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Background/AimsTo provide longer-term data on efficacy, safety, immunogenicity and pharmacokinetics (PK) of ranibizumab biosimilar SB11 compared with the reference ranibizumab (RBZ) in patients with neovascular age-related macular degeneration (nAMD).Methods Setting: Multicentre. Design: Randomised, double-masked, parallel-group, phase III equivalence study. Patient population: ≥50 years old participants with nAMD (n=705), one ‘study eye’. Intervention: 1:1 randomisation to monthly intravitreal injection of 0.5 mg SB11 or RBZ. Main outcome measures: Visual efficacy endpoints, safety, immunogenicity and PK up to 52 weeks.ResultsBaseline and disease characteristics were comparable between treatment groups. Of 705 randomised participants (SB11: n=351; RBZ: n=354), 634 participants (89.9%; SB11: n=307; RBZ: n=327) completed the study until week 52. Previously reported equivalence in primary efficacy remained stable up to week 52 and were comparable between SB11 and RBZ. The adjusted treatment difference between SB11 and RBZ in full analysis set at week 52 of change from baseline in best-corrected visual acuity was −0.6 letters (90% CI −2.1 to 0.9) and of change from baseline in central subfield thickness was −14.9 µm (95% CI –25.3 to –4.5). The incidence of ocular treatment-emergent adverse events (TEAEs) (SB11: 32.0% vs RBZ: 29.7%) and serious ocular TEAE (SB11: 2.9% vs RBZ: 2.3%) appeared comparable between treatment groups, and no new safety concerns were observed. The PK and immunogenicity profiles were comparable, with a 4.2% and 5.5% cumulative incidence of antidrug antibodies up to week 52 for SB11 and RBZ, respectively.ConclusionsLonger-term results of this study further support the biosimilarity established between SB11 and RBZ.

PurposeTo characterize relationships between Consensus on Neovascular Age-Related Macular Degeneration Nomenclature (CONAN) Study Group classifications of macular neovascularization (MNV) and visual responses to ranibizumab in patients with neovascular age-related macular degeneration (nAMD).MethodsThis was a post hoc analysis of the phase 3 HARBOR trial of ranibizumab in nAMD. Analyses included ranibizumab-treated eyes with baseline multimodal imaging data; baseline MNV; subretinal and/or intraretinal fluid at screening, baseline, or week 1; and spectral-domain optical coherence tomography images through month 24 (n = 700). Mean best-corrected visual acuity (BCVA) over time and mean BCVA change at months 12 and 24 were compared between eyes with type 1, type 2/mixed type 1 and 2 (type 2/M), and any type 3 MNV at baseline.ResultsAt baseline, 263 (37.6%), 287 (41.0%), and 150 (21.4%) eyes had type 1, type 2/M, and any type 3 lesions, respectively. Type 1 eyes had the best mean BCVA at baseline (59.0 [95% CI: 57.7–60.3] letters) and month 24 (67.7 [65.8–69.6] letters), whereas type 2/M eyes had the worst (50.0 [48.6–51.4] letters and 60.8 [58.7–62.9] letters, respectively). Mean BCVA gains at month 24 were most pronounced for type 2/M eyes (10.8 [8.9–12.7] letters) and similar for type 1 (8.7 [6.9–10.5] letters) and any type 3 eyes (8.3 [6.3–10.3] letters).ConclusionDifferences in BCVA outcomes between CONAN lesion type subgroups support the use of an anatomic classification system to characterize MNV and prognosticate visual responses to anti-vascular endothelial growth factor therapy for nAMD.Trial registrationClinicalTrials.gov identifier: NCT00891735. Date of registration: April 29, 2009.

Purpose To evaluate the 1-year efficacy, durability, and safety of faricimab versus aflibercept in patients with neovascular age-related macular degeneration (nAMD) enrolled in the Japan subgroup of the TENAYA trial. Study design TENAYA (NCT03823287) was a global, phase 3, multicenter, randomized, active comparator–controlled, double-masked, noninferiority, parallel-group, 112-week trial. After completion of global enrollment, additional patients were enrolled in the Japan extension of TENAYA. Methods Treatment-naïve patients aged ≥ 50 years with nAMD were randomized (1:1) to intravitreal faricimab 6 mg up to every 16 weeks (Q16W) after 4 initial Q4W doses based on disease activity at weeks 20 and 24 or aflibercept 2 mg Q8W after 3 initial Q4W doses. Primary endpoint was mean change in best-corrected visual acuity (BCVA) from baseline averaged over weeks 40, 44, and 48. Anatomical/durability outcomes were assessed. Results Overall, 133 patients were included in the TENAYA Japan subgroup analysis (faricimab, n = 66; aflibercept, n = 67). The adjusted mean (95% confidence interval) BCVA changes were + 7.1 (4.6‒9.7) and + 7.7 (5.2‒10.1) letters in the faricimab and aflibercept treatment groups, respectively. At week 48, 66.1%, 22.6%, and 11.3% of patients in the faricimab group were on Q16W, Q12W, Q8W and dosing intervals, respectively. Ocular adverse event rates were similar between treatment groups (faricimab, n = 14 [21.2%] versus aflibercept, n = 17 [25.4%]). Conclusion The TENAYA Japan subgroup analysis showed that faricimab up to Q16W had sustained efficacy with an acceptable safety profile. These findings are consistent with the global TENAYA and LUCERNE findings.

PurposePost hoc analysis of the phase III HAWK and HARRIER studies to compare the reductions in subretinal hyper-reflective material (SHRM) thickness following brolucizumab 6 mg or aflibercept 2 mg treatment and to assess SHRM thickness and thickness variability as a potential biomarker of visual outcomes in patients with neovascular age-related macular degeneration (nAMD).MethodsOptical coherence tomography images from the brolucizumab (n=700) and aflibercept (n=696) arms were analysed for the maximum SHRM thickness across the macula over 96 weeks. In a pooled treatment-agnostic analysis, the effect of week 12 SHRM thickness and SHRM thickness variability on best-corrected visual acuity (BCVA) through week 96 were also assessed.ResultsBrolucizumab was associated with numerically higher percentage reductions from baseline in SHRM thickness versus aflibercept in all patients (week 96: 54.4% vs 47.6%, respectively) and also in the matched subgroups with disease activity at week 16 (week 96: 51.6% vs 33.8%, respectively). In eyes with lower SHRM measurements at week 12, mean BCVA gains from baseline were higher at week 96 (<200 µm, +6.47 Early Treatment Diabetic Retinopathy Study letters; ≥200 µm, +3.10 letters). Eyes with the lowest SHRM thickness variability from week 12 to week 96 showed the greatest mean BCVA gains from baseline (week 96: <12 µm, +7.42 letters; >71 µm, −2.95 letters).ConclusionsIn HAWK and HARRIER, greater reductions in maximum SHRM thickness from baseline were observed with brolucizumab compared with aflibercept. Furthermore, the data suggest that SHRM thickness postloading and SHRM thickness variability over time are biomarkers for visual outcomes in patients with nAMD.

Background/aimTo assess the long-term safety and efficacy of epimacular brachytherapy (EMB) for chronic, active, neovascular age-related macular degeneration (nAMD).MethodsThis pivotal, randomised, controlled surgical device trial recruited patients with chronic nAMD receiving intravitreal ranibizumab from 24 UK hospitals. Participants were randomised to either pars plana vitrectomy with 24 Gray EMB and pro re nata (PRN) ranibizumab (n=224) or PRN ranibizumab monotherapy (n=119). Although masking was not possible, masked clinicians assessed best-corrected visual acuity (BCVA) and imaging. After month 24, participants reverted to standard care, with either ranibizumab or aflibercept, returning for a month 36 study visit.ResultsOf 363 participants, 309 (85.1%) completed month 36. The number of injections was 12.1±8.1 in the EMB group versus 11.4±6.1 in the ranibizumab group (difference 0.7, 95% CI of difference −0.9 to 2.3, p=0.41) between months 1 and 36, and 3.6±3.3 (n=200) versus 3.9±2.7 (n=102) (difference −0.3, 95% CI of difference −1.0 to 0.4, p=0.43) between months 25 and 36 (standard care). Over 36 months, BCVA change was −19.7±18.5 letters in the EMB group and −4.8±12.5 in the ranibizumab group (difference −14.9, 95% CI of difference −18.5 to −11.2, p<0.0001). The month 36 BCVA of 20 EMB-treated participants with microvascular abnormalities (MVAs) at month 24 was similar to EMB-treated participants without MVAs (−21.8 vs −19.4 letters, p=0.65).ConclusionEMB does not reduce the number of anti-vascular endothelial growth factor (VEGF) injections, either within or outside of a trial setting, and is associated with worse BCVA than anti-VEGF monotherapy.Trial registration numberNCT01006538.

Background/aimsTo compare fluctuations of central subfield retinal thickness (CSRT) in patients with neovascular age-related macular degeneration undergoing ranibizumab pro re nata versus aflibercept bimonthly treatment in a prospective 12 month, phase IV, randomised, multicentre study.MethodsRanibizumab was administered according to best-corrected visual acuity (BCVA) and/or disease activity detected on spectral domain optical coherence tomography. Aflibercept was administered at three initial monthly visits followed by bimonthly treatment. CSRT stability was evaluated between months 3 and 6. CSRT stability was compared between groups and correlated with functional outcomes at month 12.ResultsFluctuations of CSRT showed a least-squares (LS) mean (95% CI) difference of −4.12 (−10.22 to 1.98) µm between ranibizumab (25.16 (20.09 to 30.24) µm) and aflibercept groups (29.28 (24.14 to 34.43) µm) (p=0.1850). A predefined analysis of retinal stability, adjusted for baseline CSRT, showed a LS mean (95% CI) difference of −6.53 (−12.47 to −0.58 µm) in favour of ranibizumab (23.53 (18.58 to 28.49) µm) versus aflibercept (30.06 (25.04 to 35.07) µm) (p=0.0315). Pearson’s correlation coefficient demonstrated no correlation between the mean amplitude of CSRT fluctuation between months 3 and 6, and BCVA at month 12 (r = −0.0888). Adverse event rates were low.ConclusionsNumerical differences in retinal thickness fluctuations between months 3 and 6 were detected between treatment regimens. While the presence of fluctuations has previously been shown to have a negative impact on functional outcomes, our data showed no correlation between the mean amplitude of fluctuations and functional outcomes at month 12.

Background/objectives To characterise morphological changes in neovascular age-related macular degeneration (nAMD) during anti-angiogenic therapy and explore relationships with best-corrected visual acuity (BCVA) and development of macular atrophy (MA). Subjects/methods Post-hoc analysis of the phase III HARBOR trial. SD-OCT scans from 1097 treatment-naïve nAMD eyes were analysed. Volumes of intraretinal cystoid fluid (ICF), subretinal hyperreflective material (SHRM), subretinal fluid (SRF), pigment epithelial detachment (PED) and cyst-free retinal volume (CFRV) were measured by deep-learning model. Volumes were analysed by treatment regimen, macular neovascularisation (MNV) subtypes and topographic location. Associations of volumetric features with BCVA and MA development were quantified at month 12/24. Results Differences in feature volume changes by treatment regimens and MNV subtypes were observed. Each additional 100 nanolitre unit (AHNU) of residual ICF, SHRM and CFRV at month 1 in the fovea was associated with deficits of 10.3, 7.3 and 12.2 letters at month 12. Baseline AHNUs of ICF, CFRV and PED were associated with increased odds of MA development at month 12 by 10%, 4% and 3%. While that of SRF was associated with a decrease in odds of 5%. Associations at month 24 were similar to those at month 12. Conclusion Eyes with different MNV subtypes showed distinct trajectories of feature volume response to treatment. Higher baseline volumes of ICF or PED and lower baseline volume of SRF were associated with higher likelihoods of MA development over 24 months. Residual intraretinal fluid, including ICF and CFRV, along with SHRM were predictors of poor visual outcomes.

Purpose To evaluate 2-year efficacy, durability, and safety of faricimab in the TENAYA Japan subgroup and pooled global TENAYA/LUCERNE cohort of patients with neovascular age-related macular degeneration (nAMD). Methods Subgroup analysis of TENAYA/LUCERNE (NCT03823287/NCT03823300): phase III, multicentre, randomised, active comparator–controlled, double-masked, non-inferiority trials. Treatment-naïve patients aged ≥ 50 years with nAMD were randomised (1:1) to intravitreal faricimab (6.0 mg up to every 16 weeks [Q16W] after 4 initial Q4W doses) or aflibercept (2.0 mg Q8W after 3 initial Q4W doses). Outcomes were assessed through year 2 for the TENAYA Japan subgroup ( N  = 133) and global pooled TENAYA/LUCERNE cohort ( N  = 1329). Results Vision and anatomic improvements achieved with faricimab at year 1 were maintained over 2 years and were generally comparable between the TENAYA Japan subgroup and pooled TENAYA/LUCERNE cohort. Adjusted mean best-corrected visual acuity (BCVA) change from baseline at year 2 for the TENAYA Japan subgroup and global pooled TENAYA/LUCERNE cohort was +7.1 (3.7–10.5) and +4.4 (3.2–5.5) letters in the faricimab arm, respectively, and +5.2 (1.9–8.6) and +4.3 (3.1–5.4) letters in the aflibercept arm, respectively. At week 112, the proportion of faricimab-treated patients on Q16W dosing was 61.0% and 63.1% in the TENAYA Japan subgroup and pooled TENAYA/LUCERNE cohort. Faricimab was well tolerated through year 2. Conclusion Year 2 TENAYA Japan subgroup findings for faricimab were generally consistent with the pooled global TENAYA/LUCERNE results in patients with nAMD. Vision and anatomical benefits with faricimab were similar to those with aflibercept but with fewer injections.

Background and Objective This was a prospective multicenter, randomized, double-masked, active-controlled study, the aim of which was to demonstrate the efficacy and safety of intravitreal ONS-5010 (bevacizumab-vikg) in eyes with neovascular age-related macular degeneration (nAMD). This was a phase III trial on ONS-5010 (NORSE TWO). Materials and Methods Treatment-naïve nAMD patients aged 50 years and older with a best-corrected distance visual acuity (BCVA) of 25 to 67 Early Treatment Diabetic Retinopathy Study (ETDRS) letters and evidence of disease activity were included. Subjects randomized to ONS-5010 received monthly intravitreal doses of 1.25 mg of ONS-5010, bevacizumab-vikg (Outlook Therapeutics) for 12 months. Subjects randomized to ranibizumab received 0.50 mg of ranibizumab on days 0, 30, 60, 150, and 240 based on the PIER study dosing regimen. Results The primary end point was the proportion of subjects who gained ≥ 15 letters from baseline in BCVA at 11 months, and evaluating the safety and tolerability of intravitreal injections of ONS-5010 administered monthly from baseline to 12 months. One hundred thirteen subjects were included in the ONS-5010 group and 115 subjects were included in the ranibizumab group. Respectively, 41.7% and 23.1% of patients gained ≥ 15 letters (3 lines) of visual acuity, with a risk difference of 0.1859 [95% CI = 0.0442, 0.3086]; P = 0.0052. The change in BCVA from baseline to 11 months was found to be 11.2 ± 12.19 and 5.8 ± 14.80 ETDRS letters, respectively. The number of subjects gaining ≥ 5 and ≥ 10 letters and subjects losing < 15 letters was significantly higher in the ONS-5010 group. Similarly, subjects with a Snellen visual acuity equivalent of 20/200 (35 ETDRS letters) or worse at 11 months were significantly fewer in the ONS-5010 group. Only one subject in the ONS-5010 group had a study-related serious ocular adverse event (SAE), namely, elevated intraocular pressure. The most common adverse event in the ONS-5010 group was conjunctival hemorrhage (8.8%), and reduced visual acuity in the ranibizumab group (12.2%). Conclusions In the prescribed treatment plan, ONS-5010 exhibited strong effectiveness in improving or stabilizing visual acuity and was also well tolerated. Bevacizumab and ranibizumab displayed a comparable safety profile. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX–XX.]

Aim To determine the efficacy of 2.0 mg aflibercept in the management of patients with recalcitrant exudative age-related macular degeneration (AMD). Methods In this prospective, open-label, single-arm clinical trial, patients were seen monthly and given mandatory 2.0 mg aflibercept at baseline, months 1, 2 and 4. Pro re nata (PRN) retreatment at months 3 and 5 was performed upon evidence of disease on spectral domain-optical coherence tomography (SD-OCT). End point at month 6: mean change in Early Treatment Diabetic Retinopathy Study best corrected visual acuity (ETDRS BCVA) and central subfield thickness (CST), mean number of aflibercept injections, percentage of PRN injections required, patients with no fluid on SD-OCT and patients losing >15 letters. Results At baseline, 46 patients with a mean of 42 prior antivascular endothelial growth factor-A (anti-VEGF) intravitreal treatments had a mean of 74.2 letters (Snellen equivalent 20/32) and mean CST of 347 µm. ETDRS letters remained stable throughout the trial; at month 6, mean BCVA change was +0.2 letters (range −10 to +13, p=0.71). Anatomically, mean CST improved significantly from baseline at each study visit including −23.6 µm at month 1 and −27.3 µm at month 6 (p=0.018). Seventy-one of 90 (79%) possible PRN injections were required and a mean of 5.6 aflibercept injections out of the maximum six were administered. Ten of 45 (22%) patients had no retinal fluid on SD-OCT at month 6. No patient lost >15 letters. Conclusions Aflibercept 2.0 mg treatment maintained mean visual acuity improvements previously achieved with high-dose 2.0-mg ranibizumab injections in recalcitrant wet AMD patients. Aflibercept 2.0 mg treatment led to significant anatomic improvement and was required monthly in most patients. Clinical Trials Registration FDA IND#12462. NCT 01543568. Trial Details IND 12462, NCT 01543568 http://clinicaltrials.gov/show/NCT01543568.