Biosimilar SB15 versus reference aflibercept in neovascular age-related macular degeneration: 1-year and switching results of a phase 3 clinical trial.

BACKGROUND/AIMS: To 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). DESIGN: Prospective, double-masked, randomised, phase 3 trial. METHODS: Participants with nAMD were randomised 1:1 to receive SB15 (N=224 participants) or AFL (N=225). At week 32, participants either continued on SB15 (SB15/SB15, N=219) or AFL (AFL/AFL, N=108), or switched from AFL to SB15 (AFL/SB15, N=111). This manuscript reports 1-year and switching results of secondary efficacy endpoints such as changes from baseline to week 56 in best-corrected visual acuity (BCVA), central subfield thickness (CST, from internal limiting membrane (ILM) to retinal pigment epithelium), and total retinal thickness (TRT, from ILM to Bruch's membrane). Additional endpoints included safety, PK and immunogenicity. RESULTS: Efficacy results were comparable between groups. The least squares mean (LSmean) change in BCVA from baseline to week 56 was 7.4 letters for SB15/SB15 and 7.0 letters for AFL/AFL (difference (95% CI)=0.4 (-2.5 to 3.2)). The LSmean changes from baseline to week 56 in CST and TRT were -119.2 µm and -132.4 µm for SB15/SB15 and -126.6 µm and -136.3 µm for AFL/AFL, respectively (CST: difference (95% CI)=7.4 µm (-6.11 to 20.96); TRT: difference (95% CI)=3.9 µm (-18.35 to 26.10)). Switched and non-switched participants showed similar LSmean changes in BCVA from baseline to week 56 (AFL/SB15, 7.9 letters vs AFL/AFL, 7.8 letters; difference (95% CI)=0.0 (-2.8 to 2.8)). Safety, PK and immunogenicity were comparable between groups. CONCLUSIONS: Efficacy, safety, PK and immunogenicity were comparable between SB15 and AFL and between switched and non-switched participants.

Efficacy and Safety of the Aflibercept Biosimilar SB15 in Neovascular Age-Related Macular Degeneration: A Phase 3 Randomized Clinical Trial.

Importance: Aflibercept biosimilars can expand available treatment options in retinal diseases and have the potential to improve patient access to safe and effective therapy. Objective: 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). Design, Setting, and Participants: 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. Intervention: 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. Main Outcomes and Measures: 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. Results: 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. Conclusions and Relevance: In this phase 3 randomized clinical trial, SB15 and AFL showed equivalent efficacy and comparable safety, pharmacokinetics, and immunogenicity in participants with nAMD. Trial Registration: ClinicalTrials.gov Identifier: NCT04450329.

Seven-year outcomes following intensive anti-vascular endothelial growth factor therapy in patients with exudative age-related macular degeneration.

BACKGROUND: Anti-vascular endothelial growth factor (VEGF) therapy is currently the most effective therapy of exudative age-related macular degeneration (AMD). The aim of this study was to assess long-term benefits of intensive aflibercept and ranibizumab anti-VEGF therapy in patients with exudative AMD. METHODS: Two clinical trial sites recruited their original subjects for a re-evaluation 7 years after the baseline visit of the phase-3 Vascular Endothelial Growth Factor (VEGF) Trap-Eye: Investigation of Efficacy and Safety in Wet Age-Related Macular Degeneration (VIEW 2) trial. Forty-seven eyes of 47 patients with AMD originally treated with ranibizumab (14 eyes) or aflibercept (33 eyes) were included. RESULTS: Mean number of injections was 17.8 ± 3.0 during participation in the VIEW 2 trial. Fourteen of 47 (30%) eyes were given additional injections with a mean number of 5.7 ± 4.5 after the trial. At a mean follow-up time of 82 ± 5 months best corrected visual acuity (BCVA) remained stable or improved (≤ 10 letters lost) in 55% of patients in the entire study population, in 43% in the ranibizumab group and in 60% in the aflibercept group. In both groups combined mean BCVA was 54 ± 13 letters at baseline, 65 ± 17 letters at the end of the intensive phase and 45 ± 25 letters at the end of follow-up. There was no statistically significant difference in BCVA between the two groups at baseline (p = 0.88) and at the end of follow-up (p = 0.40). Macular atrophy was observed in 96% of eyes, average area was 7.22 ± 6.31 mm2 with no statistically significant difference between groups (p = 0.47). Correlation between BCVA at end-of-follow-up and the area of atrophy was significant (p < 0.001). At the end of follow-up, fluid was detected in 7 of 47 eyes (15%) indicating disease activity. CONCLUSION: Long-term efficacy of aflibercept and ranibizumab was largely consistent. Following a two-year intensive therapy with as-needed regimen, BCVA was maintained or improved in almost half of the patients and in the ranibizumab group and more than half of the patients in the aflibercept group with very few injections. In a remarkable proportion of eyes, BCVA declined severely which underlines the need for long-term follow-ups and may indicate a more prolonged intensive therapy. TRIAL REGISTRATIONS: VIEW 2 study: ClinicalTrials.gov ID: NCT00637377, date of registration: March 18, 2008. Long-term follow-up: IRB nr.: SE RKEB 168/2022, ClinicalTrials.gov ID: NCT05678517, date of registration: December 28, 2022, retrospectively registered.