Mark C. Gillies

Description:Objective: To study the long-term outcomes of anti-VEGF treatment for neovascular age-related macular degeneration (nAMD) in the Netherlands, where off-label bevacizumab is used as the first choice, compared to countries that typically use ranibizumab or aflibercept. Design: Prospective real-world observational study. Methods: A total of 1,617 Dutch eyes were compared with 8,667 eyes from a reference group derived from 13 socio-economically comparable countries. The primary outcome was the mean visual acuity (VA) measured at annual intervals up to 60 months. Secondary outcomes included injection frequency and the rate of switching to an alternative injection type. Results: Dutch eyes exhibited higher VA, received two additional injections annually and switched to alternative treatments more frequently (65.2% vs. 50.1%) and sooner (14.6 months vs. 17.9 months). Conclusion: Dutch patients achieved higher VA after 60 months compared to the reference group. This higher VA was associated with a greater number of injections and a tendency to switch to a more expensive registered anti-VEGF injection type.

Description:Background: To evaluate long-term outcomes of anti-VEGF therapy for neovascular age-related macular degeneration (nAMD) in the Netherlands (NL), where bevacizumab is the mandated first-line drug, compared to high-income countries using ranibizumab or aflibercept as initial treatments. Methods: Five-year data from the Fight Retinal Blindness! (FRB) registry, a real-world prospective registry, were analyzed. Outcomes from 1473 Dutch eyes (1229 patients) treated with bevacizumab were compared with 7144 eyes (5884 patients) in a reference group (RG) from 13 socioeconomically similar countries. The primary outcome was mean visual acuity (VA) at yearly intervals; secondary outcomes included injection frequency and switching rates to alternative anti-VEGF agents. Results: Throughout the 60 months, mean VA was consistently higher in Dutch eyes (baseline: NL 60.2 vs. RG 59.2; 60 months: NL 64.9 vs. RG 62.6). The Dutch group cumulatively received 14.5 more injections over 5 years and had a higher rate of switching (70.9% vs. 50.9%) with a shorter median time to switching (11.9 months vs. 17.7 months). Conclusions: Patients treated in Dutch FRB! clinics have good long-term outcomes with a 2.3-letter higher mean VA at the 60-month timepoint compared to FRB! clinics in the RG. The Dutch patients, who began treatment with bevacizumab, received 14.5 more injections over 5 years and had a 40% higher rate of switching to an alternative drug, with switching occurring 5.8 months earlier. This study highlights the benefits of early and more intensive management to optimize visual outcomes, which appear more important than the choice and price of the first-line drug.

Description:Background: The evolution of treatment patterns in neovascular age-related macular degeneration (nAMD) warrants investigation into the impact of patients' adherence to anti-vascular endothelial growth factor (VEGF) treatment on visual outcomes. This retrospective, non-randomized, non-comparative study aimed to investigate real-world adherence to anti-VEGF treatment. Methods: Patient (eyes) (≥ 50 years) with a diagnosis of nAMD who had a first injection of aflibercept or ranibizumab between January 2016 and December 2018 and 12 months of follow-up were included. Visual acuity (VA; logMAR letters) and duration of injection intervals were recorded. Adherence was defined as < 20% of visits deviating from the schedule by ≥ 14 days. Results: Overall, 133 patient eyes were included: 129 adherent, and four non-adherent. Mean (standard deviation) baseline VA was 57.0 (23.6) and 53.8 (35.3) letters in adherent and non-adherent patient eyes, respectively. Mean change in VA by month 12 was higher in adherent (6.3 letters) than non-adherent patient eyes (- 11 letters). Compared with the previous visit, adherent visits were associated with a mean increase in VA of 0.67 letters and non-adherent visits with a decrease of 2.30 letters. Conclusions: These results emphasize the importance of adherence to appropriate dosing regimens to optimize visual outcomes in patients with nAMD.

Description:The macula is preferentially affected in some common retinal diseases (such as age-related macular degeneration, diabetic retinopathy and macular telangiectasia type 2), whereas most inherited retinal degenerations (e.g., retinitis pigmentosa) tend to initially affect the peripheral retina. This pattern suggests the macula may have intrinsic vulnerabilities in its oxidative stress defences, compared to the periphery. Profiling of single-cell level transcriptional changes found that the peripheral retina exhibited greater transcriptional alterations than the macula in response to stress. One pronounced change was in a subgroup of Müller glia (MG) that was dominant in the peripheral retina. Genes more abundantly expressed in peripheral MG were mainly associated with redox regulation, oxidative stress responses and cellular detoxification and were more influenced by oxidative insults, such as light-induced stress. In contrast, genes highly expressed in macular MG were primarily involved in cellular homeostasis and neuroprotection, showing less responsiveness to oxidative challenges. Notably, Metallothionein 1 (MT1), A-Kinase Anchor Protein 12 (AKAP12) and MAF BZIP Transcription Factor F (MAFF) were significantly more expressed in peripheral MG than in macular MG, indicating a region-specific redox regulatory mechanism. Knockdown of these genes in primary MG led to decreased viability under oxidative stress, suggesting their role in antioxidant defence. Our findings indicate that macular MG prioritise retinal function over redox adaptation, which may contribute to their vulnerability to degenerative diseases associated with oxidative damage. These insights underscore the importance of region-specific redox homeostasis in retinal health and disease.

Description:Objective: To compare the efficacy and safety of brolucizumab 6 mg and aflibercept 2 mg using an identical 4-week adjustment Treat-and-Extend regimen in patients with neovascular age-related macular degeneration (nAMD). Methods: Randomized, double-masked, multicenter, active-controlled, 2-arm, Phase IIIb study. Methods: Patients (N=737) with untreated, active choroidal neovascularization secondary to nAMD. Methods: Patients were randomized 1:1 to either brolucizumab 6 mg or aflibercept 2 mg with injections at Week 0, 4, 8, and 16 followed by 4-week interval adjustments depending on disease activity (DA) up to intervals of 16 weeks. After introduction of the urgent safety measure, patients requiring 4-week interval were discontinued from study treatment and moved to standard of care. Methods: Co-primary endpoints were distribution of last treatment interval with no DA at Week 32 and average change in best-corrected visual acuity (BCVA) from baseline to Week 28 and 32. Key secondary endpoints included average change from baseline in central subfield thickness (CSFT), presence of intraretinal fluid (IRF) and/or subretinal fluid (SRF), and sub-retinal pigment epithelium (RPE) fluid at Week 28 and 32. Safety endpoints included incidence of ocular and non-ocular adverse events (AEs), and AEs of special interest (AESIs). Results: Brolucizumab achieved superiority to aflibercept in the distribution of last interval with no DA at Week 32 (proportion of patients on 12-week treatment intervals: 38.5% vs 19.8%; 8 weeks: 35.8% vs 39.9%; 4 weeks: 25.7% vs 40.2%, respectively; P<0.0001) and non-inferiority to aflibercept for LS mean difference in average change in BCVA from baseline at Week 28 and 32 (+5.2 vs +5.1; P<0.0001). LS mean difference in average change in CSFT (μm) from baseline at Weeks 28 and 32 (brolucizumab -172.8 vs aflibercept -142.5) was -30.3 (P=0.002). Fewer brolucizumab vs aflibercept patients had IRF and/or SRF and sub-RPE fluid. Incidences of ocular AEs, serious ocular AEs, and AESIs in the brolucizumab vs aflibercept arms were 29.2% vs 26.1%, 2.5% vs 0.5%, and 5.5% vs 1.1%, respectively. Conclusions: In TALON, more brolucizumab-treated patients achieved longer treatment interval without DA than aflibercept with comparable visual gains. Brolucizumab showed improved anatomical outcomes and demonstrated an overall favorable benefit/risk profile.