Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, non-inferiority trials.
Lancet. 2022 Jan 21:S0140-6736(22)00010-1.
Heier JS, Khanani AM, Quezada Ruiz C, Basu K, Ferrone PJ, Brittain C, Figueroa MS, Lin H, Holz FG, Patel V, Lai TYY, Silverman D, Regillo C, Swaminathan B, Viola F, Cheung CMG, Wong TY; TENAYA and LUCERNE Investigators.
Background: Faricimab is a bispecific antibody that acts through dual inhibition of both angiopoietin-2 and vascular endothelial growth factor A. We report primary results of two phase 3 trials evaluating intravitreal faricimab with extension up to every 16 weeks for neovascular age-related macular degeneration (nAMD).
Methods: TENAYA and LUCERNE were randomised, double-masked, non-inferiority trials across 271 sites worldwide. Treatment-naive patients with nAMD aged 50 years or older were randomly assigned (1:1) to intravitreal faricimab 6·0 mg up to every 16 weeks, based on protocol-defined disease activity assessments at weeks 20 and 24, or aflibercept 2·0 mg every 8 weeks. Randomisation was performed through an interactive voice or web-based response system using a stratified permuted block randomisation method. Patients, investigators, those assessing outcomes, and the funder were masked to group assignments. The primary endpoint was mean change in best-corrected visual acuity (BCVA) from baseline averaged over weeks 40, 44, and 48 (prespecified non-inferiority margin of four letters), in the intention-to-treat population. Safety analyses included patients who received at least one dose of study treatment. These trials are registered with clinicaltrials.gov (TENAYA NCT03823287 and LUCERNE NCT03823300).
Findings: Across the two trials, 1329 patients were randomly assigned between Feb 19 and Nov 19, 2019 (TENAYA n=334 faricimab and n=337 aflibercept), and between March 11 and Nov 1, 2019 (LUCERNE n=331 faricimab and n=327 aflibercept). BCVA change from baseline with faricimab was non-inferior to aflibercept in both TENAYA (adjusted mean change 5·8 letters [95% CI 4·6 to 7·1] and 5·1 letters [3·9 to 6·4]; treatment difference 0·7 letters [-1·1 to 2·5]) and LUCERNE (6·6 letters [5·3 to 7·8] and 6·6 letters [5·3 to 7·8]; treatment difference 0·0 letters [-1·7 to 1·8]). Rates of ocular adverse events were comparable between faricimab and aflibercept (TENAYA n=121 [36·3%] vs n=128 [38·1%], and LUCERNE n=133 [40·2%] vs n=118 [36·2%]).
Interpretation: Visual benefits with faricimab given at up to 16-week intervals demonstrates its potential to meaningfully extend the time between treatments with sustained efficacy, thereby reducing treatment burden in patients with nAMD.
Efficacy, durability, and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with diabetic macular oedema (YOSEMITE and RHINE): two randomised, double-masked, phase 3 trials.
Lancet.2022 Jan 21;S0140-6736(22)00018-6.
Wykoff CC, Abreu F, Adamis AP, Basu K, Eichenbaum DA, Haskova Z, Lin H, Loewenstein A, Mohan S, Pearce IA, Sakamoto T, Schlottmann PG, Silverman D, Sun JK, Wells JA, Willis JR, Tadayoni R; YOSEMITE and RHINE Investigators.
Background: To reduce treatment burden and optimise patient outcomes in diabetic macular oedema, we present 1-year results from two phase 3 trials of faricimab, a novel angiopoietin-2 and vascular endothelial growth factor-A bispecific antibody.
Methods: YOSEMITE and RHINE were randomised, double-masked, non-inferiority trials across 353 sites worldwide. Adults with vision loss due to centre-involving diabetic macular oedema were randomly assigned (1:1:1) to intravitreal faricimab 6·0 mg every 8 weeks, faricimab 6·0 mg per personalised treatment interval (PTI), or aflibercept 2·0 mg every 8 weeks up to week 100. PTI dosing intervals were extended, maintained, or reduced (every 4 weeks up to every 16 weeks) based on disease activity at active dosing visits. The primary endpoint was mean change in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Efficacy analyses included the intention-to-treat population (non-inferiority margin 4 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); safety analyses included patients with at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (YOSEMITE NCT03622580 and RHINE NCT03622593).
Findings: 3247 patients were screened for eligibility in YOSEMITE (n=1532) and RHINE (n=1715). After exclusions, 940 patients were enrolled into YOSEMITE between Sept 5, 2018, and Sept 19, 2019, and 951 patients were enrolled into RHINE between Oct 9, 2018, and Sept 20, 2019. These 1891 patients were randomly assigned to faricimab every 8 weeks (YOSEMITE n=315, RHINE n=317), faricimab PTI (n=313, n=319), or aflibercept every 8 weeks (n=312, n=315). Non-inferiority for the primary endpoint was achieved with faricimab every 8 weeks (adjusted mean vs aflibercept every 8 weeks in YOSEMITE 10·7 ETDRS letters [97·52% CI 9·4 to 12·0] vs 10·9 ETDRS letters [9·6 to 12·2], difference -0·2 ETDRS letters [-2·0 to 1·6]; RHINE 11·8 ETDRS letters [10·6 to 13·0] vs 10·3 ETDRS letters [9·1 to 11·4] letters, difference 1·5 ETDRS letters [-0·1 to 3·2]) and faricimab PTI (YOSEMITE 11·6 ETDRS letters [10·3 to 12·9], difference 0·7 ETDRS letters [-1·1 to 2·5]; RHINE 10·8 ETDRS letters [9·6 to 11·9], difference 0·5 ETDRS letters [-1·1 to 2·1]). Incidence of ocular adverse events was comparable between faricimab every 8 weeks (YOSEMITE n=98 [31%], RHINE n=137 [43%]), faricimab PTI (n=106 [34%], n=119 [37%]), and aflibercept every 8 weeks (n=102 [33%], n=113 [36%]).
Interpretation: Robust vision gains and anatomical improvements with faricimab were achieved with adjustable dosing up to every 16 weeks, demonstrating the potential for faricimab to extend the durability of treatment for patients with diabetic macular oedema.
What about the fellow eye in treatment of neovascular age-related macular degeneration? Analysis of data from the Swedish macula register.
Acta Ophthalmol. 2022 Jan 22.
Lövestam Adrian M, Schroeder M, Westborg I.
Purpose: To analyse the development of neovascular age-related macular degeneration (nAMD) in the fellow eye in patients initially presenting with unilateral nAMD, using data from the Swedish Macula Register.
Methods: This observational study included data on treatment-naïve patients who initially underwent unilateral treatment for nAMD, and then required bilateral treatment, between 2010 and 2018, according to the Swedish Macula Register (SMR). The data were also stratified according into three time periods (2010-2013; 2014-2016; 2017-2018). Treatment duration, best-corrected visual acuity (BCVA) in the first and second eye, number of injections in the first eye before falling ill in the second, and the time between the last injection in the first eye and the start of treatment of the fellow eye were analysed.
Results: 5216 out of 28 670 (18%) patients treated for nAMD subsequently required bilateral treatment. The mean age was 77.7 ± 7.3 years, and 69% were female. The mean duration of treatment of the first eye before nAMD was diagnosed in the fellow eye was 1.58 years, and the mean number of injections in the first eye was 8.9 ± 8.6. Best-corrected visual acuity, according to the ETDRS chart, was higher in the second eye at the time when treatment started in that eye compared to treatment start in the first eye: 62.8 (14.7) versus 57.6 (15.5); p < 0.001, and was higher in the 66% whose first eye was still undergoing treatment: 63.6 ± 14.5 versus 61.0 ± 14.8; p = 0.001.
Conclusions: The mean duration of treatment of the first eye before treatment started in the fellow eye was 19 months, and treatment of the second eye had started within 2 years in 61% of the patients. Best-corrected visual acuity was higher in the second eye than in the first eye at the start of treatment of that eye and was higher in the second eye at the start of treatment of that eye when the first eye was still being treated.
Three-year safety and efficacy of the 0.19-mg fluocinolone acetonide intravitreal implant for diabetic macular edema: the PALADIN study.
Ophthalmology. 2022 Jan 18:S0161-6420(22)00067-7.
Singer MA, Sheth V, Mansour SE, Coughlin B, Gonzalez VH.
Objective: To assess the long-term safety and efficacy of the 0.19-mg fluocinolone acetonide (FAc) intravitreal implant (ILUVIEN®) in patients with diabetic macular edema (DME)
Design: Three-year, phase 4, non-randomized, open-label observational study
Participants: Patients with DME who previously received corticosteroid treatment without a clinically significant rise in intraocular pressure (IOP) (All eyes n = 202 eyes in 159 patients; 36-month completers n = 94 eyes)
Methods: A prospective, observational study in which patients received a 0.19-mg FAc intravitreal implant at baseline and were then observed for safety-, visual-, anatomical-, and treatment burden-related outcomes for up to 36 months
Main Outcome Measures: Primary safety outcomes included changes in IOP and interventions to manage IOP elevations. Secondary outcomes included changes in best-corrected visual acuity (BCVA), central subfield thickness (CST), and adjunctive DME treatment frequency
Results: At 36 months post FAc implant, study eyes had a mean BCVA increase of 3.61 letters (P-value = 0.0222) and mean CST decrease of 60.69 μm (P-value < 0.0001) compared to baseline. Overall median treatment frequency decreased from 3.4 treatments/year in the 36 months pre FAc implant to 1 treatment/year in the 36 months post FAc implant, a treatment burden reduction of 67.6%. Furthermore, among the 36-month completer group (n = 94 eyes), 25.53% of eyes remained treatment free through 36 months. Mean IOP remained stable throughout the study, and IOP increases to > 30 mmHg occurred in 10.89% of eyes. IOP-related procedures were infrequent, with a surgical rate of 2.97% with 1.49% attributable to steroid (vs surgeries attributable primarily to neovascular glaucoma). In addition, an IOP response below 25 mmHg after the steroid challenge predicted that 96.92% of eyes would have a similar outcome to 0.19-mg FAc implant at the last visit. IOP increases that did occur were manageable with standard treatments (n = 202 eyes).
Conclusions: In patients with DME, the 0.19-mg FAc implant provided improved visual outcomes and reduced treatment burden compared with previous treatments while maintaining a favorable safety profile.
Short-term outcomes after interim treatment with brolucizumab: a retrospective case series of a single center experience.
Retina. 2022 Jan 17.
Awh CC, Davis EC, Thomas MK, Thomas AS.
Purpose: To examine outcomes of eyes with neovascular age-related macular degeneration that were switched to brolucizumab due to an unsatisfactory response to bevacizumab, ranibizumab, and/or aflibercept and then switched back due to the presence or risk of intraocular inflammation.
Methods: Retrospective case series of 51 eyes. Visual acuity (VA) and retinal anatomy on optical coherence tomography were recorded at the first brolucizumab injection (T1), the final brolucizumab injection (T2), and 6 months following the final brolucizumab injection (T3).
Results: At T2, 41 eyes (41/51, 80%) had decreased SRF (31 eyes), IRF (12 eyes), or PED height (12 eyes). At T3, decreased SRF was sustained in 17 eyes (17/31, 55%), decreased IRF was sustained in 8 eyes (8/12, 67%), and decreased PED height was sustained in 8 eyes (8/12, 67%). Mean logMAR VA at T1, T2, and T3 was 0.396 (∼20/50), 0.441 (∼20/55), and 0.468 (∼20/59), respectively. During the brolucizumab treatment period, eleven eyes (11/51, 22%) developed intraocular inflammation, including one case of retinal vasculitis.
Conclusions: Interim treatment with brolucizumab resulted in anatomic improvements in 41 eyes (41/51, 80%) that were maintained in 22 of these eyes (22/41, 54%) for at least 6 months after switching back to the original anti-VEGF therapeutic. There were no corresponding significant changes in VA.
IMPACT OF VISION LOSS
Quality of life impact of eye diseases: a Save Sight Registries study.
Clin Exp Ophthalmol. 2022 Jan 26.
Kandel H, Nguyen V, Piermarocchi S, Ceklic L, Teo K, Arnalich-Montiel F, Miotto S, Daien V, Gillies MC, Watson SL.
Background: The objectives of this study were to evaluate the quality-of-life (QoL) impact of eye diseases (keratoconus; neovascular age-related macular degeneration, AMD; retinal vein occlusion, RVO; and diabetic macular edema, DME) using the Impact of Vision Impairment (IVI) questionnaire, and to determine the relationship between the IVI scores and visual acuity.
Methods: This cross-sectional, multicentre, real-world study utilized the prospective, web-based Save Sight Registries. The IVI was completed by 1,557 patients: 307 with keratoconus, 1,049 with AMD, 148 with RVO and 53 with DME. Statistical analysis included Rasch analysis, Welch t-test, one-way ANOVA, Tukey’s test, Pearson correlation, multiple regression
Results: The IVI scales (Overall; Visual Function, VF; Emotional, EM) had robust psychometric properties. The keratoconus patients had the worst Overall (adjusted mean: 48.2 vs DME 58.8, RVO 64.6, AMD 67.6), VF (47.7 vs DME 59.4, RVO 65.9, AMD 68.9) and EM (50.8 vs DME 63.1, RVO 69.2, AMD 71.8) scores (all p<0.05). The IVI scales scores weakly correlated with better and worse eye visual acuity (Pearson’s r 0.25 to 0.39, all p<0.05). The correlations were similar in the better eye (Overall 0.35, VF 0.39, EM 0.24) and the worse eye (Overall 0.31, VF 0.33, EM 0.25). Correlations with visual acuity were stronger for VF than for the EM scores.
Conclusions: The IVI was a psychometrically robust QoL questionnaire. Keratoconus patients had worse IVI scores than patients with retinal diseases. The low strength of correlations between visual acuity and QoL scores, although statistically significant, suggested that a complex relationship exists. This article is protected by copyright. All rights reserved.
Longitudinal Impact of Vision Impairment on Concern About Falling in People with Age-Related Macular Degeneration.
Transl Vis Sci Technol. 2022 Jan 3;11(1):34.
White UE, Black AA, Delbaere K, Wood JM.
Purpose: To explore the longitudinal impact of central vision loss on concern about falling (CF), over a 12-month period, in people with age-related macular degeneration (AMD).
Methods: Participants included 60 community-dwelling older people (age, 79.7 ± 6.4 years) with central vision impairment due to AMD. Binocular high-contrast visual acuity, contrast sensitivity, and visual fields were assessed at baseline and at 12 months. CF was assessed at both time points using the Falls Efficacy Scale-International (FES-I). Sensorimotor function (sit to stand, knee extension, postural sway, and walking speed) and neuropsychological function (reaction time, symptoms of anxiety and depression) were also assessed at both time points using validated instruments. Falls data were collected using monthly diaries during the 12 months.
Results: CF increased by a small but significant amount over the 12-month follow-up (2.1 units; P = 0.01), with increasing prevalence of high levels of CF (FES-I score ≥ 23), from 48% at baseline to 65% at 12 months. Linear mixed models showed that reduced contrast sensitivity was significantly associated with increased concern about falling (P = 0.004), whereas declines in both visual acuity and contrast sensitivity during the follow-up period were associated with increases in CF over the 12-month follow-up (P = 0.041 and P = 0.054, respectively), independent of age, gender, falls history, or number of comorbidities.
Conclusions: Higher levels of CF are common in older people with AMD, and levels increase over time; this increase is associated with declines in both visual acuity and contrast sensitivity. These findings highlight the need for regular assessment of both visual acuity and contrast sensitivity to identify those at greatest risk of developing higher CF.
Translational Relevance: Routine assessment of visual acuity and contrast sensitivity in older people with AMD will assist in identifying those at risk of developing high CF.