To compare combined dexamethasone implant (DEX) and intravitreal aflibercept (AFB) to AFB monotherapy treatment in diabetic macular edema (DME). This open-label RCT involved randomization of DME patients (n=50) to pro re nata treatment with combined DEX and AFB or AFB alone according to pre-specified retreatment criteria. Best-corrected visual acuity (BCVA), central subfield retinal thickness (CST), and adverse events were monitored monthly for 48 weeks. The combined treatment and the AFB monotherapy group demonstrated CST reductions at each visit. The difference (95% CI) in the change from baseline in CST between the groups was -32.9 (-81.5, 15.6) µm at week 48, favoring the combination therapy group without significance (p=0.183). The difference in the change from baseline in BCVA was -3.3 (-9.2, 2.5) letters read at week 48 (p=0.266). Injection number was numerically higher in the aflibercept monotherapy group (mean ± SD, 5.9 ± 1.8) than in the combination group (4.9 ± 1.5). The AFB monotherapy group had a 90% higher injection rate over the study period (IRR [95% CI]=1.9 [0.9, 4.0]) without statistical significance (p=0.081). The combined treatment group achieved quicker time to resolution of DME (log-rank p-value=0.013) by a median difference (95% CI) of 12 (0, 24) weeks. Three eyes and two eyes in the combined therapy group developed worsening cataracts and IOP elevation requiring medical management, respectively. Combined treatment achieved similar anatomic and visual outcomes compared with AFB monotherapy, with quicker DME resolution but higher cataract and IOP risks.

Diabetic macular edema (DME) is a predominant cause of visual impairment among patients. The concurrent administration of anti-vascular endothelial growth factor (VEGF) agents and corticosteroids may yield synergistic therapeutic benefits. In this study, we evaluated the efficacy and safety of aflibercept (AFL) in combination with dexamethasone (DEX) intravitreal implant for the treatment of DME. A total of 80 patients with DME admitted to a hospital from June 2022 to June 2024 were enrolled. 42 patients in the AFL group received monotherapy, and 38 patients in the AFL+DEX group received combination therapy. The best corrected visual acuity (BCVA), central macular thickness (CMT), intraocular pressure (IOP) and aqueous humor inflammatory factors (IL-1β, MCP-1, IL-6, VEGF) were evaluated monthly. Efficacy was graded according to criteria at 4 months after treatment, and adverse events were recorded. The findings revealed no statistically significant difference in the overall clinical efficacy rate between the AFL+DEX group and the AFL group (P>0.05). However, the AFL+DEX group demonstrated superior best-corrected visual acuity (BCVA) at 1, 3 and 6 months post-treatment, alongwith a significant reduction in central macular thickness (CMT) compared to the AFL group (P<0.05). Furthermore, aqueous humor analysis indicated markedly lower levels of inflammatory cytokines in the AFL+DEX group following treatment (P<0.05). In terms of safety profiles, the AFL+DEX group required fewer intravitreal injections (P<0.05). These findings underscore the potential of AFL combined with DEX intravitreal implant to enhance visual outcomes and modulate intraocular inflammation in DME patients, highlighting its substantial clinical utility.

e15563 Background: FOLFIRI plus aflibercept (AFL) or bevacizumab (BEV) are significant therapeutic options for patients with metastatic colorectal cancer (mCRC) who have failed prior oxaliplatin-based chemotherapy. While accumulating evidence suggests an association between the tumor microenvironment, inflammation, and the prognosis of mCRC, biomarkers predictive of response to these chemotherapy regimens remain unknown. Studies have demonstrated that AFL exerts biological effects on macrophages within the tumor microenvironment. Methods: We conducted a multi-institutional retrospective biomarker study to analyze the relationship between CD68, CD163 (M2 macrophage), iNOS (M1 macrophage), and S100A4 expression in biopsy or surgical colon samples and the efficacy of FOLFIRI plus AFL (cohort A) or plus BEV (cohort B) in Japanese patients with mCRC who failed prior treatment with 5-fluorouracil + oxaliplatin + anti-EGFR agent. The primary outcome was overall response rate (ORR), and the secondary outcome was progression-free survival (PFS) according to the biomarker status. The expression of biomarkers was evaluated independently using immunohistochemical staining scores (IHCSS) by three investigators, including a board-certified pathologist. Statistical analyses were performed using the chi-square test and log-rank test. Results: Forty patients were enrolled in the study, including 19 in cohort A and 21 in cohort B. The median age was 67.5 years (range, 36-79), and 25 patients (62.5%) were male. The ORR was 26.3% in cohort A and 19.0% in cohort B, while median PFS was 11.1 months and 7.1 months, respectively. The percentage of cases that were positive for CD68, CD163, iNOS, and S100A4 were 78.9%, 26.3%, 57.9%, and 89.5% in cohort A, 42.9%, 38.1%, 81.0%, and 81.0% in cohort B. Among these biomarkers, none demonstrated a statistically significant association with outcomes, although the Kaplan-Meier plot and PFS at 6 and 12 months indicated a potential trend suggesting that patients with iNOS-negative tumors may exhibit improved PFS, particularly in cohort A (Table). Conclusions: In our biomarker study of patients with mCRC treated with FOLFIRI plus AFL or BEV, none of the analyzed biomarkers associated with macrophages in the tumor microenvironment demonstrated significant correlations with treatment outcomes. The observed trend towards improved PFS in iNOS-negative tumors treated with AFL merits further investigation, and larger prospective studies are necessary to elucidate this potential relationship. Progression-free survival at 6 and 12 months. Progression-free survival 6 months 12 months All iNOS pos (n=28 ) 46.4 % (13) 21.4 % (6) iNOS neg (n= 12) 83.3 % (10) 50.0 % (6) Cohort A iNOS pos (n= 11) 45.5 % (5) 18.2 % (2) iNOS neg (n= 8) 87.5 % (7) 50.0 % (4) Cohort B iNOS pos (n= 17) 47.1 % (8) 23.5 % (4) iNOS neg (n= 4) 75.0 % (3) 50.0 % (2)

71 Background: FOLFIRI in combination with Aflibercept (AFL) or Ramucirumab (RAM) prolongs overall survival compared with FOLFIRI alone in patients with advanced colorectal cancer (aCCR) as second-line therapy, however, there are no comparative studies between them. Methods: Utilizing the TriNetX Global Collaborative Network, a platform that operates globally based on anonymized and aggregated clinical data, a sample of aCCR patients from 128 healthcare organizations (HCOs) who met the initial criteria was selected. 5-year overall survival (OS) was analyzed between these cohorts using a Kaplan-Meier analysis. Hazard Ratio (HR) and its 95% confidence interval (95%CI) were calculated to evaluate the difference between cohorts. Propensity Score Matching (PSM) was used to balance the cohorts based on age, gender, and race mitigating possible cofounding variables. All statistical analyses were conducted utilizing the TriNetX Analytics function in the online research platform. Results: A total of 1046 patients met the study criteria and were included in our study. 523 received AFL and 523r received RAM-based therapy. Patients treated with AFL showed a significant better OS compared to patients treated with RAM, both previous to PSM and before PSM (post-PMS median OS 430 days vs 317 days, HR 0.797, 95%CI 0.683-0.930). Conclusions: In this study, based on Real World data, Aflibercept showed superior results to Ramucirumab in advanced colorectal cancer patients treatment. To date this is the largest study comparison between this two therapeutic options.

147 Background: The HGCSG1801 trial evaluated the treatment outcomes of aflibercept (AFL) plus FOLFIRI for patients(pts) with metastatic colorectal cancer (mCRC) refractory to an oxaliplatin-based regimen combined with an anti-EGFR agent. Here we report results of the updated efficacy, safety, and a biomarker analysis. Methods: This was a prospective open-label phase II trial. AFL (4 mg/kg iv) followed by FOLFIRI (irinotecan 180 mg/m 2 , leucovorin 200 mg/m 2 iv, bolus 5-fluorouracil [5-FU] 400 mg/m 2 , and infusional 5-FU 2400 mg/m 2 /46 h) was given every 2 weeks until progression or unacceptable toxicities. The primary endpoint was 6-month progression-free survival (PFS) rate, and the secondary endpoints included overall survival (OS), PFS, overall response rate (ORR), disease control rate (DCR), and adverse events. Angiogenic factors were analyzed in plasma sample using a Luminex multiplex assay using the Cox proportional hazards model. This study was sponsored by the Non-Profit Organization Hokkaido Gastrointestinal Cancer Study Group and supported by a grant from Sanofi. Results: Forty-three pts were enrolled between November 2019 and October 2022. The data cut-off date was April 30, 2024. The 6-month PFS rate was 59.0% (90% confidence interval [CI], 45.8–72.1%). Median PFS and OS were 7.3 months (95% CI, 5.5–11.0 months) and 18.8 months (95% CI, 12.9–26.6 months), respectively. The ORR was 20.9% (95% CI, 10.0–36.0%) and DCR was 88.4% (95% CI, 74.9–96.1%). No deaths and no new safety signals with a causal relation to the study treatment were observed. A biomarker analysis using pretreatment plasma samples showed a trend toward better PFS in pts with low VEGF-A (hazard ratio [HR] 0.40 [95% CI, 0.18-0.91]), TSP-2 (HR 0.40 [95% CI, 0.18-0.88]) or IL-8 levels (HR 0.43 [95% CI, 0.20-0.93]). There was also a trend toward better OS in pts with low levels of TSP-2 (HR 0.30 [95% CI, 0.11-0.81]) or TIMP-1 (HR 0.20 [95% CI, 0.06-0.69]). Conclusions: These updated data further support the activity and manageable safety profile of AFL plus FOLFIRI for pts with mCRC who failed an oxaliplatin-based regimen combined with an anti-EGFR agent. It was suggested the association between some angiogenic factors in plasma samples and the activity of AFL plus FOLFIRI in mCRC. Clinical trial information: jRCTs011190006 .

The advent of biomacromolecules antagonizing vascular endothelial growth factor (VEGF) has revolutionized the treatment of neovascular age‐related macular degeneration (nAMD). However, frequent intravitreal injections of these biomacromolecules impose an enormous burden on patients and create a massive workload for healthcare providers. This causes patients to abandon therapy, ultimately leading to progressive and irreversible vision loss. In order to address this unmet clinical need, a noninvasive treatment for nAMD is developed. An optimized cell‐penetrating peptide derivative, bxyPenetratin (bxyWP), is used to non‐covalently complex with the anti‐VEGF protein aflibercept (AFL) via reversible hydrophobic interaction. The interaction is crucial for AFL delivery, neither impairing the affinity of AFL to pathological VEGF, nor being interfered by endogenous proteins in tear fluids. AFL/bxyWP eye drops exhibit prolonged retention on the eye and excellent absorption into the posterior ocular segment following topical administration, with significant drug distribution to the retina and choroid. In a laser‐induced choroidal neovascularization model on cynomolgus monkeys, AFL/bxyWP eye drops efficiently reduce lesion size and leakage comparable to conventional intravitreal injection of AFL. These results suggest that AFL/bxyWP eye drops are feasible self‐administered treatment for neovascular retinal diseases and potentially become a substitute for intravitreal injections.

Abstract This study aimed to determine how resveratrol combination separately with the anti-VEGF agents ranibizumab, aflibercept and ziv-aflibercept affects ARPE-19 cells in vitro. The cells were assigned to twelve groups as follows: Control, Cobalt Chloride (Cob), Resveratrol (RSV), Ranibizumab (RNZ), Aflibercept (AFL), Ziv-aflibercept (ZFL), RNZ + RSV, AFL + RSV, ZFL + RSV, RNZ + RSV + Cob, AFL + RSV + Cob and ZFL + RSV + Cob. The Control group was incubated for 48 hours with no treatment, while the remaining groups received RSV, RNZ, AFL or ZFL (alone or in combination) for 24 hours and then the cells in the relevant groups were exposed to CoCl2 for 24 hours more. Mitochondrial reactive oxygen species (MitROS), cytosolic reactive oxygen species (CytROS), mitochondrial membrane depolarization (MitDep), caspase-3, caspase-8, caspase-9, cell viability, apoptosis and VEGF-A levels were assessed by confocal microscopy, plate reader and ELISA techniques. Resveratrol, alone or in combination with anti-VEGF’s, significantly decreased the levels of MitROS, MitDep, CytROS, caspase-3, caspase-8 and caspase-9 (p &lt; 0.001). Resveratrol also increased cell viability and decreased apoptosis and VEGF-A levels (p &lt; 0.001). According to our findings, combining resveratrol with anti-VEGFs may have a beneficial therapeutic effect on the treatment of AMD.

Aflibercept (AFL) plus FOLFIRI prolongs overall survival (OS) in patients with metastatic colorectal cancer (mCRC). However, there is limited evidence on the efficacy and safety of AFL plus FOLFIRI previously treated with anti-epidermal growth factor receptor (EGFR) agents. Therefore, we conducted a prospective open-label phase II trial evaluating the efficacy and safety of AFL plus FOLFIRI in Japanese patients with mCRC failing a prior oxaliplatin-based chemotherapy plus an anti-EGFR agent. AFL (4 mg/kg iv) followed by FOLFIRI (irinotecan 180 mg/m2, leucovorin 200 mg/m2 iv, bolus 5-fluorouracil [5-FU] 400 mg/m2, and infusional 5-FU 2400 mg/m2/46 h) was given every 2 weeks until progression or unacceptable toxicities. The primary endpoint was progression-free survival (PFS) rate at 6 months. Forty three patients were enrolled between November 2019 and October 2022. The primary endpoint was met: 6-month PFS rate was 58.8% (90% confidence interval [CI], 45.7%-72.0%). Median PFS and OS were 7.3 months (95% CI, 5.5-11.0 months) and 18.8 months (95% CI, 12.9-26.6 months), respectively. The overall response rate was 20.9% (95% CI, 10.0-36.0%) and disease control rate was 88.4% (95% CI, 74.9-96.1%). The main grade ≥3 adverse events included hypertension (62.8%), neutropenia (55.8%), leukopenia (25.6%), febrile neutropenia (11.6%), fatigue (9.3%), anorexia (9.3%), proteinuria (9.3%), and diarrhea (7.0%). No deaths and no new safety signals with a causal relation to the study treatment were observed. This study suggests that AFL plus FOLFIRI shows a high response rate and a manageable safety profile in Japanese patients with mCRC who failed prior oxaliplatin-based chemotherapy plus an anti-EGFR agent.

The aim of this study was to investigate the retinal morpho-functional characteristics of patients with neovascular wet age-related macular degeneration (nAMD) treated with intravitreal injection (IV) of aflibercept (AFL). The study was conducted on 35 patients previously diagnosed with type 1 nAMD who received a fixed-dosing regimen of aflibercept injections over 12 months. The goal was to assess trends in visual abilities over time by measuring visual acuity (VA), contrast sensitivity (CS), visual evoked potentials (VEPs), and spectral domain-optical coherence tomography (SD-OCT). The same psychophysical, electro-functional, and morphological tests administered at baseline (T0) were repeated 4 to 8 weeks after the last aflibercept injection (Tn), resulting in a total of six examinations. At Tn, all subjects exhibited improved VA for both far and near distances compared to values detected at T0. Similarly, VEP amplitude and latency values at Tn showed a greater P100 improvement than those observed at T0. Additionally, the CS examination at Tn demonstrated improvement, particularly at high spatial stimulation frequencies. The Tn SD-OCT results highlighted a reduction in macular thickness compared to T0 values. This exploratory research indicates that intravitreal injections of AFL, following a fixed-dosing regimen, represent a valuable therapeutic approach for enhancing visual performance. This conclusion is supported by comprehensive statistical analysis of psychophysical, electro-functional, and morphological examinations within the same group of patients with nAMD, as demonstrated for the first time.

Anti-VEGF (vascular endothelial growth factor) drugs such as aflibercept (AFL) and bevacizumab (BVZ) inhibit pathological neo-angiogenesis and vascular permeability in retinal vascular diseases. As cytokines and growth factors are produced by Müller glial cells under stressful and pathological conditions, we evaluated the in vitro effect of AFL (Eylea®, 0.5 mg/mL) and BVZ (Avastin®, 0.5 mg/mL) on cell viability/metabolism, and cytokine/growth factor production by Müller cells (MIO-M1) under cobalt chloride (CoCl2)-induced hypoxia after 24h, 48h and 72h. Cell viability/metabolism were analyzed by Trypan Blue and MTT assays and cytokine/growth factors in supernatants by Luminex xMAP-based multiplex bead-based immunoassay. Cell viability increased with AFL at 48h and 72h and decreased with BVZ or hypoxia at 24h. BVZ-treated cells showed lower cell viability than AFL at all exposure times. Cell metabolism increased with AFL but decreased with BVZ (72h) and hypoxia (48h and72h). As expected, AFL and BVZ decreased VEGF levels. AFL increased PDGF-BB, IL-6 and TNF-α (24h) and BVZ increased PDGF-BB (72h). Hypoxia reduced IL-1β, -6, -8, TNF-α and PDGF-BB at 24h, and its suppressive effect was more prominent than AFL (EGF, PDGF-BB, IL-1β, IL-6, IL-8, and TNF-α) and BVZ (PDGF-BB and IL-6) effects. Hypoxia increased bFGF levels at 48h and 72h, even when combined with anti-VEGFs. However, the stimulatory effect of BVZ predominated over hypoxia for IL-8 and TNF-α (24h), as well as for IL-1β (72h). Thus, AFL and BVZ exhibit distinct exposure times effects on MIO-M1 cells viability, metabolism, and cytokines/growth factors. Hypoxia and BVZ decreased MIO-M1 cell viability/metabolism, whereas AFL likely induced gliosis. Hypoxia resulted in immunosuppression, and BVZ stimulated inflammation in hypoxic MIO-M1 cells. These findings highlight the complexity of the cellular response as well as the interplay between anti-VEGF treatments and the hypoxic microenvironment.

113 Background: Aflibercept (AFL) combined with FOLFIRI prolongs overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC) who failed a prior oxaliplatin-based regimen. However, there is limited evidence on the efficacy and safety of AFL plus FOLFIRI in RAS / BRAF wild type pts previously treated with anti-epidermal growth factor receptor (EGFR) agents. Therefore, we conducted a phase II trial evaluating the efficacy and safety of AFL plus FOLFIRI in Japanese pts with mCRC failing a prior oxaliplatin-based chemotherapy combined with an anti-EGFR agent. Methods: This was a prospective open-label phase II trial. AFL (4 mg/kg iv) followed by FOLFIRI (irinotecan 180 mg/m2, leucovorin 200 mg/m2 iv, bolus 5-FU 400 mg/m2 and infusional 5-FU 2400 mg/m2/46 h) was given every 2 weeks until progression or unacceptable toxicities. The primary endpoint was progression-free survival (PFS) rate at 6 months; secondary endpoints included OS, PFS, overall response rate (ORR), disease control rate (DCR), adverse events, and relative dose intensity (RDI) for each drug. Given a PFS rate threshold at 6 months of 38.9% and an expected PFS rate of 58.4% with AFL plus FOLFIRI, a sample size of 41 pts was required (two-sided alpha, 0.1; beta, 0.2). Analyses were conducted in the full analysis set (FAS) of pts satisfying eligibility criteria. Results: Forty-three patients were enrolled between November 2019 and October 2022, and 43 were analyzed (median age 68 years (range 27-80); male, 69.8%; ECOG PS 0/1, 72.1%/27.9%; left sided primary tumor, 90.7%). The primary endpoint was met: 6-month PFS rate was 58.7% (90%CI, 45.5%-71.9%). Median PFS and OS were 7.3 months (95%CI, 5.5-11.0 months) and 18.8 months (95%CI, 12.9-26.6 months), respectively. The ORR was 23.3 % (95%CI, 11.8-38.6%) and DCR was 88.4% (95%CI, 74.9- 96.1%). Mean RDI of AFL, irinotecan, bolus 5-FU and infusional 5-FU were 75.3% (SD, 26.2), 50.6% (SD, 12.5), 31.6% (SD, 26.6), and 58.7% (SD, 7.21), respectively. The main grade ≥3 adverse events included hypertension (62.8%), neutropenia (55.8%), leukopenia (25.6%), febrile neutropenia (11.6%), fatigue (9.3%), anorexia (9.3%), proteinuria (9.3%) and diarrhea (7.0%). No deaths and no new safety signals with a causal relation to the study treatment were observed. Conclusions: Results of this prospective phase II study suggest that AFL plus FOLFIRI shows a high response rate and a manageable safety profile in Japanese pts with mCRC who failed a first-line oxaliplatin-based plus anti-EGFR regimen. Clinical trial information: jRCTs011190006 .

Background/aimsTo evaluate efficacy, safety, pharmacokinetics (PK) and immunogenicity of SB15 versus reference aflibercept (AFL), and switching from AFL to SB15 in neovascular age-related macular degeneration (nAMD).DesignProspective, double-masked, randomised, phase 3...

Introduction: The purpose of this study is to analyze incidence rates of endophthalmitis after intravitreal injection(s) of bevacizumab (BEVA), brolucizumab (BROL), aflibercept (AFL), ranibizumab (RAN), dexamethasone implant (DEXA), and triamcinolone acetonide (TRIA). Methods: In this retrospective cohort study data was collected from patients who received intravitreal injections from January 2020 through November 2021, of AFL, BEVA, BROL, DEXA, TRIA and RAN. Data collected includes patient identification number, injection dates, medication injected, and procedure codes. Endophthalmitis rates were compared amongst medications and total percentage tabulated. Result: From January 2020 through November 2021, 109,202 injections were administered. Of the 109,202 injections administered: 66,095 were aflibercept, 28,762 bevacizumab, 8,650 ranibizumab, 3,010 brolucizumab, 1,958 dexamethasone implant, and 95 triamcinolone acetonide. Thirty-nine (0.036%) endophthalmitis cases occurred. Of the 39 endophthalmitis cases, 22 of the cases occurred (0.033% of total aflibercept injections) after aflibercept injection(s), 5 (0.688% of total triamcinolone acetonide injections) after triamcinolone acetonide injection(s), 5 (0.03% of total bevacizumab injections) after bevacizumab injection(s), 3 (0.153% of total dexamethasone implants) after dexamethasone implantation(s), 2 (0.066% of total brolucizumab injections) after brolucizumab injection(s), 2 (0.023% of total ranibizumab injections) after ranibizumab injection(s).(Table 1) Using a student’s t-test, the rate of endophthalmitis for TRIA versus all other medications was statistically significant with a p-value of 0.00152. Conclusion: Results show an endophthalmitis incidence rate of 0.036% after intravitreal injection(s) administration. This review suggests triamcinolone acetonide (TRIA) yielded a significantly higher incidence rate of endophthalmitis as compared to the other medications.

This project aimed to produce a biosimilar version of aflibercept (AFL) and evaluate the effect of the co-treatment of AFL with other vascular endothelial growth factor (VEGF) blocker drugs. For this purpose, the optimized gene was inserted into the pCHO1.0 plasmid and transfected into the CHO-S cell line. The final concentration of biosimilar-AFL for the selected clone was 782 mg/L. Results revealed that the inhibition potential of the biosimilar-AFL on HUVEC cells was significant at 10 and 100 nM concentrations and in a dose-dependent manner. Furthermore, co-treatment of biosimilar-AFL with Everolimus (EVR), Lenvatinib (LEN), and Sorafenib (SOR) could reduce HUVEC cell viability/proliferation, more than when used alone. When LEN and SOR were co-treated with biosimilar-AFL, their cytotoxicity increased 10-fold. The most and least efficient combination was seen when biosimilar-AFL combined with LEN and EVR, respectively. Finally, biosimilar-AFL may improve the efficiency of LEN, EVR, and SOR in reducing the VEGF effect on endothelial cells.

Aflibercept biosimilars can expand available treatment options in retinal diseases and have the potential to improve patient access to safe and effective therapy. To establish equivalence in efficacy and similarity in safety, pharmacokinetics, and immunogenicity of SB15 and reference aflibercept (AFL) in neovascular age-related macular degeneration (nAMD). This was a randomized double-masked parallel group phase 3 trial conducted at 56 centers in 10 countries from June 2020 to March 2022, including follow-up through 56 weeks. Of 549 screened participants, 449 participants 50 years and older with treatment-naive nAMD were included and randomly assigned to SB15 (n = 224) or AFL (n = 225). Key exclusion criteria included considerable scarring, fibrosis, atrophy, and hemorrhage. This report includes results up to the end of the parallel group period at week 32. Of the 449 randomized participants, 438 (97.6%) completed week 32 follow-up. Participants were randomized 1:1 to receive 2 mg of SB15 or AFL every 4 weeks for the first 12 weeks (3 injections), followed by dosing every 8 weeks up to week 48, with final assessments at week 56. The primary end point was the change in best-corrected visual acuity (BCVA) from baseline to week 8 with predefined equivalence margins of -3 letters to 3 letters. Other key end points were changes in BCVA and central subfield thickness up to week 32, safety, pharmacokinetics, and immunogenicity. The mean (SD) age among the 449 included participants was 74.0 (8.1) years, and 250 participants (55.7%) were female. Baseline demographic characteristics and most disease characteristics were comparable between treatment groups. The least squares mean change in BCVA from baseline to week 8 in the SB15 group was equivalent to that in the AFL group (6.7 letters vs 6.6 letters, respectively; difference, 0.1 letters; 95% CI, -1.3 to 1.4). Comparable efficacy between treatment groups was maintained up to week 32 (least squares mean change from baseline in BCVA: SB15, 7.6 letters vs AFL, 6.5 letters; least squares mean change from baseline in central subfield thickness: SB15, -110.4 μm vs AFL, -115.7 μm). No clinically relevant differences were observed in the incidence of treatment-emergent adverse events (TEAEs) (SB15, 107/224 [47.8%] vs AFL, 98/224 [43.8%]) and ocular TEAEs in the study eye (SB15, 41/224 [18.3%] vs AFL, 28/224 [12.5%]). The serum concentration profiles and cumulative incidences of overall antidrug antibody positive participants were comparable. In this phase 3 randomized clinical trial, SB15 and AFL showed equivalent efficacy and comparable safety, pharmacokinetics, and immunogenicity in participants with nAMD. ClinicalTrials.gov Identifier: NCT04450329.

The purpose of this study was to compare the efficacy and safety of aflibercept (AFL) versus ranibizumab (RAN) for the treatment of diabetic macular edema (DME). The PubMed, Embase, Cochrane Library, and CNKI databases were searched up to September 2022 to identify prospective randomized controlled trials (RCTs) comparing AFL with RAN for the treatment of DME. Review Manager 5.3 software was used for data analysis. We used the GRADE system to evaluate the quality of the evidence for each outcome. A total of 8 RCTs involving 1067 eyes (939 patients) were included; there were 526 eyes in the AFL group and 541 eyes in the RAN group. Meta-analysis revealed that there was no significant difference between RAN and AFL in the best-corrected visual acuity (BCVA) of DME patients at 6 months (WMD: -0.05, 95% CI = -0.12 to 0.01, moderate quality) and 12 months after injection (WMD: -0.02, 95% CI = -0.07 to 0.03, moderate quality). Additionally, there was no significant difference between RAN and AFL in the reduction of central macular thickness (CMT) at 6 months (WMD: -0.36, 95% CI = -24.99 to 24.26, very low quality) and 12 months after injection (WMD: -6.36, 95% CI = -16.30 to 3.59, low quality). Meta-analysis showed that the number of intravitreal injections (IVIs) for AFL was significantly lower than that for RAN (WMD: -0.47, 95% CI = -0.88 to -0.05, very low quality). There were fewer adverse reactions to AFL than to RAN, but the difference was not significant. This study found that there was no difference in BCVA, CMT or adverse reactions between AFL and RAN at 6 and 12 months of follow-up, but AFL needed fewer IVIs than RAN.

IntroductionNeovascular age-related macular degeneration (nAMD) is the world’s leading cause of blindness in elderly people. While anti-vascular endothelial growth factor (VEGF) treatments are used as the first option for patients with nAMD, they are generally expensive and need repeated injections. This study aimed to evaluate the cost-effectiveness of anti-VEGF therapies, focusing on the newly launched ranibizumab biosimilar (RBZ BS) in patients with nAMD from a Japanese societal perspective.MethodsA Markov model was developed to simulate the lifetime transitions of a cohort of treatment-naïve patients with nAMD through health states that were based on the involvement of nAMD (single eye vs. both eyes), the treatment status of the patients, and decimal best-corrected visual acuity. The model compared RBZ BS with branded RBZ, aflibercept (AFL), and AFL as loading dose switched to RBZ BS in maintenance in the treat-and-extend (TAE) regimen (RBZ TAE, AFL TAE, and AFL to RBZ BS TAE, respectively), and with branded RBZ in the pro re nata (PRN) regimen, as well as best supportive care (BSC). All processes were validated by five clinical experts.ResultsWhen TAE regimens were compared, RBZ BS was dominant (higher quality-adjusted life-years (QALYs) and lower total cost) to AFL TAE and AFL to RBZ BS TAE. The result was robust regardless of whether the clinical data were taken from the direct head-to-head clinical trial or from indirect treatment comparison. RBZ BS TAE was cost-saving compared to RBZ TAE. RBZ BS TAE was estimated to be dominant to BSC owing to a lower societal cost. Like TAE regimens, RBZ BS was cost-saving compared to RBZ PRN and was dominant to BSC in PRN regimens.ConclusionThis study suggests that RBZ BS is dominant to other anti-VEGF treatments in patients with nAMD in both TAE and PRN regimens and BSC from a Japanese societal perspective.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40123-023-00715-y.

Purpose: To evaluate the incidence and clinical characteristics of intravitreal injection-related endophthalmitis cases with antivascular endothelial growth factor (anti-VEGF) medications manufactured as prefilled syringes or non-prefilled preparations. Methods: This retrospective chart review comprised eyes that received intravitreal anti-VEGF at a single-specialty retina practice from January 1, 2014, to December 31, 2019. Eyes diagnosed with injection-related endophthalmitis were identified. Demographic and clinical data were abstracted from medical records, including the type of anti-VEGF agent, baseline and follow-up corrected visual acuity (VA), and microbiologic findings. Results: The review identified 88 cases of intravitreal anti-VEGF injection-related endophthalmitis and 325 990 total injections. Total injections included 32 045 (9.8%) bevacizumab (BEV), 93 073 (28.6%) ranibizumab (RAN), 122 947 (37.7%) aflibercept (AFL), and 77 925 (23.9%) ranibizumab prefilled syringe (RANPFS). Ten of the endophthalmitis cases were related to BEV, 21 to RAN, 45 to AFL, and 12 to RANPFS. The endophthalmitis rate was lowest for RANPFS (0.0154%) (BEV, 0.0312%; RAN, 0.0226%; AFL, 0.0366%) (P = .030). Thirty-four (41.5%) of 82 samples were culture positive. RANPFS had a significantly lower rate of culture-proven postinjection endophthalmitis than the other agents (P = .003). The mean VA for endophthalmitis cases related to RANPFS vs non-prefilled agents was similar at presentation (Snellen 20/2092 vs 20/2327) and at the 3-month follow-up (Snellen 20/201 vs 20/272) (both P > .05). Conclusions: Anti-VEGF medications in prefilled syringes may reduce the risk for medication contamination during injection preparation. RANPFS was associated with a lower rate of injection-related endophthalmitis than non-prefilled anti-VEGF medications.

The aim of this study was to compare the outcomes of diabetic macular edema (DME) treated with aflibercept (AFB) or ranibizumab (RNB) only, and after switching from RNB to AFB. This was a retrospective, real-world, multicenter (7 cities) 24 month study. Overall, 212 eyes in the AFB group, 461 in the RNB group, and 141 in the RNB to AFB group were included. The primary endpoints were differences in visual acuity (VA) and central macular thickness (CMT) from baseline to the final visit. The secondary outcomes were the percentage of eyes that achieved ≥10 letters gain and ≥10 letters loss in vision at month 12 and 24, and the percentage of eyes that achieved a thinning of ≥20% in CMT at month 3 and month 6. The results showed that VA did not significantly differ at baseline (AFB: 0.62 ± 0.38, RNB: 0.61 ± 0.36, RNB to AFB: 0.61 ± 0.38), at checkpoints, or at the final visit (AFB: 0.46 ± 0.38, RNB: 0.5 ± 0.37, RNB to AFB: 0.53 ± 0.36) (p > 0.05). Though the mean CMT at baseline was significantly thicker in the RNB to AFB group (479 ± 129.6 μm) when compared to the AFB (450.5 ± 122.6 μm) and RNB (442 ± 116 μm) groups (p < 0.01), similar measurements were obtained after 12 months. The percentages of eyes that gained or lost ≥10 letters in the AFB, RNB, and RNB to AFB groups at year 1 and 2 were similar, as was the percentages of eyes that demonstrated ≥20% CMT thinning at month 3 and 6. Our study showed similar visual improvements in non-switchers (AFB and RNB groups) and switchers (RNB to AFB group) through 2 years follow-up, however, AFB patients required fewer injections, visits, or need for additional treatments.

BackgroundThe first-line chemotherapy for patients with RAS and BRAF wild-type metastatic colorectal cancer (mCRC) commonly involves cytotoxic regimens, such as FOLFOX and FOLFIRI, combined with epidermal growth factor receptor (EGFR) antibodies. When progression occurs following anti-EGFR antibody-combined chemotherapy, anti-angiogenic inhibitors can be used as second-line treatment. Although randomized controlled trials have shown that anti-angiogenic inhibitors [bevacizumab, ramucirumab, and aflibercept (AFL)] carry survival benefit when combined with FOLFIRI as second-line chemotherapy, such trials did not provide data on patients with mCRC refractory to anti-EGFR antibody-combined chemotherapy. Therefore, our group planned a multicenter, nonrandomized, single-arm, prospective, phase II study to investigate the safety and efficacy of FOLFIRI plus AFL as a second-line chemotherapy for patients with mCRC refractory to oxaliplatin-based chemotherapy combined with anti-EGFR antibodies.MethodsFOLFIRI (irinotecan 180 mg/m2, l-leucovorin 200 mg/m2, bolus 5-FU 400 mg/m2, and infusional 5-FU 2400 mg/m2/46 h) and AFL (4 mg/kg) will be administered every 2 weeks until progression or unacceptable toxicities occur. The primary endpoint will be the 6-month progression-free survival (PFS) rate, whereas the secondary endpoints will include overall survival, PFS, response rate, disease control rate, adverse events, and relative dose intensity for each drug. A sample size of 41 participants will be required. This study will be sponsored by the Non-Profit Organization Hokkaido Gastrointestinal Cancer Study Group and will be supported by a grant from Sanofi.DiscussionThere is only an observational study reporting data on FOLFIRI plus AFL for patients with mCRC who previously received anti-EGFR antibodies; therefore, a prospective clinical trial is needed. This study will prospectively evaluate the efficacy and safety of FOLFIRI plus AFL in patients with mCRC who are resistant to anti-EGFR antibodies and have limited data. Moreover, this study will reveal predictive biomarkers for AFL-based chemotherapy.Clinical trial registrationJapan Registry of Clinical Trials, jRCTs011190006. Registered 19 November, 2019, https://jrct.niph.go.jp/latest-detail/jRCTs011190006.