THE LATEST PUBLISHED RESEARCH

Welcome to Review of Ophthalmology's Retina Online newsletter. Each month, Medical Editor Philip Rosenfeld, MD, PhD, and our editors provide you with this timely and easily accessible report to keep you up to date on important information affecting the care of patients with vitreoretinal disease.

INSIDE THIS ISSUE:

• Archway Randomized Phase III Trial Paves the Way for Susvimo Approval
• Biosimilar SB11 vs. Reference Ranibizumab in nAMD
• Outcomes of Patients with Submacular Hemorrhage Secondary to AMD in the IVAN Trial
• Real-world Outcomes & Treatment Patterns in Patients Treated with Anti-VEGF for nAMD in Sweden
• Occurrence of Rare Variants in Complement Factor H Gene in Early-onset Drusen Maculopathy
• Six-year Incidence of AMD & Correlation to OCT-derived Drusen Volume
• Choroidal Vascularity Index Association & GA Progression
• Assessing Reading Performance in GA Secondary to AMD with Visual Function and Structural Biomarkers
• Temporal Variation of OCT Biomarkers as Predictors of Anti-VEGF Treatment Outcomes in DME
• Visual Outcomes & Morphologic Biomarkers of Vision Loss in DME Eyes Treated with Anti-VEGF Therapy
  
• Cost Effectiveness Analysis of Intravitreal Aflibercept for Preventing Progressive DR
• Noteworthy

 

Archway Randomized Phase III Trial Paves the Way for Susvimo Approval

Genentech’s Port Delivery System with ranibizumab was recently approved in the United States for the treatment of neovascular age-related macular degeneration, and was given the new brand name of Susvimo. The approval was based on the data from the Phase III, open-label, randomized Archway study. Here’s a look at the study’s findings.

Patients with nAMD diagnosed within nine months of screening previously treated with and responsive to anti-vascular endothelial growth factor therapy were included. They were randomized 3:2 to treatment with the PDS with ranibizumab 100 mg/mL with fixed 24-week refill-exchanges (PDS Q24W) or intravitreal ranibizumab 0.5 mg injections every four weeks (monthly ranibizumab).

The primary endpoint was change in best-corrected visual acuity score from baseline averaged over weeks 36 and 40 (NI margin, -4.5 Early Treatment Diabetic Retinopathy Study letters; equivalence margin, ±4.5 ETDRS letters).

Archway enrolled 418 patients; 251 were randomized to and 248 received treatment with PDS Q24W, and 167 were randomized to and received treatment with monthly ranibizumab. Baseline BCVA was 74.4 (PDS Q24W) and 75.5 (monthly ranibizumab) ETDRS letters (Snellen equivalent 20/32). Adjusted mean (standard error) change in BCVA score from baseline averaged over weeks 36 and 40 was +0.2 (0.5) ETDRS letters in the PDS Q24W arm and +0.5 (0.6) in the monthly ranibizumab arm (difference, -0.3; CI, -1.7 to 1.1). Here are some of the findings:
• The PDS Q24W was noninferior and equivalent to monthly ranibizumab.
• Of 246 PDS-treated patients assessed for supplemental ranibizumab treatment, 242 (98.4 percent) didn’t receive supplemental ranibizumab treatment before the first refill-exchange procedure, including four patients who discontinued treatment before the first refill-exchange procedure.
• Prespecified ocular adverse events of special interest (AESIs) were reported in 47 (19 percent) PDS Q24W and 10 (6 percent) monthly ranibizumab patients.
• Ocular AESIs in PDS-treated patients included four (1.6 percent) endophthalmitis cases, two (0.8 percent) retinal detachments, 13 (5.2 percent) vitreous hemorrhages, six (2.4 percent) conjunctival erosions and five (2 percent) conjunctival retractions.
• Most ocular adverse events in PDS patients occurred within one month of implantation.

Investigators wrote that PDS Q24W demonstrated noninferior and equivalent efficacy to monthly ranibizumab with 98.4 percent of PDS-treated patients not receiving supplemental treatment in the first 24-week interval.

SOURCE: Holekamp NM, Campochiaro PA, Chang M, et al. Archway randomized phase 3 trial of the port delivery system with ranibizumab for neovascular age-related macular degeneration. Ophthalmology 2021; Sep 28. [Epub ahead of print].

 

Biosimilar SB11 vs. Reference Ranibizumab in nAMD  

Researchers provided 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, as part of a randomized, double-masked, parallel-group, Phase III equivalence study.

The patient population was patients who were at least 50 years old with nAMD (n=705); one eye of each patient was studied. The intervention was 1:1 randomization to monthly intravitreal injection of 0.5 mg SB11 or RBZ. Main outcome measures included visual efficacy endpoints, safety, immunogenicity and PK up to 52 weeks.

Here are some of the findings:
• Baseline and disease characteristics were comparable between treatment groups.
• Of 705 randomized participants (SB11: n=351; RBZ: n=354), 634 participants (89.9 percent; 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 (CI, -2.1 to 0.9) and of change from baseline in central subfield thickness was -14.9 µm (CI, -25.3 to -4.5).
• The incidence of ocular treatment-emergent adverse events (TEAEs) (SB11: 32 percent vs. RBZ: 29.7 percent) and serious ocular TEAE (SB11: 2.9 percent vs. RBZ: 2.3 percent) appeared comparable between treatment groups, and no new safety concerns were observed.
• The PK and immunogenicity profiles were comparable, with a 4.2 percent and 5.5 percent cumulative incidence of antidrug antibodies up to week 52 for SB11 and RBZ, respectively.

Researchers found that the findings further support the biosimilarity established between SB11 and RBZ.

SOURCE: Bressler NM, Veith M, Hamouz J, et al. Biosimilar SB11 versus reference ranibizumab in neovascular age-related macular degeneration: 1-year phase III randomised clinical trial outcomes. Br J Ophthalmol 2021 Oct 16. [Epub ahead of print].

Outcomes of Patients with Submacular Hemorrhage Secondary to AMD in the IVAN Trial

Researchers compared demographics, visual acuity and retinal morphology between those with and without baseline submacular hemorrhage (SMH) for patients enrolled in the Inhibit VEGF in Age-related Choroidal Neovascularization trial (IVAN).

The secondary analyses of RCT image and clinical data included clinical trial data collected in 23 UK hospitals of IVAN study eyes (with untreated neovascular age-related macular degeneration (at randomization) with at least 12 months’ follow-up and adequate imaging.

Study eyes were randomly assigned to monthly ranibizumab, as-needed ranibizumab, monthly bevacizumab or as-needed bevacizumab. Imaging at baseline graded independently for presence, type, position and extent of SMH. Main outcome measures included visual acuity (primary outcome), subretinal fibrosis, atrophic scarring, and retinal thickness outcomes at 12 and 24 months

A total of 535 of 605 IVAN trial participants were included. Here are some of the findings:
• Patients with SMH at baseline (286, 53 percent) were older (p=0.010), and affected eyes were more likely to have intraretinal fluid present (p=0.038).
• VA was significantly worse in those with baseline SMH at month zero (p<0.001; estimate of difference: six letters with 95 percent confidence intervals of four to eight letters), but the difference decreased and wasn’t significant at month 12 or 24.
• No significant association was found between baseline SMH and subretinal fibrosis, atrophic scarring or central retinal thickness.

Researchers determined that presence of SMH at baseline was associated with age, intraretinal fluid and reduced baseline VA, although VA was no longer significantly different by month 12.

SOURCE: Mehta A, Steel DH, Muldrew A, et al. Associations and outcomes of patients with submacular haemorrhage secondary to age-related macular degeneration in the IVAN trial. Am J Ophthalmol 2021; Oct 5. [Epub ahead of print].

Real-world Outcomes & Treatment Patterns in Patients Treated with Anti-VEGF for nAMD in Sweden

Investigators analyzed and compared the number and interval of anti-vascular endothelial growth factor injections in neovascular age-related macular degeneration patients, as well as visual development in patients followed up for one to three years in clinical practice and during different index periods.

The observational study included treatment-naïve eyes with nAMD from the Swedish Macula Register that started treatment between 2007 and 2017. The eyes were stratified by different index periods (2007 to 2010; 2011 to 2013; 2014 to 2015; and 2016 to 2017) and by follow-up cohorts for each index period of one, two or three years (cohorts 1 to 3). Their intravitreal anti-VEGF treatment was assessed by number of injections, injection intervals, visual acuity and near VA change.

Here are some of the findings:
• From the earliest index period (2007 to 2010) to the latest (2016 to 2017), the number of injections increased for the comparable follow-up time: 6.2 ±1.4 vs. 8.3 ±2 injections after year one, 4.8 ±1.6 vs. 6.7 ±2.4 during year two.
• The last injection interval was 73 ±34 days after one, 71 ±33 after two, and 67 ±32 after three years of follow-up for the index period 2014 to 2015.
• For the same period, the percentage of eyes with at least two consecutive 12- to 16-week injection intervals over one-, two- and three-year follow-up increased 5.2 percent, 15 percent and 17.5 percent, respectively.
• Baseline VA for eyes indexed 2016 to 2017 increased and presented with 62.1 ±13.4 letters compared with 57.7 ±13.5 letters in 2007 to 2010; p<0.0001.

Investigators reported, from the earliest to the latest index periods, the number of injections increased for the comparable follow-up time. At the same time, they wrote, baseline and near VA, and outcomes improved continuously.

SOURCE: Schroeder M, Westborg I, Fluur C, et al. Exploration of real-world outcomes and treatment patterns in patients treated with anti-vascular endothelial growth factors for neovascular age-related macular degeneration in Sweden. Acta Ophthalmol 2021; Sep 20. [Epub ahead of print].

Occurrence of Rare Variants in Complement Factor H Gene in Early-onset Drusen Maculopathy

Early-onset drusen maculopathy (EODM) is a severe disease and can lead to advanced macular degeneration early in life; however, genetic and phenotypic characteristics of individuals with EODM are not well-studied, according to researchers. They aimed to identify genotypic and phenotypic characteristics of individuals with EODM.

This case-control study collected data from the European Genetic Database from September 2004 to October 2019. A total of 89 patients with EODM diagnosed at 55 years or younger, and 91 patients with age-related macular degeneration diagnosed at 65 years or older were included.

Coding regions of CFH, CFI, C3, C9, CFB, ABCA4, PRPH2, TIMP3 and CTNNA1 genes were sequenced, genetic risk scores were calculated based on 52 AMD-associated variants and phenotypic characteristics on color fundus photographs were analyzed comparing patients with EODM and AMD.

Main outcomes and measures included genetic risk scores, frequency of rare genetic complement variants, and phenotypic characteristics.

This case-control study included 89 patients with EODM (mean age, 51.8 ±8.7 years; 58 ±65.2 percent were female) and 91 patients with AMD (mean age, 77.6 ±6.1 years; 45 [49.5 percent] were female).
• At a mean age of 56.4 ±7.3 years, 40 of 89 patients with EODM (44.9 percent) were affected by geographic atrophy or choroidal neovascularization.
• A lower GRS was observed in patients with EODM compared with patients with AMD (1.03 vs. 1.60; p=0.002), and 27 of 89 patients with EODM (30.3 percent) carried rare variants in the CFH gene compared with seven of 91 patients with AMD (7.7 percent).
• Carriership of a rare CFH variant was associated with EODM (OR, 7.2; CI, 2.7 to 19.6; p<0.001).
• A large macular drusen area (more than half-covered with drusen) was observed in patients with EODM (24 of 162 eyes [14.8 percent]) compared with patients with AMD (nine of 164 eyes [5.5 percent]) (OR, 4.57; CI, 1.5 to 14.1; p=0.008).

Researchers determined that a large proportion of patients with EODM in the study carried rare CFH variants, with most of the identified CFH variants clustered in the first seven complement control protein domains affecting factor H and factor H-like 1. Because EODM frequently leads to advanced macular degeneration at an early age and can result in many years of vision loss, they wrote that the study supports targeting the complement system and sequencing the CFH gene in patients with EODM to improve genetic counseling and future treatments for AMD.

SOURCE: de Breuk A, Heesterbeek TJ, Bakker B, et al. Evaluating the occurrence of rare variants in the complement factor H gene in patients with early-onset drusen maculopathy. JAMA Ophthalmol 2021; Oct 14. [Epub ahead of print].

Six-year Incidence of AMD & Correlation to OCT-derived Drusen Volume

Scientists reported the six-year incidence of optical coherence tomography-derived age-related changes in drusen volume and related systemic and ocular associations.

Chinese adults ages 40 years and older were assessed at baseline and six years with color fundus photography (CFP) and spectral-domain optical coherence tomography. CFPs were graded for AMD features, and drusen volume was generated using commercially available automated software.

A total of 4,172 eyes of 2,580 participants (mean age: 58.12 ±9.03 years; 51.12 percent women) had baseline and six-year follow-up CFP for grading. Of these, 2,130 eyes of 1,305 participants had gradable SD-OCT images, available for analysis. Here are some of the findings:
• Based on CFP grading, 136 participants (3.39 percent) developed incident early AMD and 10 (0.25 percent) developed late AMD. Concurrently, retinal pigment epithelial-Bruch's membrane (RPE-BrC) volumes decreased, remained stable and increased in 6.8 percent, 78.5 percent and 14.7 percent, respectively, over six years.
• Having eyes with RPE-BrC volumes >0 mm³ at baseline was associated with twofold higher prevalence rate of any AMD at baseline (p<0.001).
• Multivariable analysis showed that, in comparison to eyes in which RPE-BrC volume was unchanged, volume decrease was significantly associated with older age (OR=1.30; p<0.001), smoking (OR=2.21; p=0.001) and chronic kidney disease (OR=3.4, p=0.008), while an increase was associated with older age (OR=1.36; p<0.001) and hypertension (OR=1.43; p=0.016).

Scientists concluded that AMD incidence detected at six years on CFP had a low correlation to OCT-derived drusen volume measurement change. They added that older age and some systemic risk factors were associated with drusen volume change, providing new insights into the relationship between systemic risk factors and outer retinal morphology in Asian eyes.

SOURCE: Tan AC, Chee ML, Fenner BJ, et al. Six-year incidence of age-related macular degeneration and correlation to OCT-derived drusen volume measurements in a Chinese population. Br J Ophthalmol 2021; Oct 4. [Epub ahead of print].

Choroidal Vascularity Index Association & GA Progression

Investigators assessed the correlation between choroidal vascularity index (CVI) and the enlargement of geographic atrophy lesions secondary to age-related macular degeneration during two-year follow-up.

In this longitudinal observational study, 26 eyes (26 patients, mean age 75.7 ±8.8 years) affected by GA were included. CVI was calculated in the subfoveal 3,000-μm area. The main outcome measure included correlation analysis between baseline CVI and the rate of GA enlargement.

Here are some of the findings:
• During the two-year follow-up, mean GA area increased between the first and second year from 6.99 ±5.28mm² to 10.69 ±6.61 mm² (p<0.001), respectively, accounting for a growth rate of 0.35 ±0.20 and 0.31 ±0.17 mm/year after the square root transformation.
• Stromal choroidal area (SCA) significantly decreased during the two-year follow-up (p=0.002).
• A significant correlation was found between baseline CVI and rate of GA enlargement (r=-0.432, p=0.027), and between SCA and rate of GA enlargement (r=0.422, p=0.032).
• No other significant relationship was found among choroidal parameters with the rate of GA enlargement.

Investigators wrote that CVI impairment was related to the rate of enlargement during the one-year and two-year follow-up in patients affected by GA. As such, they added, CVI could be considered a predictor of GA progression in the clinical setting, and as a new potential biomarker in the efficacy evaluation of new GA interventions.

SOURCE: Sacconi R, Battista M, Borrelli E, et al. Choroidal vascularity index is associated with geographic atrophy progression. Retina 2021; Sep 17. [Epub ahead of print].

Assessing Reading Performance in GA Secondary to AMD with Visual Function and Structural Biomarkers

Researchers prospectively evaluated reading performance in geographic atrophy and assessed its association with established visual function assessments and structural biomarkers.

The noninterventional, prospective natural history study (Directional Spread in Geographic Atrophy) included patients with geographic atrophy secondary to AMD recruited at the University Hospital in Bonn, Germany. Participants were enrolled from June 2013 to June 2016. Analysis began December 2019 and ended January 2021.

Reading acuity and reading speed were assessed using Radner charts. Longitudinal fundus autofluorescence and infrared reflectance images were semi-automatically annotated for geographic atrophy, followed by extraction of shape-descriptive variables. Linear mixed-effects models were applied to investigate the association of the variables with reading performance.

A total of 150 eyes of 85 participants were included in this study (median [IQR] age, 77.9 [72.4 to 82.1] years; 51 women [60 percent]; 34 men [40 percent]). Here are some of the findings:
• Reading performance was impaired, with a median (IQR) monocular reading acuity of 0.9 (0.4 to 1.3) logarithm of the reading acuity determination and a reading speed of 52.8 (zero to 123) words per minute.
• In the multivariable cross-sectional analysis, best-corrected visual acuity, area of geographic atrophy in the central Early Treatment Diabetic Retinopathy Study subfield, classification of non-center vs. center-involving geographic atrophy, and area of geographic atrophy in the inner-right ETDRS subfield showed strongest associations with reading acuity (cross-validated R2 for reading acuity=0.69).
• Regarding reading speed, the most relevant variables were best-corrected visual acuity, low-luminance visual acuity; and area of geographic atrophy in the central ETDRS subfield, in the inner-right ETDRS subfield and in the inner-upper ETDRS subfield (R2 for reading speed=0.67).
• In the longitudinal analysis, a similar prediction accuracy for reading performance was determined (R2 for reading acuity=0.73; R2 for reading speed=0.70).
• Prediction accuracy didn’t improve when follow-up time was added as an independent variable.
• Binocular reading performance didn’t differ from reading performance in the better-seeing eye.

Researchers concluded that the association of reading acuity and speed with visual functional and structural biomarkers supported the validity of reading performance as a meaningful endpoint in clinical trials. These findings suggested that measures in clinical and low-vision care for patients with geographic atrophy should focus primarily on the better-seeing eye.

SOURCE: Künzel SH, Lindner M, Sassen J, et al. Association of reading performance in geographic atrophy secondary to age-related macular degeneration with visual function and structural biomarkers. JAMA Ophthalmol 2021; Sept 30. [Epub ahead of print].

 

Temporal Variation of OCT Biomarkers as Predictors of Anti-VEGF Treatment Outcomes in DME

Scientists reported a longitudinal analysis of specific optical coherence tomography features in eyes with diabetic macular edema-treated with anti-VEGF.

A total of 133 eyes of 103 consecutive patients with center-involving DME were included in the study. The eyes were treated between August 2008 and April 2019, with three monthly intravitreal anti-VEGF injections—with or without prompt or deferred laser—followed by pro re nata (PRN) retreatment. The following OCT biomarkers were evaluated:

• subfoveal neuroretinal detachment (SND) (defined as present [SND+] or absent [SND-]);
• hyperreflective retinal foci (HRF) number (defined as: absent/few [HRF-] or moderate/many [HRF+]);
• external limiting membrane (ELM) integrity;
• central macular thickness (CMT); and
• central retinal thickness (CRT).

The researchers evaluated changes in SND status and in the number of HRF at each DME recurrence throughout the follow-up period. They also assessed mutual correlation among OCT biomarkers and their relationship with visual and anatomic outcomes both at baseline and over the follow-up period.

The mean follow-up was 71.2 months (SD 28.4; minimum 12-maximum 111). Here are some of the findings:
• At baseline, the prevalence of SRD+ was 27.8 percent, and a high number of HRF were detected in 41.4 percent of eyes.
• A significant reduction in the number of HRF, CMT, CRT and in the prevalence of SND was recorded in the post-loading phase (p<0.0001).
• In DME recurrences, presence of SND+ and HRF+ was significantly more frequent in eyes with baseline SND+ and HRF+ compared to eyes presenting baseline SND- and HRF- (p<0.0001).
• No role of SND (p=0.926) and HRF (p=0.281) as baseline predictors of visual and anatomic outcomes was demonstrated, while a worse visual outcome was significantly correlated with a higher incidence of relapsing SND+ (p<0.0001) and HRF+ (p<0.0028) throughout the follow-up period.

In this study, SND and HRF were frequently present in DME recurrences with the same pattern exhibited at baseline, suggesting that these OCT biomarkers may characterize a specific pattern of DME that repeats over time. Moreover, the results suggested that the persistence and recurrence of SND and HRF may account for a decrease in visual function more than the baseline prevalence of these biomarkers. Further studies are required to confirm these findings

 

Source: Maggio E, Mete M, Sartore M, et al. Temporal variation of optical coherence tomography biomarkers as predictors of anti-VEGF treatment outcomes in diabetic macular edema. Graefes Arch Clin Exp Ophthalmol 2021; Oct 18. [Epub ahead of print].