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Pharmacology: Pharmacodynamics: Aflibercept is a recombinant fusion protein consisting of portions of human VEGF receptor 1 and 2 extracellular domains fused to the Fc portion of human IgG1.
Aflibercept is produced in Chinese hamster ovary (CHO) K1 cells by recombinant DNA technology.
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.
Mechanism of Action: Vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PlGF) are members of the VEGF family of angiogenic factors that can act as potent mitogenic, chemotactic, and vascular permeability factors for endothelial cells. VEGF acts via two receptor tyrosine kinases; VEGFR-1 and VEGFR-2, present on the surface of endothelial cells. PlGF binds only to VEGFR-1, which is also present on the surface of leucocytes. Excessive activation of these receptors by VEGF-A can result in pathological neovascularisation and excessive vascular permeability. PlGF can synergize with VEGF-A in these processes and is also known to promote leucocyte infiltration and vascular inflammation.
Clinical Studies: wet AMD: The safety and efficacy of aflibercept were assessed in two randomised, multi-centre, double-masked, active-controlled studies in patients with wet AMD (VIEW1 and VIEW2) with a total of 2412 patients treated and evaluable for efficacy (1817 with aflibercept). Patient ages ranged from 49 to 99 years with a mean of 76 years. In these clinical studies, approximately 89% (1616/1817) of the patients randomised to treatment with aflibercept were 65 years of age or older, and approximately 63% (1139/1817) were 75 years of age or older. In each study, patients were randomly assigned in a 1:1:1:1 ratio to 1 of 4 dosing regimens: 1) Aflibercept administered at 2 mg every 8 weeks following 3 initial monthly doses (aflibercept 2Q8); 2) Aflibercept administered at 2 mg every 4 weeks (aflibercept 2Q4); 3) Aflibercept administered at 0.5 mg every 4 weeks (aflibercept 0.5Q4); and 4) ranibizumab administered at 0.5 mg every 4 weeks (ranibizumab 0.5Q4).
In the second year of the studies, patients continued to receive the initially randomised dose but on a modified dosing schedule guided by assessment of visual and anatomic outcomes with a protocol-defined maximum dosing interval of 12 weeks.
In both studies, the primary efficacy endpoint was the proportion of patients in the Per Protocol Set who maintained vision, i.e. losing fewer than 15 letters of visual acuity at week 52 from baseline.
In the VIEW1 study, at week 52, 95.1% of patients in the aflibercept 2Q8 group maintained vision compared to 94.4% patients in the ranibizumab 0.5Q4 group. In the VIEW2 study, at week 52, 95.6% of patients in the aflibercept 2Q8 group maintained vision compared to 94.4% patients in the ranibizumab 0.5Q4 group. In both studies aflibercept was shown to be non-inferior and clinically equivalent to the ranibizumab 0.5Q4 group.
Detailed results from the combined analysis of both studies are shown in Table 1 and Figure 1 as follows: See Table 1 and Figure 1.
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Click on icon to see table/diagram/imageIn combined data analysis of VIEW1 and VIEW2, aflibercept demonstrated clinically meaningful changes from baseline in pre-specified secondary efficacy endpoint National Eye Institute Visual Function Questionnaire (NEI VFQ-25) without clinically meaningful differences to ranibizumab. The magnitude of these changes was similar to that seen in published studies, which corresponded to a 15-letter gain in Best Corrected Visual Acuity (BCVA).
In the second year of the studies, efficacy was generally maintained through the last assessment at week 96, and 2-4% of patients required all injections on a monthly basis, and a third of patients required at least one injection with a treatment interval of only one month.
Decreases in mean CNV area were evident in all dose groups in both studies.
Efficacy results in all evaluable subgroups (e.g., age, gender, race, baseline visual acuity, lesion type, lesion size) in each study and in the combined analysis were consistent with the results in the overall populations.
ALTAIR was a 96-week multicentre, randomised, open-label study in 247 Japanese patients with treatment naive wet AMD, designed to assess the efficacy and safety of aflibercept following two different adjustment intervals (2-weeks and 4-weeks) of a treat-and-extend dosing regimen.
All patients received monthly doses of aflibercept 2 mg for 3 months, followed by one injection after a further 2-month interval. At week 16, patients were randomised 1:1 into two treatment groups: 1) aflibercept treat-and-extend with 2-week adjustments and 2) aflibercept treat-and-extend with 4-week adjustments. Extension or shortening of the treatment 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 groups). 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 or 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 up to week 52, 56.8% 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 beyond.
In the second year of the study, efficacy was generally maintained up to and including the last assessment at week 96, with a mean gain from baseline of 7.6 letters for the 2-week adjustment group and 6.1 letters for the 4-week adjustment group. The proportion of patients who extended their treatment interval to 12 weeks or beyond was 56.9% in the 2-week adjustment group and 60.2% in the 4-week adjustment group. At the last visit prior to week 96, 64.9% and 61.2% of patients in the 2-week and 4-week adjustment groups, respectively had their next injection scheduled at an interval of 12 weeks or beyond.
During the second year of treatment patients in both the 2-week and 4-week adjustment groups received an average of 3.6 and 3.7 injections, respectively. Over the 2-year treatment period patients received an average of 10.4 injections.
Ocular and systemic safety profiles were similar to the safety observed in the pivotal studies VIEW1 and VIEW2.
ARIES was a 104-week multicentre, randomised, open-label, active-controlled study in 269 patients with treatment naive wet AMD, designed to assess the non-inferiority in terms of efficacy as well as the safety of a treat-and-extend dosing regimen initiated after 3 consecutive monthly doses followed by extension to a 2 monthly treatment interval vs. a treat-and-extend dosing regimen initiated after the first year of treatment.
The ARIES study also explored the percentage of patients that required more frequent treatment than every 8 weeks based on the investigator's decision. Out of the 269 patients 62 patients received more frequent dosing at least once during the course of the study. Such patients remained in the study and received treatment according to the investigator's best clinical judgement but not more frequently than every 4 weeks and their treatment intervals could be extended again afterwards. The average treatment interval after the decision to treat more frequently was 6.1 weeks. Week 104 BCVA was lower in patients requiring more intensive treatment at least once over the course of the study compared with patients who did not and the mean change in BCVA from baseline to end of the study was +2.3±15.6 letters. Among the patients treated more frequently, 85.5% maintained vision, i.e., lost less than 15 letters, and 19.4% gained 15 letters or more. The safety profile of patients treated more frequently than every 8 weeks was comparable to the safety data in VIEW 1 and VIEW 2.
Macular oedema secondary to CRVO: The safety and efficacy of aflibercept were assessed in two randomised, multi-centre, double-masked, sham-controlled studies in patients with macular oedema secondary to CRVO (COPERNICUS and GALILEO) with a total of 358 patients treated and evaluable for efficacy (217 with aflibercept). Patient ages ranged from 22 to 89 years with a mean of 64 years. In the CRVO studies, approximately 52% (112/217) of the patients randomised to treatment with aflibercept were 65 years of age or older, and approximately 18% (38/217) were 75 years of age or older. In both studies, patients were randomly assigned in a 3:2 ratio to either 2 mg aflibercept administered every 4 weeks (2Q4), or the control group receiving sham injections every 4 weeks for a total of 6 injections.
After 6 consecutive monthly injections, patients received treatment only if they met pre-specified retreatment criteria, except for patients in the control group in the GALILEO study who continued to receive sham (control to control) until week 52. From this timepoint all patients were treated if pre-specified criteria were met.
In both studies, the primary efficacy endpoint was the proportion of patients who gained at least 15 letters in BCVA at week 24 compared to baseline. A secondary efficacy variable was change in visual acuity at week 24 compared to baseline.
The difference between treatment groups was statistically significant in favour of aflibercept in both studies. The maximal improvement in visual acuity was achieved at month 3 with subsequent stabilisation of visual acuity and CRT until month 6. The statistically significant difference was maintained through week 52.
Detailed results from the analysis of both studies are shown in Table 2 and Figure 2 as follows. (See Table 2 and Figure 2.)
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Click on icon to see table/diagram/imageIn GALILEO, 86.4% (n=89) of the aflibercept group and 79.4% (n=54) of the sham group had perfused CRVO at baseline. At week 24, this was 91.8% (n=89) in the aflibercept group and 85.5% (n=47) in the sham group. These proportions were maintained at week 76, with 84.3% (n=75) in the aflibercept group and 84.0% (n=42) in the sham group.
In COPERNICUS, 67.5% (n=77) of the aflibercept group and 68.5% (n=50) of the sham group had perfused CRVO at baseline. At week 24, this was 87.4% (n=90) in the aflibercept group and 58.6% (n=34) in the sham group. These proportions were maintained at week 100 with 76.8% (n=76) in the aflibercept group and 78% (n=39) in the sham group. Patients in the sham group were eligible to receive aflibercept from week 24.
The beneficial effect of aflibercept treatment on visual function was similar in the baseline subgroups of perfused and non-perfused patients. Treatment effects in other evaluable subgroups (e.g., age, gender, race, baseline visual acuity, CRVO duration) in each study were in general consistent with the results in the overall populations.
In combined data analysis of GALILEO and COPERNICUS, aflibercept demonstrated clinically meaningful changes from baseline in pre-specified secondary efficacy endpoint National Eye Institute Visual Function Questionnaire (NEI VFQ-25). The magnitude of these changes was similar to that seen in published studies, which corresponded to a 15-letter gain in Best Corrected Visual Acuity (BCVA).
Macular oedema secondary to BRVO: The safety and efficacy of aflibercept were assessed in a randomised, multi-centre, double-masked, active-controlled study in patients with macular oedema secondary to BRVO (VIBRANT) which included Hemi-Retinal Vein Occlusion. A total of 181 patients were treated and evaluable for efficacy (91 with aflibercept). Patient ages ranged from 42 to 94 years with a mean of 65 years. In the BRVO study, approximately 58% (53/91) of the patients randomised to treatment with aflibercept were 65 years of age or older, and approximately 23% (21/91) were 75 years of age or older. In the study, patients were randomly assigned in a 1:1 ratio to either 2 mg aflibercept administered every 8 weeks following 6 initial monthly injections or laser photocoagulation administered at baseline (laser control group). Patients in the laser control group could receive additional laser photocoagulation (called 'rescue laser treatment') beginning at week 12 with a minimum interval of 12 weeks. Based on pre-specified criteria, patients in the laser group could receive rescue treatment with aflibercept 2 mg from week 24, administered every 4 weeks for 3 months followed by every 8 weeks.
In the VIBRANT study, the primary efficacy endpoint was the proportion of patients who gained at least 15 letters in BCVA at week 24 compared to baseline and the aflibercept group was superior to laser control.
A secondary efficacy endpoint was change in visual acuity at week 24 compared to baseline, which was statistically significant in favour of aflibercept in the VIBRANT study. The course of visual improvement was rapid and peaked at 3 months with maintenance of the effect until month 12.
In the laser group 67 patients received rescue treatment with aflibercept beginning at week 24 (Active Control/ aflibercept 2 mg group), which resulted in improvement of visual acuity by about 5 letters from week 24 to 52.
Detailed results from the analysis of the VIBRANT study are shown in Table 3 and Figure 3 as follows. (See Table 3 and Figure 3.)
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Click on icon to see table/diagram/imageAt baseline, the proportion of perfused patients in the aflibercept and laser groups was 60% and 68%, respectively. At week 24 these proportions were 80% and 67%, respectively. In the aflibercept group the proportion of perfused patients was maintained through week 52. In the laser group, where patients were eligible for rescue treatment with aflibercept from week 24, the proportion of perfused patients increased to 78% by week 52.
Diabetic macular oedema (DME): The safety and efficacy of aflibercept were assessed in two randomised, multi-centre, double-masked, active-controlled studies in patients with DME (VIVIDDME and VISTADME). A total of 862 patients were treated and evaluable for efficacy, 576 with aflibercept. Patient ages ranged from 23 to 87 years with a mean of 63 years. In the DME studies, approximately 47% (268/576) of the patients randomised to treatment with aflibercept were 65 years of age or older, and approximately 9% (52/576) were 75 years of age or older. The majority of patients in both studies had Type II diabetes.
In both studies, patients were randomly assigned in a 1:1:1 ratio to 1 of 3 dosing regimens: 1) Aflibercept administered 2 mg every 8 weeks following 5 initial monthly injections (aflibercept 2Q8); 2) Aflibercept administered 2 mg every 4 weeks (aflibercept 2Q4); and 3) Macular laser photocoagulation (active control).
Beginning at week 24, patients meeting a pre-specified threshold of vision loss were eligible to receive additional treatment: patients in the aflibercept groups could receive laser and patients in the control group could receive aflibercept.
In both studies, the primary efficacy endpoint was the mean change from baseline in BCVA at week 52 and both aflibercept 2Q8 and aflibercept 2Q4 groups demonstrated statistical significance and were superior to the control group. This benefit was maintained through week 100.
Detailed results from the analysis of the VIVIDDME and VISTADME studies are shown in Table 4 and Figure 4 as follows. (See Table 4 and Figure 4.)
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Click on icon to see table/diagram/imageTreatment effects in evaluable subgroups (e.g., age, gender, race, baseline HbA1c, baseline visual acuity, prior anti-VEGF therapy) in each study and in the combined analysis were generally consistent with the results in the overall populations.
In the VIVIDDME and VISTADME studies, 36 (9%) and 197 (43%) patients received prior anti-VEGF therapy, respectively, with a 3-month or longer washout period. Treatment effects in the subgroup of patients who had previously been treated with a VEGF inhibitor were similar to those seen in patients who were VEGF inhibitor naïve.
Patients with bilateral disease were eligible to receive anti-VEGF treatment in their fellow eye if assessed necessary by the physician. In the VISTADME study, 217 (70.7%) of aflibercept patients received bilateral aflibercept injections until week 100; in the VIVIDDME study, 97 (35.8%) of aflibercept patients received a different anti-VEGF treatment in their fellow eye.
An independent comparative trial (DRCR.net Protocol T) utilised a flexible 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 2Q8 group in VIVIDDME and VISTADME, while overall efficacy of the aflibercept treatment group in Protocol T was comparable to the aflibercept 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. Safety outcomes demonstrated that overall incidences of ocular and non-ocular adverse events (including ATEs) were comparable across all treatment groups in each of the studies and between the studies.
VIOLET, a 100-week multicentre, randomised, open-label, active controlled study in patients with DME compared three different dosing regimens of aflibercept 2 mg for treatment of DME after at least one year of treatment at fixed intervals, where treatment was initiated with 5 consecutive monthly doses followed by dosing every 2 months. The study evaluated non-inferiority of aflibercept 2 mg dosed according to a treat-and-extend regimen (2T&E where injections intervals were kept at a minimum of 8 weeks and gradually extended based on clinical and anatomical outcomes) and aflibercept 2 mg dosed as needed (2PRN where patients were observed every 4 weeks and injected when needed based on clinical and anatomical outcomes), compared to aflibercept 2 mg dosed every 8 weeks (2Q8) for the second and third year of treatment.
The primary efficacy endpoint (change in BCVA from baseline to week 52) was 0.5±6.7 letters in the 2T&E group and 1.7±6.8 letters in the 2PRN group compared to 0.4±6.7 letters in the 2Q8 group, achieving statistical non-inferiority (p<0.0001 for both comparisons; NI margin 4 letters). The changes in BCVA from baseline to week 100 were consistent with the week 52 results: -0.1±9.1 letters in the 2T&E group and 1.8±9.0 letters in the 2PRN group compared to 0.1±7.2 letters in the 2Q8 group. The mean number of injections over 100 weeks were 12.3, 10.0 and 11.5 for 2Q8fix, 2T&E and 2PRN, respectively.
Ocular and systemic safety profiles in all 3 treatment groups were similar to those observed in the pivotal studies VIVID and VISTA.
In the 2T&E group, the increments and decrements for the injection intervals were at the investigator's discretion; increments of 2 weeks were recommended in the study.
Myopic choroidal neovascularisation (myopic CNV): The safety and efficacy of aflibercept were assessed in a randomised, multi-centre, double-masked, sham-controlled study in treatment-naïve, Asian patients with myopic CNV. A total of 121 patients were treated and evaluable for efficacy (90 with aflibercept). Patient ages ranged from 27 to 83 years with a mean of 58 years. In the myopic CNV study, approximately 36% (33/91) of the patients randomised to treatment with aflibercept were 65 years of age or older, and approximately 10% (9/91) were 75 years of age or older.
Patients were randomly assigned in a 3:1 ratio to receive either 2 mg aflibercept intravitreally or sham injections administered once at study start with additional injections given monthly in case of disease persistence or recurrence until week 24, when the primary endpoint was assessed. At week 24, patients initially randomised to sham were eligible to receive the first dose of aflibercept. Following this, patients in both groups continued to be eligible for additional injections in case of disease persistence or recurrence.
The difference between treatment groups was statistically significant in favour of aflibercept for the primary endpoint (change in BCVA) and confirmatory secondary efficacy endpoint (proportion of patients who gained 15 letters in BCVA) at week 24 compared to baseline. Differences for both endpoints were maintained through week 48.
Detailed results from the analysis of the MYRROR study are shown in Table 5 and Figure 5 as follows. (See Table 5 and Figure 5.)
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Click on icon to see table/diagram/imageSTUDY MYL-1701P-3001: Study MYL-1701P-3001 was a multicenter, randomized, double masked, active controlled, comparative clinical study to demonstrate that no clinically meaningful differences exist between MYL-1701P and US-licensed Eylea regarding efficacy, safety, and immunogenicity in subjects with Diabetic Macular Edema (DME). Study MYL-1701P-3001 enrolled subjects with DME following type 1 or type 2 diabetes mellitus, with baseline CRT of ≥300 μm and BCVA at 4 m from 73 to 38 letters (ETDRS chart) equivalent to Snellen visual acuity of 20/40 to 20/200 in the study eye.
MYL-1701P (a proposed biosimilar to Eylea, reference aflibercept) or Eylea for intravitreal injection, administered at a dose of 2 mg (0.05 mL) every 4 weeks for a total of 5 injections, and then every 8 weeks (with optional doses to continue at every 4 weeks) through the remainder of the 52-week treatment period, with the last dose at 48 weeks.
A total of 355 subjects were randomized with 179 subjects to the MYL-1701P arm and 176 subjects to the Eylea arm. A total of 172 (96.1%) subjects in the MYL-1701P arm and 173 (98.3%) in the Eylea arm completed the study up through Week 8, and a total of 161 (89.9%) subjects in the MYL-1701P arm and 158 (89.8%) subjects in the Eylea arm completed Week 52.
The primary efficacy endpoint was the mean change from baseline in BCVA as assessed by ETDRS letter score, at Week 8. The primary analysis was performed on the ITT and PP analysis set (Table 6 and Table 7). The adjusted mean difference for mean change in BCVA from baseline through Week 8 for ITT and PP analysis set were 0.04 and -0.19 letters respectively, which corresponding to 95% CI of -1.40, 1.47 and -1.66, 1.27 respectively. Both ITT and PP analysis set results were well within the predefined equivalence margin of [-3, 3]. (See Table 6 and 7.)
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Click on icon to see table/diagram/imagePharmacokinetics: Aflibercept 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 in 6 neovascular wet AMD patients with frequent sampling, maximum plasma concentrations of free aflibercept (systemic Cmax) were low, with a mean of approximately 0.02 microgram/mL (range 0 to 0.054) within 1 to 3 days after a 2 mg intravitreal injection and were undetectable two weeks following dose in almost all patients. Aflibercept does not accumulate in the plasma when administered intravitreally every 4 weeks.
The mean maximum plasma concentration of free aflibercept is approximately 50 to 500 times below the aflibercept concentration required to inhibit the biologic activity of systemic VEGF by 50% in animal models, in which blood pressure changes were observed after circulating levels of free aflibercept attained approximately 10 microgram/mL and returned to baseline when levels fell below approximately 1 microgram/mL. It is estimated that after intravitreal administration of 2 mg to patients, the mean maximum plasma concentration of free aflibercept is more than 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.
In pharmacokinetic sub-studies in patients with CRVO, BRVO, DME or myopic CNV mean Cmax of free aflibercept in plasma were similar with values in the range of 0.03 to 0.05 microgram/mL and individual values not exceeding 0.14 microgram/mL. Thereafter, plasma concentrations of free aflibercept declined to values below or close to the lower limit of quantitation generally within one week; undetectable concentrations were reached before the next administration after 4 weeks in all patients.
Elimination: As aflibercept is a protein-based therapeutic, no metabolism studies have been conducted.
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.
Renal Impairment: No special studies in patients with renal impairment have been conducted with aflibercept.
Pharmacokinetic analysis of patients in the VIEW2 study, of which 40% had renal impairment (24% mild, 15% moderate, and 1% severe), revealed no differences with respect to plasma concentrations of active substance after intravitreal administration every 4 or 8 weeks.
Similar results were seen in patients with CRVO in the GALILEO study, in patients with DME in the VIVIDDME study, and in patients with myopic CNV in the MYRROR study.
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.
Erosions and ulcerations of the respiratory epithelium in nasal turbinates in monkeys treated with aflibercept intravitreally were observed at systemic exposures in excess of the maximum human exposure.
The systemic exposure based on Cmax and AUC for free aflibercept were approximately 200- and 700-fold higher, respectively, when compared to corresponding values observed in humans after an intravitreal dose of 2 mg. At the No Observed Adverse Effect Level (NOAEL) of 0.5 mg/eye in monkeys the systemic exposure was 42- and 56-fold higher based on Cmax and AUC, respectively.
No studies have been conducted on the mutagenic or carcinogenic potential of aflibercept.
An effect of aflibercept on intrauterine development was shown in embryo-foetal 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.
Effects on male and female fertility were assessed as part of a 6-month study in monkeys with intravenous administration of aflibercept at doses ranging from 3 to 30 mg/kg. Absent or irregular menses associated with alterations in female reproductive hormone levels and changes in sperm morphology and motility were observed at all dose levels. Based on Cmax and AUC for free aflibercept observed at the 3 mg/kg intravenous dose, the systemic exposures were approximately 4900-fold and 1500-fold higher, respectively, than the exposure observed in humans after an intravitreal dose of 2 mg. All changes were reversible.
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