IMPACT OF RETINAL FLUID-FREE MONTHS ON OUTCOMES IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: A Treatment Agnostic Analysis of the HAWK and HARRIER Studies.

PURPOSE: To assess the effect of the total number of fluid-free months after loading on visual and anatomical outcomes in neovascular age-related macular degeneration patients receiving anti-vascular endothelial growth factor therapy. METHODS: This post hoc analysis pooled patient-level data from the brolucizumab 6 mg (n = 718) and aflibercept 2 mg (n = 715) arms of the HAWK and HARRIER randomized clinical trials. Based on data from Weeks 12 to 96, patients were assigned to one of five categories based on fluid-free visits (FFVs; the total number of monthly visits at which they were observed to be without retinal fluid). Three definitions of "fluid-free" were explored based on the location of the fluid observed. RESULTS: Patients allocated to Categories 4 (15-21 FFV) and 5 (22 FFV, always dry) consistently had the best visual and anatomical outcomes at Week 96, whereas patients allocated to Categories 1 (0 FFV, never dry) and 2 (1-7 FFV) consistently had the worst visual and anatomical outcomes. Variability in retinal thickness over time was lowest in Categories 4 and 5. CONCLUSION: Absence of retinal fluid at more visits after loading has a positive association with visual and anatomic outcomes in neovascular age-related macular degeneration patients, regardless of fluid type.

Brolucizumab 12- and 16-Week Fixed Dosing Potential in Neovascular AMD: A post hoc Evaluation of Data from the HAWK and HARRIER Trials.

INTRODUCTION: This post hoc analysis applies a fixed dosing stratification approach to patient-level brolucizumab data from the phase III HAWK and HARRIER trials to determine the proportion of patients who would have been assigned to fixed dosing regimens with treatment intervals of 8, 12, or 16 weeks (q8w, q12w, or q16w) based on the presence/absence of disease activity (DA) following the loading phase. The analysis also simulates central subfield thickness (CSFT) data to estimate the anatomical outcomes if the patients had been thus assigned. Of note, the limitations of this analysis include the post hoc nature of the work and the inability to directly compare HAWK and HARRIER with TENAYA and LUCERNE due to the differences in design. DESIGN: This study was a post hoc modelling analysis of patient-level data. METHODS: Using patient-level data from HAWK and HARRIER, patients (n = 730) were allocated to a fixed q16w, q12w, or q8w regimen based on assessment of DA at weeks 16 and 20. Two definitions of DA were used: DA 1, based on a phase II study of faricimab, and DA 2, a definition derived from common clinical consideration including visual acuity and anatomical changes. CSFT simulations were performed using a pharmacokinetic/pharmacodynamic model describing CSFT response to anti-VEGF treatment. Outcome measures were modelled patient allocation to fixed regimens and mean CSFT reduction. RESULTS: Using DA definitions 1 and 2, respectively, 78% and 76% of patients in the brolucizumab arm were allocated to a greater than or equal to q12w regimen, and 56% and 52% were allocated to a q16w regimen. Mean reduction in CSFT was similar between the two study drugs with both DA definition assumptions. CONCLUSIONS: This analysis demonstrates the potential durability of action and effectiveness of brolucizumab.

Spinal neurenteric cysts: Associated developmental anomalies and rationale of surgical approaches.

BACKGROUND: Neurenteric cysts (NC) occur due to failure of separation of neurectoderm from endoderm at the 3rd week of embryogenesis. This study focuses on key clinico-radiological features of NCs, with emphasis on surgical nuances involved in resecting anteriorly placed NC, especially at the foramen magnum (FM). METHOD: Sixteen consecutive patients having a spinal NC were included. Their clinico-radiological status, surgical nuances and follow-up status were noted. RESULTS: The duration of spasticity/paraparesis/quadriparesis ranged from 15 days to 48 months. Twelve patients had an intradural extramedullary (IDEM; nine anterior and three anterolateral) cyst and four had an intramedullary (IM) cyst. Six of them had an anteriorly placed FM lesion (five IDEM and one IM). Amongst ten subaxial NCs, four were anterior, two antero-lateral and one postero-lateral; three were IM. Three patients had the characteristic stigmata of occult spinal dysraphism: two, a large mesenteric cyst, and one, a posterior mediastinal cyst. Excision was total in 13 patients. Subtotal excision of tumour capsule was performed for two recurrent cysts and an IM cyst. A far lateral approach was adopted for anteriorly placed FM lesions and posterior laminectomy for subaxial lesions. Histopathology revealed eight type A cysts, four type B cysts and four type C cysts. At follow-up (range, 8 months to 12 years; median, 60 ± 45.84 months), complete neurological recovery occurred in seven patients; six patients had persistent spasticity but only minor disability; two patients had difficulty in walking; and one patient with an anteriorly placed thoracic recurrent NC had sustained neurological deterioration. CONCLUSIONS: Surgical difficulties in addressing NCs are related to their anterior or IM location, presence of adhesions and inability to dissect the tumour capsule from the spinal cord due to fibrous or lipomatous connections. The associated developmental anomalies must be specifically sought and addressed.

Antivascular endothelial growth factor agents for wet age-related macular degeneration: an IRIS registry analysis.

OBJECTIVE: To evaluate treatment patterns and outcomes of patients in the United States who received antivascular endothelial growth factor (anti-VEGF) agents for wet age-related macular degeneration (AMD). DESIGN: Retrospective study PARTICIPANTS: Patients with wet AMD. METHODS: Using the Intelligent Research in Sight Registry, we studied patients with wet AMD who received ≥1 anti-VEGF injection, who were ≥50 years old, and with ≥1.5 years of follow-up. Patients were grouped based on follow-up duration (in years): ≥1.5 (cohort 1), ≥2.5 (cohort 2), and ≥3.5 (cohort 3). RESULTS: Patient characteristics were similar between treatment groups. 36.8%, 34.5%, and 39.2% of ranibizumab, aflibercept, and all anti-VEGF eyes, respectively, had an injection interval <8 weeks in length at the end of year 1. Results were similar at year 2 and 3. In cohorts 1-3, visual acuity (VA) changes from baseline ranged from 0.3 to 0.7 (year 1), -1.3 to -1.7 (year 2), and -2.8 to -3.1 (year 3) Early Treatment Diabetic Retinopathy Study letters. By the end of year 3, 41%, 39%, and 42% of ranibizumab, aflibercept, and all anti-VEGF eyes, respectively, had discontinued treatment (no injection for >6 months). CONCLUSION: Approximately one-third of eyes had injection intervals <8 weeks in length at the end of year 1. VA was slightly better at the end of year 1 and declined after the first year despite treatment. By the end of year 3, more than one-third of eyes had discontinued treatment. Given the high treatment burden, wet AMD patients may benefit from more durable approaches that require less frequent dosing.

Efficacy Outcomes of Brolucizumab Versus Aflibercept in Neovascular Age-Related Macular Degeneration Patients with Early Residual Fluid.

OBJECTIVE: To compare the outcomes of brolucizumab versus aflibercept in patients with neovascular age-related macular degeneration with early residual fluid in the HAWK and HARRIER studies. DESIGN: Post hoc analysis using pooled data from the phase 3 studies HAWK (NCT02307682) and HARRIER (NCT02434328). PARTICIPANTS: The early residual fluid cohort for this post hoc analysis consisted of patients treated with either brolucizumab 6 mg (n = 730 patients) or aflibercept 2 mg (n = 729 patients) and who had the presence of intraretinal fluid (IRF), subretinal fluid (SRF), or both verified by spectral-domain OCT at the week 12 clinic visit. METHODS: After 3 initial monthly doses, patients treated with brolucizumab received injections every 12 weeks (q12w) or every 8 weeks (q8w), depending on the neovascular age-related macular degeneration disease activity, whereas patients treated with aflibercept received fixed q8w dosing. MAIN OUTCOME MEASURES: The mean change in best-corrected visual acuity and central subfield thickness (CST) from the baseline to that at weeks 48 and 96, the proportion of patients treated with brolucizumab remaining on q12w dosing to week 96, and the change in fluid status at weeks 48 and 96. RESULTS: All analyses were based on 149 of 730 (20.4%) patients treated with brolucizumab and 217 of 729 (29.8%) patients treated with aflibercept with spectral-domain OCT-verified IRF, SRF, or both at their week 12 visit. The best-corrected visual acuity improvements from baseline at weeks 48 and 96 were numerically better for brolucizumab than for aflibercept (least square mean [standard error] 7.9 ± 1.1 vs. 4.6 ± 0.9 and 7.4 ± 1.3 vs. 2.9 ± 1.1 letters, respectively). The CST reductions from baseline at weeks 48 and 96 were consistently greater with brolucizumab than with aflibercept (least square mean [standard error], µm: -194.9 ± 13.7 vs. -123.9 ± 11.3; and -201.1 ± 14.5 vs. -134.2 ± 12.0, respectively). At weeks 48 and 96, patients treated with brolucizumab had a 40.4% and 31.3% probability of remaining on q12w dosing intervals, respectively. Fewer patients treated with brolucizumab had remaining IRF, SRF, or both at weeks 48 and 96 than patients treated with aflibercept (59.1% vs. 75.1% and 49.0% vs. 60.4%, respectively). CONCLUSIONS: In patients with early residual fluid, defined as spectral-domain OCT-verified IRF, SRF, or both at the week 12 clinic visit, brolucizumab resolved the early residual fluid and reduced CST more effectively than aflibercept, resulting in greater best-corrected visual acuity improvements through week 96 of anti-VEGF treatment.

Early Residual Fluid-Free Status and Long-Term BCVA Outcomes: A Treatment Agnostic, Post Hoc Analysis of Pooled HAWK and HARRIER Data.

PURPOSE: The aim of this study was to determine associations between early residual fluid (ERF)-free status and improved long-term visual outcomes. DESIGN: This was a retrospective clinical cohort study from a post hoc analysis of 2 phase III clinical trials' data. METHODS: Independent of treatment allocation, patients from the multicenter, prospective, randomized, double-masked HAWK and HARRIER trials who received either brolucizumab 6 mg or aflibercept 2 mg were split into 2 cohorts depending on the presence or absence of ERF at week 12. In addition, similar analyses were performed on the presence or absence of early residual intraretinal fluid (IRF) and subretinal fluid (SRF) at week 12. The 2 groups, ERF-free (n = 1051) and ERF (n = 366) patients were compared. Changes from baseline in best corrected visual acuity (BCVA) and central subfield thickness (CST) were determined. RESULTS: From week 12 to 96, patients who were ERF free had greater least squares (LS) mean increases from baseline for BCVA and CST compared to ERF patients. Greater LS mean differences in BCVA from week 12 to 96 were noted between ERF-free and ERF patients. A greater proportion of patients in the ERF-free cohort reported a ≥5, ≥10, or ≥15 letter improvement, and a higher proportion reported BCVA ≥70 letters from baseline to week 96 compared to patients with fluid. CONCLUSIONS: Improvements in visual outcomes in ERF-free patients were greater than in ERF patients occurring as early as 4 weeks (week 12) after the last loading dose and continued to week 96. Therefore, ERF status may be a useful indicator of anti-vascular endothelial growth factor treatment response.

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

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.

Anti-VEGF Treatment Patterns in Patients With Wet Age-Related Macular Degeneration in Clinical Practice.

BACKGROUND AND OBJECTIVE: To characterize on-label anti-vascular endothelial growth factor (VEGF) treatment patterns in patients with wet age-related macular degeneration (AMD) in clinical practice in the U.S. PATIENTS AND METHODS: Retrospective cohort analysis using administrative claims data from the IQVIA Open Source Databases. Treatment-naïve patients in the U.S. who received one or more wet AMD-related anti-VEGF injection from July 1, 2013, to April 30, 2017, were included. The main outcome was the injection interval closest to Month 12. RESULTS: This study included 21,960 patients who initiated an anti-VEGF agent (ranibizumab, aflibercept, or bevacizumab): 5,489 initiated aflibercept and 4,253 initiated ranibizumab. Among ranibizumab, aflibercept, and all anti-VEGF eyes, 38.1% (n = 2,035), 33.5% (n = 3,262), and 40.0% (n = 12,505) of patient eyes had injection intervals of less than 8 weeks, respectively, at Month 12 with the mean (standard deviation) number of injections over 12 months being 8.0 (2.4), 7.6 (2.4), and 7.8 (2.5). CONCLUSION: A substantial proportion of patients receive injections more frequently than every 8 weeks within the first year of treatment. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:263-272.].