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    Research update: 517

    The latest research highlights for 1 November 2021.


    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;bjophthalmol-2021-319637.

    Neil M Bressler, Miroslav Veith, Jan Hamouz, Jan Ernest, Dominik Zalewski, Jan Studnička, Attila Vajas, András Papp, Gabor Vogt, James Luu, Veronika Matuskova, Young Hee Yoon, Tamás Pregun, Taehyung Kim, Donghoon Shin, Inkyung Oh, Hansol Jeong, Mercy Yeeun Kim, Se Joon Woo

    Background/aims: To 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. 

    Results: Baseline 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. 

    Conclusions: Longer-term results of this study further support the biosimilarity established between SB11 and RBZ. 

    DOI: 10.1136/bjophthalmol-2021-319637 


    Visual acuity after intravitreal ranibizumab with and without laser therapy in the treatment of macular edema due to branch retinal vein occlusion: a 12-month retrospective analysis 

    Int J Ophthalmol.2021 Oct 18;14(10):1565-1570. 

    Reiko Umeya, Koichi Ono, Toshimitsu Kasuga

    Aim: To identify factors contributing to visual improvement after treatment of macular edema (ME) secondary to branch retinal vein occlusion (BRVO), and to assess the interaction between laser therapy and intravitreal ranibizumab (IVR). 

    Methods: We retrospectively reviewed the medical records of patients who had been treated for BRVO-related ME at our hospital. Records were traceable for at least 12mo, and evaluated factors included age, sex, medical history, smoking history, treatment methods, foveal hemorrhage, and change in visual acuity. Treatments included laser therapy, IVR, sub-Tenon’s capsule injection of triamcinolone (STTA), a combination, or no intervention. Multivariate logistic regression analysis and interaction terms were used to assess the clinical efficacy of the treatments, and odds ratios (OR) and 95% confidence intervals (CI) were calculated. 

    Results: Seventy-three patients (34 men, 39 women; 73 eyes) with a mean age of 69.4±12.1y were included. Patients who underwent IVR monotherapy, laser monotherapy, and STTA+laser had significantly higher best corrected visual acuity at 12mo compared to baseline (P<0.001, <0.001, and 0.019, respectively). Logistic regression analysis without interaction terms found that IVR was a significant visual acuity recovery factor (adjusted OR: 3.89, 95%CI: 1.25-12.1, P=0.019). Adjusted OR using an interaction model by logistic regression was 16.6 (95%CI: 2.54-108.47, P=0.003) with IVR treatment, and 8.25 (95%CI: 1.34-50.57, P=0.023) with laser treatment. No interaction was observed (adjusted OR: 0.07, 95%CI: 0.01-0.75, P=0.029). 

    Conclusion: IVR contributes to improvements in visual acuity at 12mo in ME secondary to BRVO. No interaction is observed between laser therapy and IVR treatments. 

    DOI: 10.18240/ijo.2021.10.14 


    Effect of subthreshold nanosecond laser on retinal structure and function in intermediate age-related macular degeneration 

    Clin Exp Ophthalmol.2021 Oct 15. 

    Josephine R Gunawan, Sarah H Thiele, Ben Isselmann, Emily Caruso, Robyn H Guymer, Chi D Luu

    Background: Subthreshold nanosecond laser (SNL) treatment has been studied as a potential intervention in intermediate age-related macular degeneration (iAMD). This study investigated the effect of 100 SNL treatment spots on retinal structure and function. 

    Methods: A prospective single-arm interventional pilot study. SNL treatment was delivered as 100 spots around the retinal vascular arcades of the study eye (worst visual acuity) in a single session in subjects with iAMD. Multimodal retinal imaging and dark-adapted chromatic perimetry were performed at baseline and at 0.5, 3, 6 and 12 months post treatment. Post treatment changes in best corrected visual acuity (BCVA), retinal thickness, relative ellipsoid zone reflectivity (rEZR) and rod-mediated functional parameters were compared to baseline. 

    Results: Twenty-one subjects with iAMD were recruited. SNL treatment was associated with an increase in retinal thickness (p = 0.008) and decrease in rEZR (p < 0.001) at 2 weeks post laser. Recovery of retinal thickness and rEZR was observed at the 3-month post laser visit. A gradual improvement in BCVA was observed after laser treatment. The mean change in BCVA between baseline and 12-month visit was +1.9 ± 3.3 letters for the SNL treated eyes, compared to -0.4 ± 3.0 letters for the fellow eyes (p = 0.027). Rod-mediated function improved at 3 months post laser (p < 0.001) and returned to the baseline levels at 12 months post treatment. 

    Conclusions: A single treatment with 100 SNL spots causes a short-term change in retinal structure and improvement in retinal function that are apparent at 3 months post treatment. 

    DOI: 10.1111/ceo.14018 

    Identification of fluoxetine as a direct NLRP3 inhibitor to treat atrophic macular degeneration 

    Proc Natl Acad Sci U S A.2021 Oct 12;118(41):e2102975118. 

    Meenakshi Ambati, Ivana Apicella, Shao-Bin Wang, Siddharth Narendran, Hannah Leung, Felipe Pereira , Yosuke Nagasaka, Peirong Huang, Akhil Varshney, Kirstie L Baker, Kenneth M Marion, Mehrdad Shadmehr, Cliff I Stains, Brian C Werner, Srinivas R Sadda, Ethan W Taylor, S Scott Sutton, Joseph Magagnoli, Bradley D Gelfand


    The atrophic form of age-related macular degeneration (dry AMD) affects nearly 200 million people worldwide. There is no Food and Drug Administration (FDA)-approved therapy for this disease, which is the leading cause of irreversible blindness among people over 50 y of age. Vision loss in dry AMD results from degeneration of the retinal pigmented epithelium (RPE). RPE cell death is driven in part by accumulation of Alu RNAs, which are noncoding transcripts of a human retrotransposon. Alu RNA induces RPE degeneration by activating the NLRP3-ASC inflammasome. We report that fluoxetine, an FDA-approved drug for treating clinical depression, binds NLRP3 in silico, in vitro, and in vivo and inhibits activation of the NLRP3-ASC inflammasome and inflammatory cytokine release in RPE cells and macrophages, two critical cell types in dry AMD. We also demonstrate that fluoxetine, unlike several other antidepressant drugs, reduces Alu RNA-induced RPE degeneration in mice. Finally, by analyzing two health insurance databases comprising more than 100 million Americans, we report a reduced hazard of developing dry AMD among patients with depression who were treated with fluoxetine. Collectively, these studies identify fluoxetine as a potential drug-repurposing candidate for dry AMD. 

    DOI: 10.1073/pnas.2102975118 


    Location-Specific Thickness Patterns in Intermediate Age-Related Macular Degeneration Reveals Anatomical Differences in Multiple Retinal Layers 

    Invest Ophthalmol Vis Sci.2021 Oct 4;62(13):13. 

    Matt Trinh, Vincent Khou, Michael Kalloniatis, Lisa Nivison-Smith 

    Purpose: To examine individual retinal layers’ location-specific patterns of thicknesses in intermediate age-related macular degeneration (iAMD) using optical coherence tomography (OCT). 

    Methods: OCT macular cube scans were retrospectively acquired from 84 iAMD eyes of 84 participants and 84 normal eyes of 84 participants propensity-score matched on age, sex, and spherical equivalent refraction. Thicknesses of the retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer + Henle’s fiber layer (ONL+HFL), inner- and outer-segment layers (IS/OS), and retinal pigment epithelium to Bruch’s membrane (RPE-BM) were calculated across an 8 × 8 grid (total 24° × 24° area). Location-specific analysis was performed using cluster(normal) and grid(iAMD)-to-cluster(normal) comparisons. 

    Results: In iAMD versus normal eyes, the central RPE-BM was thickened (mean difference ± SEM up to 27.45% ± 7.48%, P < 0.001; up to 7.6 SD-from-normal), whereas there was thinned outer (OPL, ONL+HFL, and non-central RPE-BM, up to -6.76% ± 2.47%, P < 0.001; up to -1.6 SD-from-normal) and inner retina (GCL and IPL, up to -4.83% ± 1.56%, P < 0.01; up to -1.7 SD-from-normal) with eccentricity-based effects. Interlayer correlations were greater against the ONL+HFL (mean |r| ± SEM 0.19 ± 0.03, P = 0.14 to < 0.0001) than the RPE-BM (0.09 ± 0, P = 0.72 to < 0.0001). 

    Conclusions: Location-specific analysis suggests altered retinal anatomy between iAMD and normal eyes. These data could direct clinical diagnosis and monitoring of AMD toward targeted locations. 

    DOI: 10.1167/iovs.62.13.13 


    No association between cataract surgery and mitochondrial DNA damage with age-related macular degeneration in human donor eyes 

    PLoS One.2021 Oct 19;16(10):e0258803. 

    Karen R Armbrust, Pabalu P Karunadharma, Marcia R Terluk, Rebecca J Kapphahn, Timothy W Olsen, Deborah A Ferrington, Sandra R Montezuma

    Purpose: To determine whether age-related macular degeneration (AMD) severity or the frequency of retinal pigment epithelium mitochondrial DNA lesions differ in human donor eyes that have undergone cataract surgery compared to phakic eyes. 

    Methods: Eyes from human donors aged ≥ 55 years were obtained from the Minnesota Lions Eye Bank. Cataract surgery status was obtained from history provided to Eye Bank personnel by family members at the time of tissue procurement. Donor eyes were graded for AMD severity using the Minnesota Grading System. Quantitative PCR was performed on DNA isolated from macular punches of retinal pigment epithelium to quantitate the frequency of mitochondrial DNA lesions in the donor tissue. Univariable and multivariable analyses were performed to evaluate for associations between (1) cataract surgery and AMD severity and (2) cataract surgery and mitochondrial DNA lesion frequency. 

    Results: A total of 157 subjects qualified for study inclusion. Multivariable analysis with age, sex, smoking status, and cataract surgery status showed that only age was associated with AMD grade. Multivariable analysis with age, sex, smoking status, and cataract surgery status showed that none of these factors were associated with retinal pigment epithelium mitochondrial DNA lesion frequency. 

    Conclusions: In this study of human donor eyes, neither retinal pigment epithelium mitochondrial DNA damage nor the stage of AMD severity are independently associated with cataract surgery after adjusting for other AMD risk factors. These new pathologic and molecular findings provide evidence against a relationship between cataract surgery and AMD progression and support the idea that cataract surgery is safe in the setting of AMD. 

    DOI: 10.1371/journal.pone.0258803 


    Anti-VEGF therapies for age-related macular degeneration: a powerful tactical gear or a blunt weapon? The choice is ours 

    Graefes Arch Clin Exp Ophthalmol.2021 Oct 20;1-7. 

    Paolo Lanzetta 

    Purpose: Blindness and vision loss are still frequent disabilities associated with a relevant impact on health care and quality of life, and a high economic burden. Supranational programs established by the World Health Organization (WHO), International Agency for the Prevention of Blindness (IAPB), and World Health Assembly (WHA) aim at reducing avoidable visual impairment. Age-related macular degeneration (AMD), diabetic retinopathy (DR), and other retinal diseases are well known causes of visual disability. Since more than a decade, intravitreal agents are available for the treatment of these diseases. The aim of this study is to review whether pharmacotherapy with anti-vascular endothelial growth factor (VEGF) drugs has led to a decrease in the prevalence of blindness with emphasis on AMD and different countries. A brief analysis of other factors correlated to changes in the rate of blindness is also presented. 

    Methods: PubMed and Scopus web platforms were used to identify relevant studies on epidemiology of blindness and vision impairment, the influence of intravitreal therapies, and the existence of different vision care models. Additional data and material was searched in web internet accessed by the web browser Firefox. 

    Results: Age-standardized prevalence of blindness secondary to AMD has started to decline as testified by a number of studies in different countries. This is due to the adoption of anti-VEGF therapy and its adequate management. The frequency of treatment and regimens applied are indirect signs of successful treatment. Local rules and regulations may represent an obstacle. 

    Conclusions: This review shows that by implementing existing health care systems and dispensing adequate therapies in the field of retinal diseases, the prevalence of blindness due to these conditions can decline. 

    DOI: 10.1007/s00417-021-05451-2 

    Anti-VEGF and Other Novel Therapies for Neovascular Age-Related Macular Degeneration: An Update 

    BioDrugs.2021 Oct 16. 

    Mariacristina Parravano, Eliana Costanzo, Giulia Scondotto, Gianluca Trifirò, Gianni Virgili


    Age-related macular degeneration (AMD) is a leading cause of visual impairment and blindness in older adults. The prognosis for the neovascular type of advanced AMD improved with the introduction of biological drugs with antiangiogenic properties, beginning with off-label bevacizumab, which was first used intravitreally in 2006. These drugs target newly formed vessels that grow beneath the center of the retina, causing loss of central vision, and they can help to maintain or improve vision. Repeated intravitreal injections are needed to achieve prolonged inhibition of proangiogenic cytokines, primarily vascular endothelial growth factor (VEGF). Major regulatory agencies have approved several molecules for AMD treatment, including ranibizumab, aflibercept, and brolucizumab. The development of further drugs was mainly targeted at prolonging anti-VEGF inhibition-thus reducing the frequency of injections-and expanding the biological targets of proangiogenic cytokine inhibition. Finally, biosimilars are already being marketed in some countries, allowing the containment of costs of AMD treatment, which are growing steadily in many settings because of the need for long-term treatment. This review summarizes the properties and clinical profiles of anti-VEGF biological drugs that are approved to treat neovascular AMD as well as ongoing research on molecules that may be marketed in the near future. 

    DOI: 10.1007/s40259-021-00499-2 


    Brevibacterium casei endophthalmitis after intravitreal dexamethasone implant 

    Arch Soc Esp Oftalmol (Engl Ed).2021 Oct;96(10):549-551. 

    A Olate-Pérez, R A Díaz-Céspedes, N Ruíz-Del-Río, D Hernández-Pérez, A Duch-Samper

    Clinical case: 49-year-old man with diabetic macular edema refractory to antiangiogenics, it is decided to perform therapy with intravitreal dexamethasone implant (Ozurdex; Allergan, California, United States of America). Seven days after treatment, he showed acute endophthalmitis suggestive signs. Despite the intravitreal injection of antibiotics, the patient got worse. Vitreous sampling was repeated for Gram and cultures, and vitrectomy was performed via pars plana. The culture suggested the development of Brevibacterium species. Through an additional test, the presence of Brevibacterium casei was confirmed. Despite the treatment adjusted by antibiogram, retinal ischemia and macular atrophy was evident. 

    Discussion: Brevibacterium casei is a Gram-positive bacterium, barely pathogenic, that mainly affects immunodepressed patients. Only two cases of endophthalmitis are described, one endogenous and the other one secondary to vegetal trauma. This is the first case of endophthalmitis, secondary to an ophthalmological procedure. 

    DOI: 10.1016/j.oftale.2020.09.010