidal choroidal vasculopathy (PCV), a subtype of wet AMD, treated with 3 monthly Aflibercept (Eylea) 2 mg injections followed by Aflibercept (Eylea) 2 mg every two months (PLANET study), similar outcomes to the VIEW studies were obtained. At week 52, there were mean decreases in retinal thickness on OCT of -138 microns for Aflibercept (Eylea) 2 mg every two months and -144 microns for Aflibercept (Eylea) 2 mg plus rescue photodynamic therapy (PDT) as indicated.
Clinical efficacy: Neovascular (wet) age-related macular degeneration: ALTAIR was a multicenter, randomized, open-label phase 4 study in 247 patients with treatment naive wet AMD, designed to assess the efficacy and safety of Aflibercept (Eylea) following two different adjustment intervals (2 weeks and 4 weeks) of a treat-and-extend dosing regimen.
All patients received 3 monthly doses of Aflibercept (Eylea) 2 mg, followed by one injection after a 2 month interval. At week 16, patients were randomized 1:1 into two treatment groups: 1) Aflibercept (Eylea) treat-and-extend with 2-week adjustments and 2) Aflibercept (Eylea) treat-and-extend with 4-week adjustments. Extension or shortening of the interval was decided based on visual and/or anatomic criteria defined by protocol with a maximum treatment interval of 16 weeks for both groups.
The primary efficacy endpoint was mean change in BCVA from baseline to week 52. The secondary efficacy endpoints were the proportion of patients who did not lose ≥15 letters and the proportion of patients who gained at least 15 letters of BCVA from baseline to week 52.
At week 52, patients in the treat-and-extend arm with 2-week adjustments gained a mean of 9.0 letters from baseline as compared to 8.4 letters for those in the 4-week adjustment group [LS mean difference in letters (95% CI): -0.4 (-3.8,3.0), ANCOVA]. The proportion of patients who did not lose ≥15 letters in the two treatment arms was similar (96.7% in the 2-week and 95.9% in the 4-week adjustment group). The proportion of patients who gained ≥15 letters at week 52 was 32.5% in the 2-week adjustment group and 30.9% in the 4-week adjustment group. The proportion of patients who extended their treatment interval to 12 weeks and beyond was 42.3% in the 2-week adjustment group and 49.6 % in the 4-week adjustment group. Furthermore, in the 4-week adjustment group 40.7% of patients were extended to 16 week intervals. At the last visit prior to week 52, 56.7% and 57.8% of patients in the 2-week and 4-week adjustment groups, respectively had their next injection scheduled at an interval of 12 weeks or more. Ocular and systemic safety profiles were similar to the safety observed in the pivotal studies VIEW1 and VIEW2.
A randomized, double-masked, multi-center, sham-controlled phase IIIb/IV study (PLANET) of Aflibercept (Eylea) monotherapy vs. Aflibercept (Eylea) plus rescue photodynamic therapy (PDT) was conducted in 333 treatment naive patients with symptomatic macular polypoidal choroidal vasculopathy (PCV), a subtype of wet AMD, as diagnosed by indocyanine green angiography (ICGA). All patients received 3 monthly doses of Aflibercept (Eylea) 2 mg and were thereafter randomized 1:1 into two treatment groups: 1) Aflibercept (Eylea) 2 mg plus sham PDT (n=157) or 2) Aflibercept (Eylea) 2 mg plus active PDT (n=161). PDT was given only if rescue criteria were met. Patients in both groups received one Aflibercept (Eylea) 2 mg injection every two months. Patients who qualified for rescue therapy received monthly injections of Aflibercept (Eylea) 2 mg plus active or sham PDT. When visual and anatomic outcomes allowed, treatment intervals were gradually extended to two months in rescue patients. Qualification for rescue therapy was based upon insufficient gain of BCVA, evidence of fluid on OCT and evidence of active polyps on ICGA.
The primary efficacy endpoint was mean change in BCVA from baseline to week 52. The secondary efficacy endpoint was the proportion of patients who did not lose ≥15 letters of BCVA from baseline to week 52.
At week 52, patients on Aflibercept (Eylea) plus sham PDT gained a mean of 10.7 letters from baseline as compared to 10.8 letters in the Aflibercept (Eylea) plus active PDT patients in the full analysis set [LS mean difference in letters (95% CI): -0.7 (-2.9,1.6), ANCOVA]. The proportion of patients who did not lose ≥15 letters was 97.5% in Aflibercept (Eylea) plus sham PDT and 96.9% in Aflibercept (Eylea) plus active PDT group [CMH adjusted difference in % (95%CI): 0.6 (-3.1; 4.3)], showing non-inferiority of both treatments for both the primary endpoint (NI margin of 5 letters) and the secondary endpoint (NI margin of 7 percentage points). No evidence of active polyps was noted in 81.7% of patients in the Aflibercept (Eylea) plus sham PDT group and 88.9% of patients in the Aflibercept (Eylea) plus active PDT group. 86.8% of patients did not require rescue therapy throughout the first year. Data obtained from patients who qualified for PDT rescue therapy (n= 42, 13.2%) did not demonstrate additional benefit on BCVA of the combined administration of verteporfin PDT and Aflibercept (Eylea) compared to Aflibercept (Eylea) monotherapy. Ocular and systemic safety profiles were similar to the safety observed in the pivotal studies VIEW1 and VIEW2.
Diabetic Macular Edema: An independent comparative trial (DRCR.net Protocol T) utilised a dosing regimen based on strict OCT and vision re-treatment criteria. In the aflibercept treatment group (n=224) at week 52, this treatment regimen resulted in patients receiving a mean of 9.2 injections, which is similar to the administered number of doses in the Aflibercept (Eylea) 2Q8 group in VIVIDDME and VISTADME, while overall efficacy of the aflibercept treatment group in Protocol T was comparable to Aflibercept (Eylea) 2Q8 group in VIVIDDME and VISTADME. A 13.3 mean letter gain with 42% of patients gaining at least 15 letters in vision from baseline was observed in Protocol T. Ocular and systemic safety profiles (including ATEs) were similar to VIVIDDME and VISTADME.
Pharmacokinetics: Aflibercept (Eylea) is administered directly into the vitreous to exert local effects in the eye.
Absorption/Distribution: Aflibercept is slowly absorbed from the eye into the systemic circulation after intravitreal administration and is predominately observed in the systemic circulation as an inactive, stable complex with VEGF; however only "free aflibercept" is able to bind endogenous VEGF.
In a pharmacokinetic sub-study with frequent sampling in AMD patients, maximum plasma concentrations of free aflibercept (systemic Cmax) were low, with a mean of approximately 0.02 microgram/mL (range: 0 to 0.054 microgram/mL) within 1 to 3 days after a 2-mg intravitreal injection, and were undetectable two weeks following dosage in almost all patients. Aflibercept does not accumulate in the plasma when administered intravitreally every 4 weeks.
It is estimated that after intravitreal administration of 2 mg to patients, the mean maximum plasma concentration of free aflibercept is more than a 100 fold lower than the concentration of aflibercept required to half-maximally bind systemic VEGF (2.91 microgram/mL) in a study of healthy volunteers. Therefore, systemic pharmacodynamic effects such as blood pressure changes are unlikely.
These pharmacokinetic results were confirmed in a pharmacokinetic sub-study in patients with CRVO (mean Cmax of free aflibercept in plasma 0.046 microgram/mL (range: 0 to 0.081 microgram/mL); undetectable concentrations reached within 1 week).
Elimination: Free aflibercept binds VEGF to form a stable, inert complex. As with other large proteins, both free and bound aflibercept are expected to be cleared by proteolytic catabolism.
Toxicology: Preclinical safety data: Effects in non-clinical studies on repeated dose toxicity were observed only at systemic exposures considered substantially in excess of the maximum human exposure after intravitreal administration at the intended clinical dose indicating little relevance to clinical use.
No studies have been conducted on the mutagenic or carcinogenic potential of aflibercept.
An effect of aflibercept on intrauterine development was shown in embryo-fetal development studies in pregnant rabbits with intravenous (3 to 60 mg/kg) as well as subcutaneous (0.1 to 1 mg/kg) administration. The maternal NOAEL was at the dose of 3 mg/kg or 1 mg/kg, respectively. A developmental NOAEL was not identified. At the 0.1 mg/kg dose, the systemic exposures based on Cmax and cumulative AUC for free aflibercept were approximately 17- and 10-fold higher, respectively, when compared to corresponding values observed in humans after an intravitreal dose of 2 mg.
