Ziv-aflibercept plus pembrolizumab in patients with advanced melanoma resistant to anti-PD-1 treatment.

BACKGROUND: Vascular endothelial growth factor is associated with reduced immune response and impaired anti-tumor activity. Combining antiangiogenic agents with immune checkpoint inhibition can overcome this immune suppression and enhance treatment efficacy. METHODS: This study investigated the combination of ziv-aflibercept anti-angiogenic therapy with pembrolizumab in patients with advanced melanoma resistant to anti-PD-1 treatment. Baseline and on-treatment plasma and PBMC samples were analyzed by multiplex protein assay and mass cytometry, respectively. RESULTS: In this Phase 1B study (NCT02298959), ten patients with advanced PD-1-resistant melanoma were treated with a combination of ziv-aflibercept (at 2-4 mg/kg) plus pembrolizumab (at 2 mg/kg), administered intravenously every 2 weeks. Two patients (20%) achieved a partial response, and two patients (20%) experienced stable disease (SD) as the best response. The two responders had mucosal melanoma, while both patients with SD had ocular melanoma. The combination therapy demonstrated clinical activity and acceptable safety, despite the occurrence of adverse events. Changes in plasma analytes such as platelet-derived growth factor and PD-L1 were explored, indicating potential alterations in myeloid cell function. Higher levels of circulating CXCL10 in non-responding patients may reflect pro-tumor activity. Specific subsets of γδ T cells were associated with poor clinical outcomes, suggesting impaired γδ T-cell function in non-responding patients. CONCLUSIONS: Although limited by sample size and follow-up, these findings highlight the potential of the combination of ziv-aflibercept antiangiogenic therapy with pembrolizumab in patients with advanced melanoma resistant to anti-PD-1 treatment and the need for further research to improve outcomes in anti-PD-1-resistant melanoma. TRIAL REGISTRATION NUMBER: NCT02298959.

Switching to ziv-aflibercept in resistant diabetic macular edema non responsive to ranibizumab injection.

BACKGROUND: Diabetic macular edema (DME) is a leading cause of visual loss in diabetic patients and is managed using multiple anti-vascular endothelial growth factor (VEGF) agents such as bevacizumab, ranibizumab and aflibercept. The present study evaluates effectiveness of intravitreal injection of ziv-aflibercept in resistant diabetic macular edema. METHODS: This is a prospective interventional study that was carried out on 59 eyes of 40 diabetic patients with diabetic macular edema resistant to three prior consecutive ranibizumab injections. On all patients, thorough ophthalmic evaluation including optical coherence tomography was performed. In patients with persistent intraretinal or subretinal fluid, ziv- aflibercept 1.25 mg (0.05 ml) was administered by intravitreal injection monthly during the 6 month study period from June to December 2019. RESULTS: The central macular thickness (CMT) decreased significantly from 395.08 ± 129.9 um at baseline to 282.39 ± 95.278, 245.36 ± 79.861 and 201.17 ± 54.042 after 1, 3 and 6 months of treatment respectively (p < 0.001). Best corrected visual acuity (BCVA) in log MAR units was significantly improved from 0.95 ± 0.21 to 0.51 ± 0.23 after 6 months (p = 0.001). After treatment, negative correlations were detected between age, number of injections, duration of DM and level of glycated hemoglobin (HbA1c) and variation of both CMT and BCVA. The only significant predictor for low final CMT after 6 months of injection was the CMT after 3 months of injection (p = 0.001). CONCLUSION: Ziv-aflibercept is a highly effective and safe drug in cases of DME resistant to previous ranibizumab injections especially in low-income countries. TRIAL REGISTRATION: This study was retrospectively registered at clinicaltrials.gov (ID: NCT04290195) on 28-2-2020.

Fundus autofluorescence in the evaluation of diabetic macular edema treatment response.

INTRODUCTION: Fundus autofluorescence (FAF) has shown sensitivity in the detection of macular edema. OBJECTIVES: To evaluate indices formed with FAF and retinal anatomical-functional variables in patients with diabetic macular edema (DME) treated with ziv-aflibercept (ziv-AFL). METHODS: Twenty-nine eyes of 15 DME patients who received ziv-AFL intravitreal injections were included in the study. Best-corrected visual acuity (BCVA), contrast sensitivity (CS), optical coherence tomography (OCT) and FAF were evaluated before treatment and at one and two months. OCT variables were central subfield thickness (CST), macular volume (MV) and macular cube average thickness (MCAT). FAF/BCVA, FAF/CS, FAF/CST, FAF/MV and AF/MCAT indices baseline values were obtained. Analysis was performed with Spearman's rank correlation coefficient and linear regression analysis. RESULTS: There was a significant correlation between baseline FAF/BCVA index and BCVA at second month (rs = - 0.78, p = 0.000), between baseline FAF/CS index and BCVA at second month (rs = -0.68, p = 0.0009) and between baseline FAF/CS index and MV at first month of follow-up (rs = 0.64, p = 0.002). CONCLUSIONS: In DME, composite indices with baseline FAF predict variables such as BCVA in the follow-up of patients receiving ziv-AFL.

INTRODUCCIÓN: La autofluorescencia retiniana (AF) ha mostrado sensibilidad en la detección del edema macular. OBJETIVOS: Evaluar índices formados con la AF y variables anatomofuncionales retinianas en pacientes con edema macular diabético (EMD) tratados con ziv-aflibercept (ziv-AFL). MÉTODOS: Fueron incluidos 29 ojos de 15 pacientes con EMD que recibieron inyecciones intravítreas de ziv-AFL. Se evaluó agudeza visual mejor corregida (AVMC), sensibilidad al contraste (SC), tomografía de coherencia óptica (TCO) y AF, antes del tratamiento, así como al primer y segundo mes de iniciado este. Las variables de la TCO fueron grosor foveal central (GFC), volumen macular (VM) y grosor promedio macular (GPM). Se obtuvieron los valores basales de AF/AVMC, AF/SC, AF/GFC, AF/VM y AF/GPM. Se realizó análisis con el coeficiente de correlación de rangos de Spearman y análisis de regresión lineal. RESULTADOS: Hubo una correlación significativa entre el índice AF/AVMC basal y la AVMC en el segundo mes (rs = −0.78, p = 0.000), entre el índice AF/SC basal y la AVMC en el segundo mes (rs = −0.68, p = 0.0009) y entre AF/SC basal y el VM en el primer mes de seguimiento (rs = 0.64, p = 0.002). CONCLUSIONES: En el EMD, los índices compuestos con AF basales predicen variables como AVMC en el seguimiento de pacientes que reciben ziv-AFL.

Pilot study of ziv-aflibercept in myopic choroidal neovascularisation patients.

BACKGROUND: Myopic choroidal neovascularization (CNV) is the most common sight-threatening complication associated with high myopia. The present study evaluated the efficacy and safety of the intravitreal injection of ziv-aflibercept in patients with myopic CNV. METHODS: This prospective interventional study was conducted on 20 eyes of 20 patients with active myopic CNV. Twelve patients were 40 years or older. This study was performed in the Ophthalmology Department of Tanta University Eye Hospital, Tanta University, Egypt. Optical coherence tomography (OCT) was performed for all patients at baseline and monthly after injection during the 6-month follow up period. The main outcome measures were changes in BCVA and CMT. The exploratory outcome measures were CNV size, IOP and the number of injections needed in each age group during the study period. RESULTS: Patients with myopic CNV younger than 40 years needed fewer injections (2.00 ± 0.76) than patients older than 40 years (2.50 ± 1.00), with no statistical significance detected between the two groups (p-value 0.246). CNV was smaller in the younger age group (p-value 0.209), best corrected visual acuity (BCVA) improved significantly in the younger and older age groups (p-values 0.001 and 0.028, respectively), and central macular thickness (CMT) decreased significantly after 6 months, from 242.88 ± 23.83 µm to 191.13 ± 13.83 µm in the younger age group and from 251.33 ± 26.60 µm to 197.08 ± 17.64 µm in the older age group (p = 0.001). No significant correlation was found between the final BCVA and either the spherical equivalent or central macular thickness after 6 months, with p-values of 0.135 and 0.145, respectively. No significant changes in IOP were detected in either group after the intravitreal injection. CONCLUSION: Ziv-aflibercept is a highly effective and safe drug in cases of active myopic CNV; however, a larger number of patients and a longer follow-up period are needed to confirm our results. This study was retrospectively registered at clinicaltrials.gov (ID: NCT04290195) on 26-2-2020.

FOLFOX plus ziv-aflibercept or placebo in first-line metastatic esophagogastric adenocarcinoma: A double-blind, randomized, multicenter phase 2 trial.

BACKGROUND: Antiangiogenic therapy is a proven therapeutic modality for refractory gastric and gastroesophageal junction adenocarcinoma. This trial assessed whether the addition of a high affinity angiogenesis inhibitor, ziv-aflibercept, could improve the efficacy of first-line mFOLFOX6 (oxaliplatin, leucovorin, and bolus plus infusional 5- fluorouracil) in metastatic esophagogastric adenocarcinoma. METHODS: Patients with treatment-naive metastatic esophagogastric adenocarcinoma were randomly assigned (in a 2:1 ratio) in a multicenter, placebo-controlled, double-blind trial to receive first-line mFOLFOX6 with or without ziv-aflibercept (4 mg/kg) every 2 weeks. The primary endpoint was 6-month progression-free survival (PFS). RESULTS: Sixty-four patients were randomized to receive mFOLFOX6 and ziv-aflibercept (43 patients) or mFOLFOX6 and a placebo (21 patients). There was no difference in the PFS, overall survival, or response rate. Patients treated with mFOLFOX6/ziv-aflibercept tended to be more likely to discontinue study treatment for reasons other than progressive disease (P = .06). The relative dose intensity of oxaliplatin and 5-fluorouracil was lower in the mFOLFOX6/ziv-aflibercept arm during the first 12 and 24 weeks of the trial. There were 2 treatment-related deaths due to cerebral hemorrhage and bowel perforation in the mFOLFOX6/ziv-aflibercept cohort. CONCLUSIONS: Ziv-aflibercept did not increase the anti-tumor activity of first-line mFOLFOX6 in metastatic esophagogastric cancer, potentially because of decreased dose intensity of FOLFOX. Further evaluation of ziv-aflibercept in unselected, chemotherapy-naive patients with metastatic esophagogastric adenocarcinoma is not warranted.

A phase Ib study of capecitabine and ziv-aflibercept followed by a phase II single-arm expansion cohort in chemotherapy refractory metastatic colorectal cancer.

BACKGROUND: Patients with chemotherapy refractory metastatic colorectal cancer (CRC) have a poor prognosis and limited therapeutic options. In this phase Ib/II clinical trial, we established the maximum tolerated dose (MTD) and recommended phase II dose (RPTD) for the combination of capecitabine and ziv-aflibercept, and then we evaluated the efficacy of the combination in patients with chemotherapy refractory metastatic CRC. METHODS: All patients were required to have a Karnofsky Performance Status > 70% and adequate organ function. The phase Ib dose escalation cohort included patients with advanced solid tumors who had progressed on all standard therapies. Using a standard 3 + 3 design, we identified the MTD and RPTD for the combination. Fifty patients with metastatic CRC who had progressed on or were intolerant of a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab were then enrolled in a single-arm phase II expansion cohort, and were treated at the RPTD. Prior EGFR antibody therapy was required for subjects with RAS wildtype tumors. The primary endpoint for the expansion cohort was progression-free survival (PFS) at two months. Secondary endpoints included objective response rate (ORR) and overall survival (OS). RESULTS: A total of 63 patients were enrolled and evaluable for toxicity (13 dose escalation; 50 expansion). The MTD and RPTD were: capecitabine 850 mg/m2, P.O. bid, days 1-14, and ziv-aflibercept 6 mg/kg I.V., day 1, of each 21-day cycle. In the expansion cohort, 72% of patients were progression-free at two months (95% confidence interval [CI], 60-84%). Median PFS and OS were 3.9 months (95% CI, 2.3-4.5) and 7.1 months (95% CI: 5.8-10.0), respectively. Among all patients evaluable for toxicity, the most common treatment related adverse events (all grade [%]; grade ≥ 3 [%]) included palmar-plantar erythrodysesthesia (41%; 6%), hypertension (33%; 22%), and mucositis (19%; 5%). RNA was isolated from archived tumor specimens and gene expression analyses revealed no association between angiogenic biomarkers and clinical outcomes. CONCLUSION: The combination of capecitabine and ziv-aflibercept at the RPTD demonstrated acceptable safety and tolerability. PFS at 2 months in patients with chemotherapy refractory metastatic CRC was significantly greater than that in historical controls, indicating that this combination warrants further study. TRIAL REGISTRATION: This clinical trial was registered in the www.clinicaltrials.gov system as NCT01661972 on July 31, 2012.

NCI 8628: A randomized phase 2 study of ziv-aflibercept and high-dose interleukin 2 or high-dose interleukin 2 alone for inoperable stage III or IV melanoma.

BACKGROUND: Interleukin 2 (IL-2) is a growth factor for T and natural killer cells, promotes proinflammatory cytokines, and can lead to durable responses in patients with melanoma. Vascular endothelial growth factor (VEGF) promotes angiogenesis and modulates host innate and adaptive immunity. High VEGF levels were found to be associated with nonresponse to IL-2. Ziv-aflibercept may deplete VEGF and thereby enhance antitumor T-cell responses, thus supporting a combination immunotherapeutic strategy with IL-2. METHODS: NCI 8628 was a phase 2 trial of ziv-aflibercept and IL-2 (arm A) versus IL-2 alone (arm B) randomized at 2:1, respectively. Eligible patients had inoperable American Joint Committee on Cancer stage III or stage IV melanoma. The primary endpoint was progression-free survival (PFS). RESULTS: A total of 89 patients were enrolled and 84 patients were treated. The median follow-up was 41.4 months. Among treated patients (55 patients in arm A and 29 patients in arm B), PFS was significantly improved in favor of arm A, with a median of 6.9 months (95% confidence interval [95% CI], 4.1-8.7 months) versus 2.3 months (95% CI, 1.6-3.5 months) (P<.001). No significant difference was noted with regard to overall survival, with a median of 26.9 months (95% CI, 14.4-63.6 months) for arm A and 24.2 months (95% CI, 11.3-36.4 months) for arm B. The response rate (according to Response Evaluation Criteria In Solid Tumors [RECIST]) was 22% in arm A (4 complete responses [CRs] and 8 partial responses [PRs]) and 17% in arm B (1 CR and 4 PRs). Stable disease or PR or CR was noted in 65% of patients in arm A and 48% of patients in arm B. The combination was found to be superior to monotherapy in patients with high and low levels of serum VEGF and VEGF receptor 2. Adverse events were consistent with the expected profiles of monotherapy with IL-2 and ziv-aflibercept. CONCLUSIONS: Ziv-aflibercept and IL-2 were found to significantly improve PFS compared with IL-2 alone, thereby meeting the primary endpoint of the current study. These findings support further study of immunotherapeutic combination strategies involving VEGF inhibitors.

Successful single treatment with ziv-aflibercept for existing corneal neovascularization following ocular chemical insult in the rabbit model.

PURPOSE: To evaluate the efficacy of ziv-aflibercept as a treatment for established corneal neovascularization (NV) and to compare its efficacy to that of bevacizumab following ocular chemical insult of sulfur mustard (SM) in the rabbit model. METHODS: Chemical SM burn was induced in the right eye of NZW rabbits by vapor exposure. Ziv-aflibercept (2 mg) was applied once to neovascularized eyes by subconjunctival injection while subconjunctival bevacizumab (5 mg) was administered twice a week, for 3 weeks. Non-treated exposed eyes served as a control. A clinical follow-up employed by slit-lamp microscope, was performed up to 12 weeks following exposure and digital photographs of the cornea were taken for measurement of blood vessels length using the image analysis software. Eyes were taken for histological evaluation 2, 4 and 8 weeks following treatment for general morphology and for visualization of NV, using H&E and Masson Trichrome stainings, while conjunctival goblet cell density was determined by PAS staining. RESULTS: Corneal NV developed, starting as early as two weeks after exposure. A single subconjunctival treatment of ziv-aflibercept at 4 weeks post exposure, significantly reduced the extent of existing NV already one week following injection, an effect which lasted for at least 8 weeks following treatment, while NV in the non-treated exposed eyes continued to advance. The extensive reduction in corneal NV in the ziv-aflibercept treated group was confirmed by histological evaluation. Bevacizumab multiple treatment showed a benefit in NV reduction, but to a lesser extent compared to the ziv-aflibercept treatment. Finally, ziv-aflibercept increased the density of conjunctival goblet cells as compared to the exposed non-treated group. CONCLUSIONS: Subconjunctival ziv-aflibercept single treatment presented a highly efficient long-term therapeutic benefit in reducing existing corneal NV, following ocular sulfur mustard exposure. These findings show the robust anti-angiogenic efficacy of ziv-aflibercept and demonstrate the advantage of this treatment over the other anti-angiogenic therapies in ameliorating corneal NV and protecting the ocular surface.

Ziv-aflibercept (Zaltrap) for the treatment of metastatic colorectal cancer.

OBJECTIVE: Review pharmacology, pharmacokinetics, efficacy, and safety of ziv-aflibercept in combination with FOLFIRI for treatment of metastatic colorectal cancer (mCRC) resistant to or progressed following oxaliplatin-containing regimens. DATA SOURCES: Articles indexed in PubMed (1948-August 2013), TOXLINE (2001-August 2013), and Google Scholar as well as meeting abstracts were identified using the search terms ziv-aflibercept and colorectal cancer. STUDY SELECTION AND DATA EXTRACTION: Available English-language articles DATA SYNTHESIS: Ziv-aflibercept, a selective vascular endothelial growth factor antagonist, was evaluated as monotherapy for treatment of mCRC in a phase 2 study and added to FOLFIRI in a phase 3 trial. Patient response to ziv-aflibercept as monotherapy did not reach statistical significance. Results suggest that response to ziv-aflibercept treatment is not influenced by prior bevacizumab therapy. A phase 3 trial compared the safety and efficacy of ziv-aflibercept plus FOLFIRI with placebo plus FOLFIRI in patients with mCRC who experienced disease progression on an oxaliplatin-containing regimen. Patients in the ziv-aflibercept arm had a median overall survival of 13.5 months, versus 12.06 months for those receiving placebo (hazard ratio [HR] = 0.817, 95% CI = 0.713 to 0.937). Progression-free survival for patients receiving ziv-aflibercept was higher compared with placebo (HR = 0.758; 95% CI = 0.661 to 0.869). The most common adverse effects observed were anemia, diarrhea, and neutropenia. CONCLUSIONS: Ziv-aflibercept is a safe and effective option in combination with FOLFIRI for the treatment of mCRC in patients who progress on oxaliplatin-containing therapy. Superiority over other antiangiogenic treatment has not been established.

A combination of suprachoroidal injection of triamcinolone using a custom-made needle and intravitreal Ziv-aflibercept every eight weeks to manage naïve/denovo central DME: a single-center retrospective case series.

BACKGROUND: Previous studies have shown promising effects of combining intravitreal bevacizumab and suprachoroidal injection of triamcinolone acetonide in treating DME. However, further research is needed. OBJECTIVE: To assess the efficacy and safety of combining both intravitreal Ziv-aflibercept and suprachoroidal injection of triamcinolone acetonide using a custom-made needle in naïve and de novo central diabetic macular edema (DME) patients every eight weeks for 24 weeks. METHODS: Central macular thickness was measured via spectral domain-optical coherence tomography, and best-corrected visual acuity was measured via a Snellen chart at baseline and at 4, 8, 12, 16, and 24 weeks postinjection. Additionally, cataract progression, intraocular pressure (IOP), and ocular safety were analyzed. RESULTS: A total of 10 eyes of 6 patients were treated with suprachoroidal injections of triamcinolone acteonid combined with an intravitreal injection of Ziv-aflibercept. Vision improved from 0.69 log minimum angle of resolution (MAR) at baseline to 0.39 log MAR after treatment. Central macular thickness significantly decreased from 462.3 ± 166 µm at baseline to 362.7 ± 77.6 µm at 24 weeks postinjection. CONCLUSION: Suprachoroidal injection of triamcinolone using a custom-made needle with the intravitreal agent Ziv-aflibercept to treat de novo/naïve central DME has favorable outcomes and adequate safety results. Moreover, this study demonstrated the benefit of adapting the previous treatment combination for extending the interval between anti-VEGF treatments from 4 to 8 weeks, which could prevent further expenses, especially in low-income countries.However, large multicenter randomized clinical trials with longer follow-up periods are needed to assess this treatment route, especially in low-income and resourced countries.

Aflibercept or ranibizumab for diabetic macular edema.

Background: Vascular endothelial growth factor (VEGF) is the primary substance involved in retinal barrier breach. VEGF overexpression may cause diabetic macular edema (DME). Laser photocoagulation of the macula is the standard treatment for DME; however, recently, intravitreal anti-VEGF injections have surpassed laser treatment. Our aim was to evaluate the efficacy of intravitreal injections of aflibercept or ranibizumab for managing treatment-naive DME. Methods: This single-center, retrospective, interventional, comparative study included eyes with visual impairment due to treatment-naive DME that underwent intravitreal injection of either aflibercept 2 mg/0.05 mL or ranibizumab 0.5 mg/0.05 mL at Al-Azhar University Hospitals, Egypt between March 2023 and January 2024. Demographic data and full ophthalmological examination results at baseline and 1, 3, and 6 months post-injection were collected, including the best-corrected distance visual acuity (BCDVA) in logarithm of the minimum angle of resolution (logMAR) notation, slit-lamp biomicroscopy, dilated fundoscopy, and central subfield thickness (CST) measured using spectral-domain optical coherence tomography. Results: Overall, the 96 eyes of 96 patients with a median (interquartile range [IQR]) age of 57 (10) (range: 20-74) years and a male-to-female ratio of 1:2.7 were allocated to one of two groups with comparable age, sex, diabetes mellitus duration, and presence of other comorbidities (all P >0.05). There was no statistically significant difference in baseline diabetic retinopathy status or DME type between groups (both P >0.05). In both groups, the median (IQR) BCDVA significantly improved from 0.7 (0.8) logMAR at baseline to 0.4 (0.1) logMAR at 6 months post-injection (both P = 0.001), with no statistically significant difference between groups at all follow-up visits (all P >0.05). The median (IQR) CST significantly decreased in the aflibercept group from 347 (166) µm at baseline to 180 (233) µm at 6 months post-injection, and it decreased in the ranibizumab group from 360 (180) µm at baseline to 190 (224) µm at 6 months post-injection (both P = 0.001), with no statistically significant differences between groups at all follow-up visits (all P >0.05). No serious adverse effects were documented in either group. Conclusions: Ranibizumab and aflibercept were equally effective in achieving the desired anatomical and functional results in patients with treatment-naïve DME in short-term follow-up without significant differences in injection counts between both drugs. Larger prospective, randomized, double-blinded trials with longer follow-up periods are needed to confirm our preliminary results.

Intravitreal Ziv-Aflibercept versus Bevacizumab for Naïve Central Retinal Vein Occlusion with Macular Edema: An Interim Analysis of a Randomized Non-Inferiority Trial.

Purpose: To compare the efficacy of intravitreal ziv-aflibercept (IVZ) and bevacizumab (IVB) injections for the treatment of macular edema secondary to central retinal vein occlusion. Methods: Participants were randomly assigned 1:1 to receive 3 monthly IVZ (1.25 mg/0.05 mL) or IVB (1.25 mg/0.05 mL) followed by the pro-re-nata protocol for persistent or recurrent macular edema. The primary outcomes were best-corrected visual acuity and central subfield thickness. An interim analysis was planned when half of the participants completed the follow-up. Results: Twenty-four participants were recruited. At 6 months, mean best-corrected visual acuity in the IVB and IVZ groups improved from 1.23 ± 0.64 to 0.76 ± 0.56 logMAR (p = 0.003) and from 1.13 ± 0.59 to 0.53 ± 0.26 logMAR (p = 0.003), respectively. The percentage of visual improvement and reduction in central subfield thickness in the IVZ group were insignificantly better than those in the IVB group (44.41 ± 26.72 vs 39.64 ± 24.22%; p = 0.65) and (51.94 ± 20.35 vs 45.78 ± 24.71%; p = 0.51), respectively. Although the mean number of injections was lower in the IVZ group (4.55 ± 1.29 vs 4.82 ±1.33), the difference was not statistically significant (p = 0.68). No ocular or systemic adverse events were observed. Conclusion: The interim analysis demonstrated that the visual and anatomical results of IVZ were insignificantly better than those of IVB at 6 months of follow-up. The results also showed that IVZ was non-inferior to IVB for anatomical improvement but inconclusive for visual improvement. Clinical Trial Registration: (identifier: TCTR20191205008).

Effectiveness of the Use of Three-Dose Intravitreal Ziv-Aflibercept in the Management of Diabetic Macular Edema in a Real-Life Setting.

Purpose: It has been reported that intravitreal Ziv-aflibercept is a safe and effective drug for the treatment of diabetes macular edema (DME). The objective of this study was to evaluate in a real-life setting, the efficacy of intravitreal Ziv-aflibercept in the treatment of DME after the administration of three consecutive monthly doses. Methods: A single arm, prospective cohort study. We included patients with DME who received three doses of intravitreal Ziv-aflibercept. Data such as best corrected visual acuity (BCVA) and tomographic biomarkers before treatment and a month after the third dose were collected. DME was staged using the Panozzo classification. Results: Thirty-eight patients participated for a total of 53 eyes. The mean age was 59 ± 8.1 years. We observed significant changes after the third dose in the parameters studied (BCVA in LogMAR pre-treatment (0.6 ± 0.33) and post-treatment (0.4 ± 0.29) [p<0.001], macular thickness pre-treatment (501 ± 167 µm) and post-treatment (324 ± 114 µm) [p<0.001], macular volume pre-treatment 10.8 (7.5-17.8) mm3 and post-treatment 9.3 (0-13.6) mm3 [p<0.005]). And 73.6% of the patients presented an advanced severe stage during their pre-treatment evaluation and after post-treatment, 64.2% of the patients no longer presented edema. No systemic or ocular adverse events occurred. Conclusion: The use of three consecutive monthly doses of intravitreal Ziv-aflibercept in a real-life setting is effective and safe in the management of diabetic macular edema.

Ziv-aflibercept in Diabetic Macular Edema: Relation of Subfoveal Choroidal Thickness with Visual and Anatomical Outcomes.

Purpose: To evaluate the effects of intravitreal ziv-aflibercept injections (IVZ) on subfoveal choroidal thickness (SCT) as well as on central macular thickness (CMT) and on best corrected visual acuity (BCVA) changes in eyes with center-involved diabetic macular edema (CI-DME). Methods: Fifty-seven eyes of 36 patients with CI-DME were included in this prospective interventional case series. Structural optical coherence tomography (OCT) and enhanced depth imaging OCT were performed at baseline followed by three monthly 1.25 mg IVZ injections. Changes of SCT, CMT, and BCVA at each follow-up session were assessed. The association between baseline SCT and its monthly changes with final visual and anatomical outcomes were also assessed. Results: CMT at baseline, and at the first, second, and third month follow-up sessions were 396 ± 119, 344 ± 115, 305 ± 89, and 296 ± 101 µm, respectively (P-value < 0.001). SCT at baseline, and at months one, two, and three were 236 ± 47, 245 ± 56, 254 ± 54, and 241 ± 54 µm, respectively (P-value > 0.99). Corresponding figures for BCVA were 0.58 ± 0.29, 0.47 ± 0.31, 0.4 ± 0.24, and 0.37 ± 0.23 LogMAR, respectively (P-value < 0.001). There was a statistically significant positive correlation between BCVA and CMT changes following IVZ injections (P-value < 0.001). However, there were no significant correlations between SCT changes and visual acuity (VA) and CMT changes following IVZ injections. Conclusion: IVZ improved visual outcomes and macular thickness profiles in patients with CI-DME. However, IVZ had no significant effect on SCT. Baseline SCT and its monthly changes had no association with visual and anatomical outcomes.

Analytical comparability assessment on glycosylation of ziv-aflibercept and the biosimilar candidate.

Ziv-aflibercept (aflibercept) is a recombinant fusion protein which combines the portions of human vascular endothelial growth factor receptors extracellular domains fused to the Fc portion of human IgG1. It is a highly sialylated glycoprotein with 5 N-glycosylation sites. In this study, a comprehensive strategy for comparability study of the complex glycosylation was developed between aflibercept and the biosimilar candidate including the investigations on N-glycosylation sites, site occupancy, site-specific glycoforms, released glycans and sialic acids. The results indicated that same N-glycosylation sites were identified, site occupancy were 100% except N68 site, site-specific glycoforms and released glycans showed similar glycan species, contents of NANA were at a same level for two products. Minor differences were found between two products. The biosimilar candidate presented lower level of aglycosylation, lower level of glycans containing one terminal sialic acid, higher level of glycans containing two terminal sialic acids, higher level of G0F and Man5, lower level of G1F and G2F compared with aflibercept. However, further studies exhibited no differences were observed in the cell-based biological potency and Fc effector function. Moreover, the biosimilar candidate showed a similar pharmacokinetics curve and bioequivalence compared with aflibercept.

Ziv-aflibercept for Better Regulating Neovascular Age-Related Macular Degeneration (ZEBRA): A Prospective, Randomized Trial.

OBJECTIVE: The purpose of this study is to determine if ziv-aflibercept is a safe and effective maintenance drug for nAMD. STUDY DESIGN AND METHODS: This is a randomized, prospective, single-blinded trial. Inclusion criteria were active nAMD, prior anti-VEGF treatment, and BCVA ≤20/200. The treatment group received ziv-aflibercept. The control group continued their existing anti-VEGF regimen. The main outcome measures were BCVA, CFT, and safety. RESULTS: Mean baseline BCVA was 1.58 ± 0.44 logMAR and 1.71 ± 0.39 logMAR in the control (n = 27) and treatment (n = 29) groups, respectively. After 24 months, the mean change in BCVA was 0.11 in the control group (equivalent to a loss of 5 ETDRS letters) and 0.01 logMAR in the treatment group (p = .48). Baseline CFT was 257 ± 33 µm and 247 ± 30 µm in the control and treatment groups, respectively, and after 24 months mean change in CFT was 26 µm and -5 µm (p = .24). There were no ocular or systemic adverse events during the study. CONCLUSION: Ziv-aflibercept is a safe and effective as a maintenance drug for patients with nAMD. It may represent a cost-effective alternative to aflibercept and second-line therapy for eye resistant bevacizumab or ranibizumab.

Stability study over time of clinical solutions of ziv-aflibercept prepared in infusion bags using a proper combination of physicochemical and functional strategies.

A range of biopharmaceutical products are used to target Vascular Endothelial Growth Factor (VEGF), including Eylea® (aflibercept, AFL) and Zaltrap® (ziv-aflibercept, ziv-AFL). The first is indicated for ophthalmological diseases such as neovascular (wet) age-related macular degeneration, while the second is used in the treatment of metastatic colorectal cancer. The stability of AFL in prefilled syringes has been widely studied; however, no research has yet been done on the stability of ziv-AFL in polyolefin infusion bags. Therefore, the purpose of the present research is to evaluate the stability of ziv-AFL (Zaltrap®) clinical solutions prepared under aseptic conditions in polyolefin infusion bags at two different concentrations, i.e. 4.0 and 0.6 mg/mL, and stored refrigerated in darkness at 2-8 °C for 14 days. With that aim, the ziv-AFL clinical solutions were assessed by analysing changes in its physicochemical and functional properties. The distribution of the particulates was studied over a range of 0.001-10 µm by Dynamic Light Scattering (DLS); oligomers were analysed by Size-Exclusion High-Performance Chromatography with Diode Array Detection (SE/HLPC-DAD); the secondary structure of the protein was studied by far UV Circular Dichroism (CD) and the tertiary structure by Intrinsic Tryptophan Fluorescence (IT-F) and Intrinsic Protein Fluorescence (IP-F); charge variants were assessed by Strong Cation Exchange Ultra-High-Performance Chromatography with UV detection (SCX/UHPLC-UV); functionality was evaluated by ELISA by measuring the biological activity as manifested in the extension of the immunological reaction of the ziv-AFL with its antigen (VEGF). Neither aggregation nor oligomerization were detected by the techniques mentioned above. Secondary and tertiary structures remained unchanged over the 14-day period, as did charge variants. The functionality observed initially was maintained along time. Therefore, it could be proposed that the ziv-AFL clinical solutions studied showed great physicochemical and functional stability over a period of two weeks, regardless of the concentration, i.e. 4 or 0.6 mg/mL.

Regression in polypoidal choroidal vasculopathy treated with ziv-aflibercept monotherapy - short term study.

PURPOSE: The aim of this study was to evaluate the effectiveness of intravitreal ziv-aflibercept (IVZ) in the treatment of polypoidal choroidal vasculopathy (PCV) and its efficacy in regard to polyp regression using optical coherence tomography (OCT) and indocyanine green angiography (ICGA). METHODS: This was a retrospective study of eight eyes of eight patients with treatment-naïve PCV. Patients received IVZ on pro re nata protocol. OCT and ICGA parameters were assessed at baseline and subsequent visits with a minimum follow-up of 6 months. ICGA was repeated at 3-6 months to determine the disease activity and quantify the changes in branching vascular network (BVN) polyps. Quantifiable OCT parameters included central macular thickness, pigment epithelial detachment (PED) height, and subfoveal choroidal thickness. RESULTS: The mean age of the study cohort was 62.3 ± 7.7 years, with a mean follow-up of 7.1 ± 1.2 months. The baseline best-corrected visual acuity improved from 0.70 ± 0.36 logarithm of the minimum angle of resolution (Snellen's equivalent 20/100) to 0.63 ± 0.34 (20/80) at last follow-up which was statistically insignificant (P = 0.5). Post IVZ injections (mean ± standard deviation: 2.6 ± 0.7), the total number of polyps reduced significantly from 3 ± 3.5 to 1 ± 1.7 (P = 0.03) along with a reduction in BVN size (3.9 ± 4.8 to 2.7 ± 3.8mm2; P = 0.07). OCT analysis revealed a significant reduction in PED height from 462.5 ± 353.8 µ to 169.9 ± 127.2 µ (P = 0.02). CONCLUSION: IVZ leads to significant morphological changes on ICGA and OCT in terms of polyp regression and reduction of PED height, respectively, with a limited change in visual acuity. IVZ may serve as a cost-effective alternative to treat eyes with PCV.

Ziv-aflibercept and bevacizumab for exudative age-related macular degeneration: A retrospective comparison of clinical outcomes and cost at 1 year.

PURPOSE: The purpose of this study was to compare intravitreal ziv-aflibercept (IVZ) monotherapy to intravitreal bevacizumab (IVB) monotherapy in patients with exudative age-related macular degeneration (eAMD). MATERIALS AND METHODS: Patients with treatment-naïve eAMD treated with pro re nata (PRN) monotherapy of IVZ (1.25 mg/0.05 ml) or IVB (1.25 mg/0.05 ml) with a minimum follow-up of 12 months were retrospectively analyzed. Study outcomes included change in best-corrected visual acuity (BCVA), central macular thickness, mean number of injections, and total medication cost in both the groups at 12 months. RESULTS: Forty-seven eyes (IVZ, 18/47 [38.3%] and IVB, 29/47 [61.7%]) from 47 treatment-naive patients were included. The change in BCVA for patients receiving IVZ was from 0.61 ± 0.33 logarithm of the minimum angle of resolution (Snellen 20/81; range: 20/38-20/174) to 0.45 ± 0.31 (Snellen 20/56; range: 20/27-20/115) at 1 year (P = 0.02). The total number of injections needed to achieve the resolution of intraretinal or subretinal fluid was 2.6 ± 1.4 and 3.5 ± 1.3 for IVZ and IVB, respectively (P = 0.029). Direct medication cost of IVZ and IVB in our cohort on PRN basis was an average of US$78 (2.6 × US$30) and US$175 (3.5 × US$50), respectively, through 1 year. CONCLUSION: IVZ-PRN monotherapy resulted in improved visual acuity, reduced treatment burden, and reduced direct medication cost in comparison to IVB-PRN monotherapy through 1 year.

Intravitreal ziv-aflibercept in diabetic vitreous hemorrhage.

BACKGROUND: To evaluate the safety and efficacy of intravitreal ziv-aflibercept (IVZ) in the management of vitreous hemorrhage (VH) in eyes with previously lasered proliferative diabetic retinopathy (PDR). METHODS: In a prospective multicenter study, previously lasered eyes who had dense VH from PDR underwent intravitreal injection of ziv-aflibercept (IVZ) (1.25 mg aflibercept). Demographic characteristics of the patients, baseline and final logMar visual acuity, number of injections, VH clearance time, and need for vitrectomy were recorded. RESULTS: Twenty-seven eyes of 21 patients were included in the study. Mean age of study patients was 61.3 ± 14.1 years with mean duration of diabetes mellitus of 22.6 ± 7.8 years. Mean logMAR BCVA at baseline was 1.41 ± 1.26 (Snellen equivalent 20/514) and at the last visit 0.55 ± 0.61 (Snellen equivalent 20/70) with a mean gain of 0.86 EDTRS line (paired student t test = 5.1; p ≤ 0.001). Mean number of IVZ 2.4 ± 1.6 (range 1-6). The mean follow-up time was 11.7 ± 11.1 months (range 1-34). Mean time for visual recovery and/or VH clearance was 5.7 ± 3.3 weeks. Eyes, which required multiple injections, the interval period between injections for recurrent VH was 6.4 ± 5.2 months. No subject required vitrectomy. No ocular or systemic adverse effects were noted. CONCLUSIONS: IVZ injections had good short-term safety and efficacy for the therapy of new or recurrent VH in previously lasered eyes with PDR reducing somewhat the need for vitrectomy.Trial registration: NCT02486484.