Pavblu Drug Information
Generic name: AFLIBERCEPT-AYYH
Vascular Endothelial Growth Factor Inhibitor [EPC]
Uses of Pavblu
Neovascular (Wet) Age-Related Macular Degeneration (AMD) 1.2 Macular Edema Following Retinal Vein
Occlusion (RVO)
Dosage & Administration of Pavblu
Side Effects of Pavblu
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials of the same or another drug and may not reflect the rates observed in practice. A total of 2980 adult patients treated with aflibercept constituted the safety population in eight phase 3 studies. Among those, 2379 patients were treated with the recommended dose of 2 mg.
Serious adverse reactions related to the injection procedure have occurred in <0.1% of intravitreal injections with aflibercept including endophthalmitis and retinal detachment. The most common adverse reactions (≥5%) reported in patients receiving aflibercept were conjunctival hemorrhage, eye pain, cataract, vitreous detachment, vitreous floaters, and intraocular pressure increased. Neovascular (Wet) Age-Related Macular Degeneration (AMD) The data described below reflect exposure to aflibercept in 1824 patients with wet AMD, including 1223 patients treated with the 2-mg dose, in 2 double-masked, controlled clinical studies (VIEW1 and VIEW2) for 24 months (with active control in year 1) . Safety data observed in the aflibercept group in a 52-week, double-masked, Phase 2 study were consistent with these results.
Table 1. Most Common Adverse Reactions (≥1%) in Wet AMD Studies Adverse Reactions Baseline to Week 52 Baseline to Week 96 Aflibercept (N=1824) Active Control (ranibizumab) (N=595) Aflibercept (N=1824) Control (ranibizumab) (N=595) Conjunctival hemorrhage 25% 28% 27% 30% Eye pain 9% 9% 10% 10% Cataract 7% 7% 13% 10% Vitreous detachment 6% 6% 8% 8% Vitreous floaters 6% 7% 8% 10% Intraocular pressure increased 5% 7% 7% 11% Ocular hyperemia 4% 8% 5% 10% Corneal epithelium defect 4% 5% 5% 6% Detachment of the retinal pigment epithelium 3% 3% 5% 5% Injection site pain 3% 3% 3% 4% Foreign body sensation in eyes 3% 4% 4% 4% Lacrimation increased 3% 1% 4% 2% Vision blurred 2% 2% 4% 3% Intraocular inflammation 2% 3% 3% 4% Retinal pigment epithelium tear 2% 1% 2% 2% Injection site hemorrhage 1% 2% 2% 2% Eyelid edema 1% 2% 2% 3% Corneal edema 1% 1% 1% 1% Retinal detachment <1% <1% 1% 1% Less common serious adverse reactions reported in <1% of the patients treated with aflibercept were hypersensitivity, retinal tear, and endophthalmitis. Macular Edema Following Retinal Vein Occlusion (RVO) The data described below reflect 6 months exposure to aflibercept with a monthly 2 mg dose in 218 patients following central retinal vein occlusion (CRVO) in 2 clinical studies (COPERNICUS and GALILEO) and 91 patients following branch retinal vein occlusion (BRVO) in one clinical study (VIBRANT) . Table 2. Most Common Adverse Reactions (≥1%) in RVO Studies Adverse Reactions CRVO BRVO Aflibercept (N=218) Control (N=142) Aflibercept (N=91) Control (N=92) Eye pain 13% 5% 4% 5% Conjunctival hemorrhage 12% 11% 20% 4% Intraocular pressure increased 8% 6% 2% 0% Corneal epithelium defect 5% 4% 2% 0% Vitreous floaters 5% 1% 1% 0% Ocular hyperemia 5% 3% 2% 2% Foreign body sensation in eyes 3% 5% 3% 0% Vitreous detachment 3% 4% 2% 0% Lacrimation increased 3% 4% 3% 0% Injection site pain 3% 1% 1% 0% Vision blurred 1% <1% 1% 1% Intraocular inflammation 1% 1% 0% 0% Cataract <1% 1% 5% 0% Eyelid edema <1% 1% 1% 0% Less common adverse reactions reported in <1% of the patients treated with aflibercept in the CRVO studies were corneal edema, retinal tear, hypersensitivity, and endophthalmitis. Diabetic Macular Edema (DME) and Diabetic Retinopathy (DR) The data described below reflect exposure to aflibercept in 578 patients with DME treated with the 2-mg dose in 2 double-masked, controlled clinical studies (VIVID and VISTA) from baseline to week 52 and from baseline to week 100 . Table 3. Most Common Adverse Reactions (≥1%) in DME Studies Adverse Reactions Baseline to Week 52 Baseline to Week 100 Aflibercept (N=578) Control (N=287) Aflibercept (N=578) Control (N=287) Conjunctival hemorrhage 28% 17% 31% 21% Eye pain 9% 6% 11% 9% Cataract 8% 9% 19% 17% Vitreous floaters 6% 3% 8% 6% Corneal epithelium defect 5% 3% 7% 5% Intraocular pressure Increased 5% 3% 9% 5% Ocular hyperemia 5% 6% 5% 6% Vitreous detachment 3% 3% 8% 6% Foreign body sensation in eyes 3% 3% 3% 3% Lacrimation increased 3% 2% 4% 2% Vision blurred 2% 2% 3% 4% Intraocular inflammation 2% <1% 3% 1% Injection site pain 2% <1% 2% <1% Eyelid edema <1% 1% 2% 1% Less common adverse reactions reported in <1% of the patients treated with aflibercept were hypersensitivity, retinal detachment, retinal tear, corneal edema, and injection site hemorrhage.
Safety data observed in 269 patients with nonproliferative diabetic retinopathy (NPDR) through week 52 in the PANORAMA trial were consistent with those seen in the phase 3 VIVID and VISTA trials (see Table 3 above).
Postmarketing Experience
The following adverse reactions have been identified during postapproval use of aflibercept. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Eye disorders: Retinal vasculitis and occlusive retinal vasculitis related to intravitreal injection with aflibercept (reported at a rate of 0.6 and 0.2 per 1 million injections, respectively, based on postmarketing experience from November 2011 until November 2023). Scleritis.
Warnings & Cautions for Pavblu
Endophthalmitis, Retinal Detachments, and Retinal Vasculitis with or without Occlusion Intravitreal injections
including those with aflibercept products, have been associated with endophthalmitis and retinal detachments and, more rarely, retinal vasculitis with or without occlusion . Proper aseptic injection technique must always be used when administering PAVBLU. Patients and/or caregivers should be instructed to report any signs and/or symptoms suggestive of endophthalmitis, retinal detachment, or retinal vasculitis without delay and should be managed appropriately .
Increase in Intraocular Pressure Acute increases in intraocular pressure have been seen
within 60 minutes of intravitreal injection, including with aflibercept products . Sustained increases in intraocular pressure have also been reported after repeated intravitreal dosing with vascular endothelial growth factor (VEGF) inhibitors. Intraocular pressure and the perfusion of the optic nerve head should be monitored and managed appropriately .
Thromboembolic Events
There is a potential risk of arterial thromboembolic events (ATEs) following intravitreal use of VEGF inhibitors, including aflibercept products. ATEs are defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause). The incidence of reported thromboembolic events in wet AMD studies during the first year was 1.8% (32 out of 1824) in the combined group of patients treated with aflibercept compared with 1.5% (9 out of 595) in patients treated with ranibizumab; through 96 weeks, the incidence was 3.3% (60 out of 1824) in the aflibercept group compared with 3.2% (19 out of 595) in the ranibizumab group. The incidence in the DME studies from baseline to week 52 was 3.3% (19 out of 578) in the combined group of patients treated with aflibercept compared with 2.8% (8 out of 287) in the control group; from baseline to week 100, the incidence was 6.4% (37 out of 578) in the combined group of patients treated with aflibercept compared with 4.2% (12 out of 287) in the control group.
There were no reported thromboembolic events in the patients treated with aflibercept in the first six months of the RVO studies.
Pregnancy Safety for Pavblu
Pregnancy Risk Summary Adequate and well-controlled studies with aflibercept have not been conducted in pregnant women. Aflibercept produced adverse embryofetal effects in rabbits, including external, visceral, and skeletal malformations. A fetal No Observed Adverse Effect Level (NOAEL) was not identified.
At the lowest dose shown to produce adverse embryofetal effects, systemic exposures (based on AUC for free aflibercept) were approximately 6 times higher than AUC values observed in humans after a single intravitreal treatment at the recommended clinical dose (see Data ). Animal reproduction studies are not always predictive of human response, and it is not known whether aflibercept can cause fetal harm when administered to a pregnant woman. Based on the anti-VEGF mechanism of action for aflibercept , treatment with aflibercept may pose a risk to human embryofetal development. PAVBLU should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data Animal Data In two embryofetal development studies, aflibercept produced adverse embryofetal effects when administered every three days during organogenesis to pregnant rabbits at intravenous doses ≥3 mg per kg, or every six days during organogenesis at subcutaneous doses ≥0.1 mg per kg. Adverse embryofetal effects included increased incidences of postimplantation loss and fetal malformations, including anasarca, umbilical hernia, diaphragmatic hernia, gastroschisis, cleft palate, ectrodactyly, intestinal atresia, spina bifida, encephalomeningocele, heart and major vessel defects, and skeletal malformations (fused vertebrae, sternebrae, and ribs; supernumerary vertebral arches and ribs; and incomplete ossification). The maternal No Observed Adverse Effect Level (NOAEL) in these studies was 3 mg per kg. Aflibercept produced fetal malformations at all doses assessed in rabbits and the fetal NOAEL was not identified.
At the lowest dose shown to produce adverse embryofetal effects in rabbits (0.1 mg per kg), systemic exposure (AUC) of free aflibercept was approximately 6 times higher than systemic exposure (AUC) observed in adult patients after a single intravitreal dose of 2 mg.
Pediatric Use of Pavblu
Pediatric Use A pediatric assessment for PAVBLU demonstrates that PAVBLU is safe and effective for pediatric patients in an indication for which EYLEA (aflibercept) is approved. However, PAVBLU is not approved for such indication due to marketing exclusivity for EYLEA (aflibercept).
Contraindications for Pavblu
Ocular or Periocular Infections
PAVBLU is contraindicated in patients with ocular or periocular infections.
Active Intraocular Inflammation
PAVBLU is contraindicated in patients with active intraocular inflammation.
Hypersensitivity
PAVBLU is contraindicated in patients with known hypersensitivity to aflibercept or any of the excipients in PAVBLU. Hypersensitivity reactions may manifest as rash, pruritus, urticaria, severe anaphylactic/anaphylactoid reactions, or severe intraocular inflammation.
Overdosage Information for Pavblu
Overdosing with increased injection volume may increase intraocular pressure. Therefore, in case of overdosage, intraocular pressure should be monitored and if deemed necessary by the treating physician, adequate treatment should be initiated.
Clinical Studies of Pavblu
Neovascular (Wet) Age-Related Macular Degeneration (AMD)
The safety and efficacy of aflibercept were assessed in two 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 aflibercept) in the two studies (VIEW1 and VIEW2). In each study, up to week 52, patients were randomly assigned in a 1:1:1:1 ratio to 1 of 4 dosing regimens: 1) aflibercept administered 2 mg every 8 weeks following 3 initial monthly doses (aflibercept 2Q8); 2) aflibercept administered 2 mg every 4 weeks (aflibercept 2Q4); 3) aflibercept 0.5 mg administered every 4 weeks (aflibercept 0.5Q4); and 4) ranibizumab administered 0.5 mg every 4 weeks (ranibizumab 0.5 mg Q4). Protocol-specified visits occurred every 28±3 days. Patient ages ranged from 49 to 99 years with a mean of 76 years. In both studies, the primary efficacy endpoint was the proportion of patients who maintained vision, defined as losing fewer than 15 letters of visual acuity at week 52 compared to baseline.
Both aflibercept 2Q8 and aflibercept 2Q4 groups were shown to have efficacy that was clinically equivalent to the ranibizumab 0.5 mg Q4 group in year 1. Detailed results from the analysis of the VIEW1 and VIEW2 studies are shown in Table 4 and Figure 13 below. Table 4. Efficacy Outcomes at Week 52 (Full Analysis Set with LOCF) in VIEW1 and VIEW2 Studies VIEW 1 VIEW 2 Aflibercept 2 mg Q8 weeks After treatment initiation with 3 monthly doses Aflibercept 2 mg Q4 weeks Ranibizumab 0.5 mg Q4 weeks Aflibercept 2 mg Q8 weeks Aflibercept 2 mg Q4 weeks Ranibizumab 0.5 mg Q4 weeks Full Analysis Set N=301 N=304 N=304 N=306 N=309 N=291 BCVA = Best Corrected Visual Acuity; CI = Confidence Interval; ETDRS = Early Treatment Diabetic Retinopathy Study; LOCF = Last Observation Carried Forward (baseline values are not carried forward); 95.1% confidence intervals were presented to adjust for safety assessment conducted during the study Efficacy Outcomes Proportion of patients who maintained visual acuity (%) (<15 letters of BCVA loss) 94% 95% 94% 95% 95% 95% Difference Aflibercept group minus the ranibizumab group (%) (95.1% CI) 0.6 (-3.2, 4.4) 1.3 (-2.4, 5.0) 0.6 (-2.9, 4.0) -0.3 (-4.0, 3.3) Mean change in BCVA as measured by ETDRS letter score from Baseline 7.9 10.9 8.1 8.9 7.6
Difference in LS mean (95.1% CI) 0.3 (-2.0, 2.5) 3.2 -0.9 (-3.1
1.3) -2.0 (-4.1, 0.2) Number of patients who gained at least 15 letters of vision from Baseline (%) 92 (31%) 114 (38%) 94 (31%) 96 (31%) 91 (29%) 99 (34%) Difference (%) (95.1% CI) -0.4 (-7.7, 7.0) 6.6 (-1.0, 14.1) -2.6 (-10.2, 4.9) -4.6 (-12.1, 2.9) Treatment effects in evaluable subgroups (e.g., age, gender, race, baseline visual acuity) in each study were in general consistent with the results in the overall populations. Figure 13. Mean Change in Visual Acuity from Baseline to Week 96 Patient dosing schedules were individualized from weeks 52 to 96 using a modified 12-week dosing regimen. in VIEW1 and VIEW2 Studies VIEW1 and VIEW2 studies were both 96 weeks in duration. However, after 52 weeks patients no longer followed a fixed dosing schedule.
Between week 52 and week 96, patients continued to receive the drug and dosage strength to which they were initially randomized on a modified 12 week dosing schedule (doses at least every 12 weeks and additional doses as needed). Therefore, during the second year of these studies there was no active control comparison arm. Figure 13
Macular Edema Following Central Retinal Vein Occlusion (CRVO)
The safety and efficacy of aflibercept were assessed in two randomized, multi-center, double-masked, sham-controlled studies in patients with macular edema following CRVO. A total of 358 patients were treated and evaluable for efficacy (217 with aflibercept) in the two studies (COPERNICUS and GALILEO). In both studies, patients were randomly assigned in a 3:2 ratio to either 2 mg aflibercept administered every 4 weeks (2Q4), or sham injections (control group) administered every 4 weeks for a total of 6 injections. Protocol-specified visits occurred every 28±7 days. Patient ages ranged from 22 to 89 years with a mean of 64 years.
In both studies, the primary efficacy endpoint was the proportion of patients who gained at least 15 letters in BCVA compared to baseline. At week 24, the aflibercept 2 mg Q4 group was superior to the control group for the primary endpoint. Results from the analysis of the COPERNICUS and GALILEO studies are shown in Table 5 and Figure 14 below.
Table 5. Efficacy Outcomes at Week 24 (Full Analysis Set with LOCF) in COPERNICUS and GALILEO Studies COPERNICUS GALILEO Control Aflibercept 2 mg Q4 weeks Control Aflibercept 2 mg Q4 weeks N=73 N=114 N=68 N=103 Efficacy Outcomes Proportion of patients who gained at least 15 letters in BCVA from Baseline (%) 12% 56% 22% 60% Weighted Difference Difference is aflibercept 2 mg Q4 weeks minus Control, Difference and CI are calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for baseline factors; 95.1% confidence intervals were presented to adjust for the multiple assessments conducted during the study (%) 44.8% p<0.01 compared with Control 38.3% (95.1% CI) Mean change in BCVA as measured by ETDRS letter score from Baseline (SD) -4.0 17.3 3.3
Difference in LS mean, LS mean and CI based on an
ANCOVA model 21.7 14.7 (95.1% CI) Figure 14. Mean Change in BCVA as Measured by ETDRS Letter Score from Baseline to Week 24 in COPERNICUS and GALILEO Studies Treatment effects in evaluable subgroups (e.g., age, gender, race, baseline visual acuity, retinal perfusion status, and CRVO duration) in each study and in the combined analysis were in general consistent with the results in the overall populations. Figure 14
Macular Edema Following Branch Retinal Vein Occlusion (BRVO)
The safety and efficacy of aflibercept were assessed in a 24-week, randomized, multi-center, double-masked, controlled study in patients with macular edema following BRVO. A total of 181 patients were treated and evaluable for efficacy (91 with aflibercept) in the VIBRANT study. In the study, patients were randomly assigned in a 1:1 ratio to either 2 mg aflibercept administered every 4 weeks (2Q4) or laser photocoagulation administered at baseline and subsequently as needed (control group). Protocol-specified visits occurred every 28±7 days. Patient ages ranged from 42 to 94 years with a mean of 65 years.
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. At week 24, the aflibercept 2 mg Q4 group was superior to the control group for the primary endpoint. Detailed results from the analysis of the VIBRANT study are shown in Table 6 and Figure 15 below.
Table 6. Efficacy Outcomes at Week 24 (Full Analysis Set with LOCF) in VIBRANT Study VIBRANT Control Aflibercept 2 mg Q4 weeks N=90 N=91 Efficacy Outcomes Proportion of patients who gained at least 15 letters in BCVA from Baseline (%) 26.7% 52.7% Weighted Difference Difference is aflibercept 2 mg Q4 weeks minus Control, Difference and CI are calculated using Mantel-Haenszel weighting scheme adjusted for region (North America vs. Japan) and baseline BCVA category (> 20/200 and ≤ 20/200) (%) 26.6% p<0.01 compared with Control (95% CI) Mean change in BCVA as measured by ETDRS letter score from Baseline (SD) 6.9
Difference in LS mean, LS mean and CI based on an
ANCOVA model 10.5 (95% CI) Figure 15. Mean Change in BCVA as Measured by ETDRS Letter Score from Baseline to Week 24 in VIBRANT Study Treatment effects in evaluable subgroups (e.g., age, gender, and baseline retinal perfusion status) in the study were in general consistent with the results in the overall populations. Figure 15
Diabetic Macular Edema (DME)
The safety and efficacy of aflibercept were assessed in two randomized, multi-center, double-masked, controlled studies in patients with DME. A total of 862 randomized and treated patients were evaluable for efficacy. Protocol-specified visits occurred every 28±7 days. Patient ages ranged from 23 to 87 years with a mean of 63 years.
Of those, 576 were randomized to aflibercept groups in the two studies (VIVID and VISTA). In each study, 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 (at baseline and then as needed). 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 laser group could receive aflibercept. In both studies, the primary efficacy endpoint was the mean change from baseline in BCVA at week 52 as measured by ETDRS letter score. Efficacy of both aflibercept 2Q8 and aflibercept 2Q4 groups was statistically superior to the control group.
This statistically superior improvement in BCVA was maintained at week 100 in both studies. Results from the analysis of the VIVID and VISTA studies are shown in Table 7 and Figure 16 below. Table 7. Efficacy Outcomes at Weeks 52 and 100 (Full Analysis Set with LOCF) in VIVID and VISTA Studies VIVID VISTA Aflibercept 2 mg Q8 weeks After treatment initiation with 5 monthly injections Aflibercept 2 mg Q4 weeks Control Aflibercept 2 mg Q8 weeks Aflibercept 2 mg Q4 weeks Control Full Analysis Set N=135 N=136 N=132 N=151 N=154 N=154 Efficacy Outcomes at Week 52 Mean change in BCVA as measured by ETDRS letter score from Baseline (SD) 10.7 10.5 1.2 10.7 12.5
Difference LS mean and CI based on an
ANCOVA model with baseline BCVA measurement as a covariate and a factor for treatment group. Additionally, protocol specified stratification factors were included in the model., Difference is aflibercept group minus Control group in LS mean 9.1 p<0.01 compared with Control 9.3 10.5 12.2 (97.5% CI) Proportion of patients who gained at least 15 letters in BCVA from Baseline (%) 33.3% 32.4% 9.1% 31.1% 41.6% 7.8% Adjusted Difference, Difference with confidence interval (CI) and statistical test is calculated using Mantel-Haenszel weighting scheme adjusted by protocol specified stratification factors (%) 24.2% 23.3% 23.3% 34.2% (97.5% CI) Efficacy Outcomes at Week 100 Mean change in BCVA as measured by ETDRS letter score from Baseline (SD) 9.4 11.4 0.7 11.1 11.5
Difference, in LS mean 8.2 10.7 10.1 10.6 (97.5% CI) Proportion of
patients who gained at least 15 letters in BCVA from Baseline (%) 31.1% 38.2% 12.1% 33.1% 38.3% 13.0% Adjusted Difference, (%) 19.0% 26.1% 20.1% 25.8% (97.5% CI) Figure 16. Mean Change in BCVA as Measured by ETDRS Letter Score from Baseline to Week 100 in VIVID and VISTA Studies Treatment effects in the subgroup of patients who had previously been treated with a VEGF inhibitor prior to study participation were similar to those seen in patients who were VEGF inhibitor naïve prior to study participation. Treatment effects in evaluable subgroups (e.g., age, gender, race, baseline HbA1c, baseline visual acuity, prior anti-VEGF therapy) in each study were in general consistent with the results in the overall populations. Figure 16
Diabetic Retinopathy (DR) Efficacy and safety data of aflibercept in diabetic retinopathy
(DR) are derived from the VIVID, VISTA, and PANORAMA studies. VIVID AND VISTA In the VIVID and VISTA studies, an efficacy outcome was the change in the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (ETDRS-DRSS). The ETDRS-DRSS score was assessed at baseline and approximately every 6 months thereafter for the duration of the studies . All enrolled patients had DR and DME at baseline. The majority of patients enrolled in these studies (77%) had moderate-to-severe nonproliferative diabetic retinopathy (NPDR) based on the ETDRS-DRSS. At week 100, the proportion of patients improving by at least 2 steps on the ETDRS-DRSS was significantly greater in both aflibercept treatment groups (2Q4 and 2Q8) when compared to the control group.
Results from the analysis of ETDRS-DRSS at week 100 in the VIVID and VISTA studies are shown in Table 8 below. Table 8. Proportion of Patients Who Achieved a ≥2-Step Improvement from Baseline in the ETDRS-DRSS Score at Week 100 in VIVID and VISTA Studies VIVID VISTA Aflibercept 2 mg Q8 weeks After treatment initiation with 5 monthly injections Aflibercept 2 mg Q4 weeks Control Aflibercept 2 mg Q8 weeks Aflibercept 2 mg Q4 weeks Control Evaluable Patients The number of evaluable patients included all patients who had valid ETDRS-DRSS data at baseline N=101 N=97 N=99 N=148 N=153 N=150 Non-gradable post-baseline ETDRS-DRSS values were treated as missing and were imputed using the last gradable ETDRS-DRSS values (including baseline values if all post-baseline values were missing or non-gradable) Number of patients with a ≥2-step improvement on ETDRS-DRSS from Baseline (%) 32 27 7 56 58 24 (32%) (28%) (7%) (38%) (38%) (16%) Difference Difference with confidence interval (CI) was calculated using Mantel-Haenszel weighting scheme adjusted by protocol specified stratification factors, Difference is aflibercept minus Control group (%) (97.5% CI) 24% p<0.01 compared with Control 21% 22% 22% Results of the evaluable subgroups (e.g., age, gender, race, baseline HbA1c, baseline visual acuity) on the proportion of patients who achieved a ≥2-step improvement on the ETDRS-DRSS from baseline to week 100 were, in general, consistent with those in the overall population. PANORAMA The PANORAMA study assessed the safety and efficacy of aflibercept in a randomized, multi-center, double-masked, controlled study in patients with moderately severe to severe nonproliferative diabetic retinopathy (NPDR) (ETDRS-DRSS of 47 or 53), without central-involved DME (CI-DME). A total of 402 randomized patients were evaluable for efficacy.
Protocol-specified visits occurred every 28±7 days for the first 5 visits, then every 8 weeks (56±7 days). Patient ages ranged from 25 to 85 years with a mean of 55.7 years. Patients were randomly assigned in a 1:1:1 ratio to 1 of 3 dosing regimens: 1) 3 initial monthly aflibercept 2 mg injections followed by one injection after 8 weeks and then one injection every 16 weeks (aflibercept 2Q16); 2) 5 monthly aflibercept 2 mg injections followed by one injection every 8 weeks (aflibercept 2Q8); and 3) sham treatment. The primary efficacy endpoint was the proportion of patients who improved by ≥2 steps on the DRSS from baseline to week 24 in the combined aflibercept groups and at week 52 in the 2Q16 and 2Q8 groups individually versus sham.
A key secondary endpoint was the proportion of patients developing the composite endpoint of proliferative diabetic retinopathy or anterior segment neovascularization through week 52. At week 52, efficacy in the 2Q16 and 2Q8 groups was superior to the sham group (see Table 9 and Table 10 ). The proportion of patients with a ≥2-step improvement over time is shown in Figure 17. Table 9. Proportion of Patients Who Achieved a ≥2-Step Improvement from Baseline in the ETDRS-DRSS Score at Weeks 24 and 52 in PANORAMA PANORAMA Week 24 Week 52 Aflibercept Combined Control (sham) Aflibercept 2Q16 Aflibercept 2Q8 Control (sham) Full Analysis Set N=269 N=133 N=135 N=134 N=133 Non-gradable post-baseline ETDRS-DRSS values were treated as missing and were imputed using the last gradable ETDRS-DRSS values (including baseline values if all post-baseline values were missing or non-gradable) Proportion of patients with a ≥2-step improvement on ETDRS-DRSS from Baseline (%) 58% 6% 65% 80% 15% Adjusted Difference Difference is aflibercept group minus sham (%) 52% p<0.01 compared with Control. p-value was calculated using a 2-sided Cochran-Mantel-Haenszel test adjusted by baseline DRSS stratification variable. 50% 65% (95% CI) Difference with CI was calculated using the Mantel-Haenszel weighting scheme adjusted by baseline DRSS stratification variable Figure 17. Proportion of Patients Who Achieved a ≥2-Step Improvement from Baseline in the ETDRS-DRSS Score Through Week 52 in PANORAMA Table 10. Effect of Aflibercept on Worsening of Diabetic Retinopathy in PANORAMA through Week 52 Aflibercept 2Q16 Aflibercept 2Q8 Control (sham) Full Analysis Set N=135 N=134 N=133 PDR = Proliferative Diabetic Retinopathy; ASNV = Anterior Segment Neovascularization Composite Endpoint of Developing PDR or ASNV As diagnosed by either the Reading Center or Investigator through week 52 Event Rate Estimated using Kaplan-Meier method 4.0% p<0.01 compared with Control 2.4% 20.1% Hazard Ratio 0.15 0.12 Development of Proliferative Diabetic Retinopathy Defined as ≥2-step worsening on the ETDRS-DRSS score through week 52 Event Rate 1.6% 0.0% 11.9% Hazard Ratio 0.11 0.00 Figure 17
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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