Anatomical and functional outcomes following switching from aflibercept to ranibizumab in neovascular age-related macular degeneration in Europe: SAFARI study

Abstract

Background/aims: Prospective data on switching anti-vascular endothelial growth factors in patients with neovascular age-related macular degeneration (nAMD) who have previously shown no/partial response are limited. This prospective study assessed the effect of switching from aflibercept to ranibizumab on anatomical and functional outcomes in patients with persistent/recurrent disease activity.

Methods: SAFARI (NCT02161575) was a 6-month, prospective, single-arm study conducted in the UK and Germany. Patients, meeting strict eligibility criteria for one of two subgroups (primary treatment failure or suboptimal treatment response), received 3 monthly intravitreal ranibizumab injections (0.5 mg). Thereafter, ranibizumab was administered pro re nata at monthly visits. The primary endpoint was change from baseline (CfB) to day 90 in central subfield retinal thickness (CSRT). Best-corrected visual acuity (BCVA) and retinal morphology parameters were assessed.

Results: One hundred patients were enrolled (primary treatment failure, 1; suboptimal treatment response, 99). In the overall population, there was a significant CfB in median CSRT of -30.75 µm (95% CI -59.50,-20.50; p<0.0001) to day 90. Improvements were also observed in other quantitative and qualitative optical coherence tomography parameters. In Early Treatment Diabetic Retinopathy Study letters assessed by category, 55% and 59% of patients gained 0-≥15 letters versus baseline at day 90 and day 180, respectively. However, mean improvements in BCVA (CfB) to each time point were small (≤2 letters). No new safety signals were identified.

Conclusion: Switching from aflibercept to ranibizumab led to a significant improvement in CSRT, with ~60% experiencing stabilised/improved BCVA. Therefore, patients with nAMD who have shown a suboptimal response to aflibercept may benefit from switching to ranibizumab.

Keywords: clinical trial; degeneration; imaging; macula; neovascularisation.

Conflict of interest statement

Competing interests: RPG: consultancy, educational grants and institutional research grants for Novartis and Bayer; IP: speakers’ fees, consulting fees and travel support from Novartis and Bayer; NE: grant/research support from Novartis and Bayer; speakers’ honoraria from: Novartis, Bayer, Allergan and Heidelberg Engineering; Advisory board member for: Novartis, Bayer, Allergan, Bausch and Lomb, Alimera Sciences and Roche; consultancy fees from Bayer; FG: consultant for Novartis and Bayer; advisory board member for Novartis and Bayer; speakers’ fees and research support from Bayer; FGH: financial support from: Acucela, Allergan, Bayer, Bioeq, CenterVue, Hoffmann-La Roche/Genentech, Heidelberg Engineering, Novartis, and Zeiss; Consultant for Acucela, Alcon, Bayer, Boehringer-Ingelheim, Hoffmann-La Roche/Genentech, Grayburg Vision, Heidelberg Engineering, Lin Bioscience, Novartis, Stealth Biotherapeutics, and Zeiss; SS-V: financial support from: Acucela, Alcon/Novartis, Allergan, Bayer, Bioeq/Formycon, Carl Zeiss MedicTec, CenterVue, Hoffman-La Roche/Genentech, Heidelberg Engineering, Katairo and Optos; consultant for: Alcon/Novartis, Bioeq/Formycon and Galimedix Therapeutics; recipient of gifts, honoraria, travel reimbursement, patent royalties and/or any other financial compensation from: Alcon/Novartis, Allergan, Bayer, Carl Zeiss MedicTec and Hoffmann-La Roche/Genentech; KB: travel grants and speakers’ fees from: Novartis, Bayer, Alimera, Topcon and Heidelberg Engineering; research grants from Novartis and Bayer; BJLB: advisory board and international conference attendance sponsored by Novartis and Bayer; SD: principal investigator on trials sponsored by: Novartis, Bayer, Roche, and Ely Lilly; speakers’ honoraria from: Novartis, Bayer, Roche and/or Eli Lilly; conference and travel support from Novartis and Eli Lilly; consultant for Hakko Kyowa and Circadian Therapeutics; grant/research support from Novartis; HE: travel grants and speakers’ fees from Novartis; advisory board member for Novartis; SG: speakers’ fees from Hoffman-La Roche and Novartis; advisory board member for, and travel grants from Bayer; DFG: travel grants from Novartis and Bayer; speakers’ fees from Novartis; RH: research support and travel grants from, and advisory board member for Novartis, Bayer, Allergan, and Ellex; AL: travel support to attend educational meetings from Bayer; NP: grant support and travel grants from Novartis and Bayer; PP: none declared; CS: speakers’ fees, consulting fees, conference and travel support from Novartis and Bayer; ST: travel grant and conference registration from Bayer; DV: travel grants from Novartis, Bayer and Allergan; Advisory board member for: Allergan, Novartis, Bayer, Alcon and Polyphotonix; investigator on clinical trials sponsored or funded by: Novartis, Bayer, Hoffmann-La Roche and Allergan; Speakers’ fees from Bayer and Novartis; GW: advisory board member for, and support to attend conferences from Novartis and Bayer; MAW: travel grants from Novartis, Bayer and Allergan; recipient of grant to develop medical education material on ophthalmology; AW: consulting fees from Novartis and Bayer; speakers’ fees from Novartis; advisory board member for Novartis; travel grants from Bayer; research support from Novartis and Bayer; RHZ: none declared; FI: employee of Novartis Pharmaceuticals UK Ltd; FA: employee of Novartis Pharmaceuticals UK Ltd.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Safari study design, patient disposition and analysis sets. Percentages=n/(patients treated at any visit)×100. A total of 10 patients were excluded from the PPS (overall) based on protocol deviations. aThe PRN regimen permitted retreatment with ranibizumab if, in the opinion of the investigator, persistent or worsening visual symptoms were attributable to nAMD, and/or if there was evidence of worsening visual acuity determined by ETDRS BCVA (>1 letter decline since last study visit), and/or the presence of persistent or worsening disease activity on OCT (eg, presence of subretinal fluid, persistent or increased number, size, or total volume of IRC, or increased central retinal or foveal thickness). BCVA, best-corrected visual acuity; CfB, change from baseline; CSRT, central subfield retinal thickness; EOS, end of study; ETDRS, Early Treatment Diabetic Retinopathy Study; FAS, full analysis set; FCP, foveal centre point; IRC, intraretinal cyst; IRF, intraretinal fluid; nAMD, neovascular age-related macular degeneration; PED, pigment epithelial detachment; PPS, per protocol set; OCT, optical coherence tomography; PRN, as required (pro re nata); SCN, screening; SF, subretinal fluid; SS, safety set.

Figure 2

Changes in quantitative retinal morphology and qualitative OCT parameters with ranibizumab treatment up to 6 months (N=100). Full analysis set. aThe primary efficacy endpoint was CFB in CSRT to day 90; ***p<0.0001. Data presented in A and B represent median±min/max (as not normally distributed) and mean±SD, respectively. Baseline was defined as the last available non-missing value collected just prior to the start of treatment in the study eye. Visit days represent day ±7 days. BL, baseline; CfB, change from baseline; CSRT, central subfield retinal thickness; FCP, foveal centre point; NA, not accessible; OCT, optical coherence tomography.

Figure 3

Change from baseline in best-corrected visual acuity (letters) (N=100). Full analysis set. aData for 1 patient are missing at day 30. Visit days represent day ±7 days.