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    Research update: 522

    The latest research highlights for 6 December 2021.


    Safety Outcomes of Brolucizumab in Neovascular Age-Related Macular Degeneration: Results from the IRIS Registry and Komodo Healthcare Map 

    JAMA Ophthalmol.2021 Nov 24. 

    Arshad M Khanani, Marco A Zarbin, Mark R Barakat, Thomas A Albini, Peter K Kaiser, Guruprasad B, Neetu Agashivala, Justin S Yu, Charles C Wykoff, Mathew W MacCumber

    Importance: Limited data exist on the real-world safety outcomes of patients with neovascular age-related macular degeneration treated with brolucizumab (Beovu). 

    Objective: To determine the real-world incidence of intraocular inflammation (IOI), including retinal vasculitis (RV) and/or retinal vascular occlusion (RO), for patients with neovascular age-related macular degeneration who underwent brolucizumab treatment. Additionally, potential risk factors associated with these adverse events were evaluated. 

    Design, setting, and participants: This cohort study included patients with neovascular age-related macular degeneration in the Intelligent Research in Sight (IRIS) Registry and Komodo Healthcare Map. Patients initiating and receiving 1 or more brolucizumab injections from October 8, 2019, to June 5, 2020, with up to 6 months of follow-up were included. 

    Intervention: Brolucizumab injections. 

    Main outcome and measures: Incidence of IOI (including RV) and/or RO and RV and/or RO and risk stratification for the identified risk factors. 

    Results: Of 10 654 and 11 161 included eyes (from the IRIS Registry and Komodo Health database, respectively), the median follow-up times were 97 and 95 days. Most eyes switched from another anti-vascular endothelial growth factor agent (9686 of 10 654 [90.9%] and 10 487 of 11 161 [94.0%], respectively), most commonly aflibercept (7160 of 9686 [73.9%] and 7156 of 10 487 [68.2%]), and most were from women (6105 of 10 654 [57.3%] and 6452 of 11 161 [57.8%]). The overall incidence of IOI and/or RO was 2.4% (255 of 10 654 eyes) and 2.4% (268 of 11 161 eyes) for the IRIS and Komodo groups, respectively, and RV and/or RO, 0.6% (59 of 10 654 eyes and 63 of 11 161 eyes), respectively. Patients with a history of IOI and/or RO in the 12 months before brolucizumab initiation had an increased observed risk rate (8.7% [95% CI, 6.0%-11.4%] and 10.6% [95% CI, 7.5%-13.7%]) for an IOI and/or RO event in the 6 months following the first brolucizumab treatment compared with patients without prior IOI and/or RO (2.0% in both data sets). There was an increased estimated incidence rate in women (2.9% [95% CI, 2.5%-3.3%] and 3.0% [95% CI, 2.6%-3.4%]) compared with men (1.3% [95% CI, 1.0%-1.7%] and 1.4% [95% CI, 1.0%-1.7%]), but this risk was not as large as that of a prior IOI and/or RO. Similar findings were observed for patients with RV and/or RO events. 

    Conclusions and relevance: The incidence rate of IOI and/or RO was approximately 2.4%. Patient eyes with IOI and/or RO in the 12 months prior to first brolucizumab injection had the highest observed risk rate for IOI and/or RO in the early months after the first brolucizumab treatment. However, given study limitations, the identified risk factors cannot be used as predictors of IOI and/or RO events, and causality with brolucizumab cannot be assessed. 

    DOI: 10.1001/jamaophthalmol.2021.4585 


    Progression of macular atrophy in patients receiving long-term anti-VEGF therapy for age-related macular degeneration; Real Life Data 

    Ophthalmologica.2021 Nov 24. 

    Styliani Blazaki, Emmanouil Blavakis, Georgios Smoustopoulos, Georgios Bontzos, Anastasios Stavrakakis, Gregory Chlouverakis, Stamatina Kabanarou, Tina Xirou, Miltiadis Tsilimbaris


    Purpose To evaluate the progression of macular atrophy (MA) based on near-infrared reflectance (NIR) and optical coherence tomography (OCT) images, in patients with age-related macular degeneration (AMD), receiving anti-vascular endothelial growth factor (anti-VEGF) treatment for at least a 6-year period. Materials and Methods This retrospective study included 53 naïve patients (53 eyes) with neovascular AMD from two centers, who were treated with anti-VEGF intravitreal injections and had no MA at baseline. MA was evaluated in an annual basis using NIR images, while all available OCT images were used to confirm that the atrophic area fulfilled the criteria proposed by the Classification of Atrophy Meetings (CAM) group for complete retinal pigment epithelium RPE and outer retinal atrophy (cRORA). Incidence and progression of MA were evaluated. Associations with best-corrected visual acuity (BCVA) and total number of injections were also studied. Results Treatment duration of our patients was 7.34 ± 1.54 years. The mean number of anti-VEGF injections was 24.4 ± 13.6. BCVA at baseline was 0.38 ± 0.27 logMAR while at final visit it was 0.60 ± 0.35 logMAR (p=0.731). The cumulative incidence of new MA at years 1, 2, 3, 4, 5, and 6 was 1.89%, 18.87% 32.08%, 39.62%, 49.06% and 50.94% respectively. In patients who developed MA, mean MA area increased from zero at baseline to 5.66 ± 7.18 mm2 at final visit. The estimated annual enlargement of MA was 0.45 mm/year based on square root transformation (1.12 mm2/year, untransformed data). MA progression does not appear to be significantly associated with age (R=0.055; p=0.784), gender (R=0.113; p=0.576), BCVA (R=0.168; p=0.404) and total number of injections (R=0.133; p=0.255). Conclusion In this real-life setting, half of neovascular AMD patients under anti-VEGF treatment, without MA at therapy initiation, developed MA over a period of at least 6 years. In this work, the number of injections did not seem to have a significant association with MA progression. 

    DOI: 10.1159/000520595 

    Aflibercept, ranibizumab and bevacizumab upcoming biosimilars: a general overview 

    Drugs Today (Barc).2021 Nov;57(11):689-697. 

    P Viola, V Testa, L Ferro Desideri, L Di Cello, C Rutigliani, A Vagge, M Nicolò, R Cian, C E Traverso


    Anti-vascular endothelial growth factors currently are the first-line treatment option for neovascular age-related macular degeneration (nAMD) and other retinal vascular disorders, and their clinical use is associated with high financial burden. Biosimilars are a type of biological product highly similar to referral biologic drugs; they are increasing competition among biologics and have the potential to reduce the overall expenditures on biologics. In this comprehensive literature review, the current investigational biosimilars acting on retinal diseases are discussed. The authors review the results of clinical studies and highlight ongoing trials. Several biosimilar candidates are under evaluation and the pipeline will rapidly change in the future, as soon as each patent expires. Clinicians have to know these new therapeutic agents, which might come in the mainstream clinical practice as a more cost-efficient option. 

    DOI: 10.1358/dot.2021.57.11.3331006 

    Real-world cost-effectiveness of anti-VEGF monotherapy and combination therapy for the treatment of polypoidal choroidal vasculopathy 

    Eye (Lond).2021 Nov 22. 

    Junxing Chay, Beau J Fenner, Eric A Finkelstein, Kelvin Y C Teo, Chui Ming Gemmy Cheung

    Objectives: For patients with polypoidal choroidal vasculopathy (PCV), intravitreal anti-vascular endothelial growth factor (anti-VEGF) combination therapy has been shown to be cost-saving relative to monotherapy in a clinical trial setting. However, whether this also applies to real-world settings is unclear. We aim to compare the real-world functional outcomes and cost-effectiveness of intravitreal anti-VEGF combination therapy relative to monotherapy, to investigate whether combination therapy is truly cost-saving. 

    Methods: We used a Markov model to simulate a hypothetical cohort of PCV patients treated at Singapore National Eye Centre. Model parameters were informed by coarsened exact matched estimates of a two-year retrospective study of patients who initiated treatment in 2015. Treatment options included intravitreal aflibercept, bevacizumab, or ranibizumab, as monotherapy or in combination with full-fluence verteporfin photodynamic therapy. 

    Results: The two-year logMAR letters gains were significant for combination therapy ( + 10.6, P = 0.006) but not monotherapy (-2.2, P = 0.459). Over 20 years, a PCV patient would cost the health system SGD 48,790 under monotherapy and SGD 61,020 under combination therapy. Quality-adjusted life-years (QALYs) were estimated to be 7.41 for monotherapy and 7.80 for combination therapy. The incremental cost-effectiveness ratio of combination therapy was SGD 31,460/QALY, which is less than the common willingness-to-pay threshold of per capita gross domestic product of Singapore (SGD 88,990/QALY). Sensitivity analysis showed that combination therapy remained incrementally cost-effective, but not cost-saving. 

    Conclusions: Our study shows that combination therapy is good value for money but is likely to increase costs when applied in real-world settings. 

    DOI: 10.1038/s41433-021-01856-9 


    Inhibition of ocular neovascularization by novel anti-angiogenic compound

    Exp Eye Res.2021 Nov 22;213:108861. 

    David Gau, Lucile Vignaud, Paul Francoeur, David Koes, Xavier Guillonneau, Partha Roy


    Aberrant angiogenesis lies at the heart of a wide range of ocular pathologies such as proliferative diabetic retinopathy, wet age-related macular degeneration and retinopathy of prematurity. This study explores the anti-angiogenic activity of a novel small molecule investigative compound capable of inhibiting profilin1-actin interaction recently identified by our group. We demonstrate that our compound is capable of inhibiting migration, proliferation and angiogenic activity of microvascular endothelial cells in vitro as well as choroidal neovascularization (CNV) ex vivo. In mouse model of laser-injury induced CNV, intravitreal administration of this compound diminishes sub-retinal neovascularization. Finally, our preliminary structure-activity relationship study (SAR) demonstrates that this small molecule compound is amenable to improvement in biological activity through structural modifications. 

    DOI: 10.1016/j.exer.2021.108861 


    Bacillary layer detachment on optical coherence tomography in exudative age-related macular degeneration 

    Eur J Ophthalmol.2021 Nov 24;11206721211064017. 

    Ramesh Venkatesh, Nikitha G Reddy, Sameeksha Agrawal, Arpitha Pereira, Naresh Kumar Yadav, Jay Chhablani

    Purpose: To report the bacillary layer detachment on optical coherence tomography in exudative age-related macular degeneration. 

    Methods: Retrospective, observational cases. 

    Case descriptions: Two cases of exudative age-related macular degeneration, one diagnosed as polypoidal choroidal vasculopathy following exudative age-related macular degeneration and other as wet age-related macular degeneration with choroidal neovascular membrane showed separation of myoid and ellipsoid zones of photoreceptor layer on optical coherence tomography. This is termed as BALAD. Other associated features noted were the presence of subretinal hyperreflective material, submacular hemorrhage and subretinal fluid. Both cases were treated with monthly intravitreal injections of Inj. Ranibizumab (0.5 mg/0.05 ml). Following 3 intravitreal injections at monthly intervals, reattachment of the bacillary layer detachment were noted in case 1 while the bacillary layer detachment persisted in case 2. 

    Conclusion: Multimodal imaging using optical coherence tomography in these cases revealed the separation of the bacillary layer following exudative age-related macular degeneration; a finding which is not routinely described in literature. 

    DOI: 10.1177/11206721211064017 

    Optical Coherence Tomography Prognostic Factors in AMD Patients with Peripapillary Choroidal Neovascularization 

    Ophthalmologica.2021 Nov 22. 

    Gilad Rabina, Anfisa Ayalon, Michael Mimouni, Nir Stanescu, Elad Moisseiev, Arie Y Nemet, Noa Geffen, Ori Segal

    Purpose: To investigate the correlation between optical coherence tomography (OCT) findings and visual acuity outcomes after treatment with intravitreal bevacizumab (IVB) injections for age related macular degeneration (AMD) patients with peripapillary choroidal neovascularization (PPCNV). 

    Methods: A retrospective case series of consecutive patients diagnosed with PPCNV secondary to AMD. All patients were treated with IVB injections with a follow-up time of one year. Data collected included best corrected visual acuity (BCVA), automated and manually measured OCT parameters. 

    Results: A total of 68 eyes were diagnosed with PPMV. Of them, 30 eyes of 30 patients aged 84.3±6.9 years of which 63.3% female gender were included. Baseline BCVA was 0.46±0.62 logMAR (Snellen 20/57), average choroidal thickness was 193.2±22 µm and mean number of IVB injections was 7.2±1.9. After one year BCVA was 0.56±0.78 logMAR (Snellen 20/72) (p=0.28). Eyes with greater central retinal thickness (r=-0.36, p=0.05), greater subretinal hyperreflective material (SHRM) area (r=-0.37, p=0.05) and greater sub retinal fluid (SRF) area (r=-0.73, p<0.001) had a significantly smaller improvement in BCVA. Eyes with pigment epithelium detachment (PED) (0.68±0.90 versus 0.21±0.12, p=0.03) had a significantly worse BCVA. 

    Conclusions: Our data suggests that AMD related PPCNV with greater foveal thickness, PED size, SHRM and SRF areas have worse final BCVA prognosis. 

    DOI: 10.1159/000520930 

    Polypoidal Choroidal Vasculopathy Diagnosis and Neovascular Activity Evaluation Using Optical Coherence Tomography Angiography 

    Biomed Res Int.2021 Nov 16;2021:1637377. 

    Georges Azar, Vivien Vasseur, Corinne Lahoud, Catherine Favard, Flore De Bats, Isabelle Cochereau, Amélie Yachvitz, Martine Mauget-Faÿsse

    Purpose: To examine choroidal neovascularization (CNV) characteristics in patients with exudative age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV), using swept-source optical coherence tomography angiography (SS-OCTA), and investigate agreement with OCT B-scan, fundus fluorescein angiography (FFA), and indocyanine green angiography (ICGA) by two different examiners. 

    Methods: This is a retrospective multicentric study that involved patients with a history of AMD and PCV. Examiner A, who had access to OCTA, B-scan OCT, FFA, and ICGA imaging, had to differentiate between AMD and PCV, study the activity of AMD using Coscas’ criteria (active vs. quiescent), and categorize PCV subtypes, while examiner B had only access to OCTA. Then, the diagnostic concordance was assessed between both examiners. 

    Results: A total of 27 patients (11 females (40.7%) and 16 males (59.3%), P = 0.231) were included in the analysis. Among those, 13 patients presented with neovascular AMD and 14 patients with PCV. There were 92.3% of correct answers regarding appropriate diagnosis and lesion characterization among AMD patients, against 61.5% of correct answers among PCV patients. The overall interrater reliability agreement between examiners, using Cohen’s kappa coefficient (κ) was 0.70 (0.5082-0.8916). Disagreement was found with one active AMD misdiagnosed as inactive AMD, three inactive PCV misdiagnosed as inactive AMD, and one inactive PCV misdiagnosed as active AMD. 

    Conclusion: SS-OCTA alone remains limited in some specific phenotypes of PCV, which suggests the ongoing role of B-scan OCT associated with FFA and ICGA in the diagnosis of these conditions. 

    DOI: 10.1155/2021/1637377 


    Epigenomic signatures in age-related macular degeneration: Focus on their role as disease modifiers and therapeutic targets 

    Eur J Ophthalmol.2021 Nov;31(6):2856-2867. 

    Valerio Caputo, Claudia Strafella, Andrea Termine, Carlo Fabrizio, Paola Ruffo, Andrea Cusumano, Emiliano Giardina, Federico Ricci, Raffaella Cascella 


    Epigenetics is characterized by molecular modifications able to shape gene expression profiles in response to inner and external stimuli. Therefore, epigenetic elements are able to provide intriguing and useful information for the comprehension and management of different human conditions, including aging process, and diseases. On this subject, Age-related Macular Degeneration (AMD) represents one of the most frequent age-related disorders, dramatically affecting the quality of life of older adults worldwide. The etiopathogenesis is characterized by an interplay among multiple genetic and non-genetic factors, which have been extensively studied. Nevertheless, a deeper dissection of molecular machinery associated with risk, onset, progression and effectiveness of therapies is still missing. In this regard, epigenetic signals may be further explored to disentangle disease etiopathogenesis, the possible therapeutic avenues and the differential response to AMD treatment. This review will discuss the epigenomic signatures mostly investigated in AMD, which could be applied to improve the knowledge of disease mechanisms and to set-up novel or modified treatment options. 

    DOI: 10.1177/11206721211028054 


    X-linked Retinoschisis: Deep Phenotyping and Genetic Characterization 

    Ophthalmology.2021 Nov 22;S0161-6420(21)00911-8. 

    Michalis Georgiou, Lucia Finocchio, Kaoru Fujinami, Yu Fujinami-Yokokawa, Gianni Virgili, Omar A Mahroo, Andrew R Webster, Michel Michaelides

    Objective: To examine the genetic and clinical features in children and adults with XLRS. 

    Design: Single-center consecutive, retrospective, observational study. 

    Setting: Single tertiary referral center. 

    Participants: Adults and children, with molecularly confirmed XLRS, followed up between 1999 and 2020. 

    Main outcomes and measures: Genetic, clinical and retinal imaging findings, including optical coherence tomography (OCT) and fundus autofluorescence (FAF), cross-sectionally and longitudinally; and explore correlations including between best corrected visual acuity (BCVA) and age, and OCT characteristics. 

    Results: One hundred and thirty-two males were identified, harbouring 66 RS1 variants, with seven being novel. The mean age of onset was 16.5 years (range 2 to 55 years). Seventy-one patients (71/75, 94.7%) were symptomatic at presentation; all had decreased BCVA. Fundoscopy findings were symmetric in 104 patients (104/108, 96.3%), with the most common finding being macular schisis (82.4%), whereas peripheral retinoschisis was present in 38.9% and macular atrophy in 11.1%. Twenty patients (18.5%) developed complications (vitreous haemorrhage and/or retinal detachment). Mean BCVA was 0.65 LogMAR (20/89 Snellen) in the right eye and 0.64 LogMAR (20/87 Snellen) in the left eye. Mean BCVA change over a mean interval of 6.7 years was 0.04 and 0.01 LogMAR for right and left eyes, respectively. FAF was normal in 16 of 106 eyes (15.1%); 45 eyes (42.5%) showed a spoke-wheel pattern, 13 (12.3%) had foveal hyperautofluorescence, while 18 (17.0%) had central reduction in signal. In total, 14 patients had evidence of FAF progression over time, indicated by change in the FAF pattern. On OCT, foveoschisis was observed in 172 eyes (172/215, 80%), parafoveal schisis in 171 (171/215, 79.5%), and foveal atrophy in 44 (44/215, 20.5%). Cystoid changes were localized to the inner nuclear layer (172/181 eyes, 95%), the outer nuclear layer (97/181, 53.6%) and the ganglion cell layer (92/181, 50.8%). Null variants were associated with worse final BCVA and aforementioned complications. 

    Conclusions and relevance: XLRS is highly phenotypically variable but with relative foveal preservation (and associated BCVA) until late adulthood, allowing more accurate prognostication. The slowly (often minimally) progressive disease course may pose a challenge in identification of early endpoints for therapeutic trials aimed at altering kinetics of degeneration. 

    DOI: 10.1016/j.ophtha.2021.11.019