Comparative assessment of subretinal hyper-reflective material in patients treated with brolucizumab versus aflibercept in HAWK and HARRIER.

PURPOSE: Post hoc analysis of the phase III HAWK and HARRIER studies to compare the reductions in subretinal hyper-reflective material (SHRM) thickness following brolucizumab 6 mg or aflibercept 2 mg treatment and to assess SHRM thickness and thickness variability as a potential biomarker of visual outcomes in patients with neovascular age-related macular degeneration (nAMD). METHODS: Optical coherence tomography images from the brolucizumab (n=700) and aflibercept (n=696) arms were analysed for the maximum SHRM thickness across the macula over 96 weeks. In a pooled treatment-agnostic analysis, the effect of week 12 SHRM thickness and SHRM thickness variability on best-corrected visual acuity (BCVA) through week 96 were also assessed. RESULTS: Brolucizumab was associated with numerically higher percentage reductions from baseline in SHRM thickness versus aflibercept in all patients (week 96: 54.4% vs 47.6%, respectively) and also in the matched subgroups with disease activity at week 16 (week 96: 51.6% vs 33.8%, respectively). In eyes with lower SHRM measurements at week 12, mean BCVA gains from baseline were higher at week 96 (<200 µm, +6.47 Early Treatment Diabetic Retinopathy Study letters; ≥200 µm, +3.10 letters). Eyes with the lowest SHRM thickness variability from week 12 to week 96 showed the greatest mean BCVA gains from baseline (week 96: <12 µm, +7.42 letters; >71 µm, -2.95 letters). CONCLUSIONS: In HAWK and HARRIER, greater reductions in maximum SHRM thickness from baseline were observed with brolucizumab compared with aflibercept. Furthermore, the data suggest that SHRM thickness postloading and SHRM thickness variability over time are biomarkers for visual outcomes in patients with nAMD.

Potential for Treatment Interval Extension in Eyes with nAMD Disease Activity Post Loading Phase in HAWK and HARRIER.

INTRODUCTION: The HAWK and HARRIER studies evaluated the efficacy and safety of brolucizumab versus aflibercept in treatment-naïve eyes with neovascular age-related macular degeneration. Based on the study design, brolucizumab-treated eyes adjusted to a q8w regimen because the presence of disease activity (DA) at the end of the matched loading phase (Week 16) could not subsequently extend to a q12w interval. The aim of this post hoc analysis was to assess subsequent DA in this subgroup to determine the potential for interval extensions during the first year of treatment. METHODS: Pooled data from the brolucizumab 6 mg arms and aflibercept arms of HAWK and HARRIER were included. Presence of DA was determined by the masked investigator based on their assessment of functional and anatomical parameters measured by optical coherence tomography. DA was compared at DA assessments, conducted at Weeks 16, 20, 32, and 44; fluid was also assessed at the primary analysis at Week 48. RESULTS: Fewer brolucizumab- (22.8%) than aflibercept-treated (32.2%) eyes had DA at the first DA assessment at Week 16. In eyes with investigator-identified DA at Week 16, BCVA change from baseline to Week 96 was comparable between treatment arms. Fewer brolucizumab- than aflibercept-treated eyes had DA at each subsequent DA assessment in Year 1: 31.8% vs 39.1% (Week 20), 27.3% vs 43.5% (Week 32), and 17.3% vs 31.2% (Week 44). Fewer eyes treated with brolucizumab than aflibercept had intraretinal and/or subretinal fluid: 35.3% vs 43.5% (Week 20), 55.8% vs 69.6% (Week 32), 30.0% vs 43.1% (Week 44), and 48.6% vs 68.6% (Week 48). CONCLUSION: These findings indicate that, in eyes that still had DA 8 weeks after the final dose of loading phase, brolucizumab-treated eyes had improved fluid resolution and higher potential for treatment interval extension than aflibercept-treated eyes during the first year of treatment.

Efficacy and safety of brolucizumab versus aflibercept in eyes with early persistent retinal fluid: 96-week outcomes from the HAWK and HARRIER studies.

OBJECTIVE: Post-hoc analysis to compare the outcomes of brolucizumab 6 mg vs. aflibercept 2 mg in neovascular age-related macular degeneration (nAMD) patients with early persistent retinal fluid in HAWK and HARRIER. METHODS: After 3 monthly loading doses, brolucizumab-treated eyes (N = 730) received injections every 12 weeks (q12w) or q8w if disease activity was detected. Aflibercept-treated eyes (N = 729) received fixed q8w dosing. Early persistent fluid was defined as the presence of subretinal fluid and/or intraretinal fluid up to Week 12. RESULTS: A lower proportion of brolucizumab patients had early persistent retinal fluid compared with aflibercept (11.2% (n = 82) vs. 19.2% (n = 140)). In these patients, 34.1% of the brolucizumab-treated group achieved a ≥ 15 ETDRS letter gain in best corrected visual acuity (BCVA) from baseline at Week 96 compared with 20.7% of the aflibercept-treated group. Brolucizumab achieved numerically better BCVA outcomes (Week 96: brolucizumab, +6.4 letters; aflibercept, +3.7 letters) and significantly greater central subfield thickness reductions versus aflibercept from baseline through Week 96 (Week 96: -202 µm vs. -145 µm; p = 0.0206). Brolucizumab demonstrated an overall favourable benefit/risk profile in this patient cohort. In their unmasked, post-hoc review, the Safety Review Committee identified two cases of retinal vasculitis and no cases of retinal vascular occlusion in the brolucizumab arm; no cases of retinal vasculitis or retinal vascular occlusion were identified in the aflibercept arm. CONCLUSION: In this analysis, anatomical and visual outcomes were better with brolucizumab compared with aflibercept. Brolucizumab may therefore achieve greater disease control than aflibercept in nAMD patients with early persistent retinal fluid.

Fluid Control in Neovascular Age-Related Macular Degeneration with Brolucizumab: An Analysis of the HAWK and HARRIER Phase 3 Trials.

INTRODUCTION: Neovascular age-related macular degeneration (nAMD) is characterized by exudation of fluid from abnormally growing blood vessels in the macula. Anti-vascular endothelial growth factor (VEGF) therapy is standard treatment for nAMD. Fluid resolution is used both as an indicator of disease control and to guide the frequency of treatment because of anti-VEGF therapy effectiveness in reducing neovascularization-related exudation. Herein reports a post hoc assessment of the HAWK and HARRIER trials comparing the efficacy and safety of brolucizumab with aflibercept in patients with nAMD. MATERIALS AND METHODS: HAWK randomized 1,078 patients with untreated, active choroidal neovascularization due to AMD in the study eye to receive brolucizumab 3, 6 mg or aflibercept 2 mg. In HARRIER, 739 patients received brolucizumab 6 mg or aflibercept 2 mg. Brolucizumab was injected at weeks 0, 4, and 8, and thereafter q12w unless disease activity was identified (injection interval: q8w). Aflibercept was injected q8w after the loading phase, aligned with approved dosing at study initiation. The objective of this analysis was to assess effects of brolucizumab versus aflibercept on retinal fluid resolution during two phase 3 trials (HAWK and HARRIER) in patients with nAMD. Anatomical assessments for intraretinal fluid (IRF) and subretinal fluid (SRF) were performed every 4 weeks by spectral domain optical coherence tomography. Sustained dryness was defined as a patient being fluid-free (SRF and IRF) on ≥3 consecutive visits. Time to sustained dryness was determined by Kaplan-Meier estimates. RESULTS: At week 96, fluid resolution (absence of IRF and SRF) was achieved by more brolucizumab- (6 mg; 76.1%) versus aflibercept-treated patients (63.1%; p = 0.0002, HAWK); 75.4% versus 61.8% (p < 0.0001, HARRIER). More patients achieved sustained dryness with brolucizumab versus aflibercept: at 96 weeks, 87.9% (brolucizumab 3 mg) and 86.1% (brolucizumab 6 mg) versus 82.0% (aflibercept) in HAWK, and 91.2% (brolucizumab) versus 78.0% (aflibercept) in HARRIER. Sustained dryness was achieved faster and hence with fewer brolucizumab injections. DISCUSSION/CONCLUSION: Brolucizumab dried the macula in patients with nAMD faster and to a greater degree than aflibercept. Achieving sustained dryness faster, and therefore with fewer injections, provides an opportunity for earlier decisions relating to treatment interval extension potentially reducing treatment burden.

A Randomized, Double-Masked, Multicenter Trial of Topical Acrizanib (LHA510), a Tyrosine Kinase VEGF-Receptor Inhibitor, in Treatment-Experienced Subjects With Neovascular Age-Related Macular Degeneration.

PURPOSE: To evaluate whether topical acrizanib (LHA510), a small-molecule vascular endothelial growth factor receptor inhibitor, could suppress the need for anti-vascular endothelial growth factor therapy over a 12-week period in patients with neovascular age-related macular degeneration. DESIGN: A phase 2 multicenter randomized double-masked, vehicle-controlled proof-of-concept study. METHODS: Trial includes n = 90 patients with active choroidal neovascularization due to neovascular age-related macular degeneration and under anti-vascular endothelial growth factor treatment. All patients received an intravitreal injection of ranibizumab at baseline and were retreated when there was evidence of disease recurrence (rescue). Patients were randomized 1:1 to receive topical LHA510 or vehicle for 12 weeks. Drops were administered twice a day for 8 weeks and then 3 times a day for the last 4 weeks. MAIN OUTCOME MEASURE: The primary outcome was the number of patients requiring rescue over 84 days of topical dosing. Key secondary outcome measures were time to first rescue, total number of ranibizumab injections, changes in central subfield thickness, and changes of visual acuity from baseline to day 84. RESULTS: The extended per protocol set included 70 patients of whom 25 of 33 patients in the LHA510 group (75.8%) and 25 of 37 patients in the placebo group (67.6%) required rescue by day 84 (P = .8466). Secondary and subgroup analysis did not support evidence of efficacy. Twenty-one of 46 patients administered LHA510 developed a reversible corneal haze that resolved with cessation of treatment and did not recur in patients restarted at once daily frequency. CONCLUSION: In spite of extensive optimization for topical efficacy, LHA510 failed to demonstrate clinical efficacy.

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.

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.

Efficacy and safety of brolucizumab versus aflibercept in eyes with polypoidal choroidal vasculopathy in Japanese participants of HAWK.

PURPOSE: To compare the efficacy and safety of brolucizumab versus aflibercept in eyes with polypoidal choroidal vasculopathy (PCV) over 96 weeks in the HAWK study. DESIGN: HAWK was a global, 2-year, randomised, double-masked, multicentre phase III trial in participants with neovascular age-related macular degeneration. METHODS: Of the Japanese participants with PCV, 39 received brolucizumab 6 mg and 30 received aflibercept 2 mg. After 3 monthly loading doses, brolucizumab-treated eyes received an injection every 12 weeks (q12w) but were adjusted to q8w if disease activity was detected. Aflibercept-treated eyes received fixed q8w dosing. Mean change in best-corrected visual acuity (BCVA), the proportion of participants on q12w, retinal thickness, retinal fluid changes and safety were assessed to Week 96. RESULTS: Mean change in BCVA (early treatment diabetic retinopathy study (ETDRS) letters) from baseline to week 48/week 96 was+10.4/+11.4 for brolucizumab and +11.6/+11.1 for aflibercept. For brolucizumab-treated eyes, the probability of only q12w dosing after loading through week 48 was 76%, and 68% through week 96. Fluid resolution was greater with brolucizumab than aflibercept: respective proportions of eyes with intraretinal fluid and/or subretinal fluid were 7.7% and 30% at week 48% and 12.8% and 16.7% at week 96. Brolucizumab exhibited an overall well-tolerated safety profile despite a higher rate of intraocular inflammation compared with aflibercept. CONCLUSION: In Japanese eyes with PCV, brolucizumab q12w/q8w monotherapy resulted in robust and consistent BCVA gains that were comparable to q8w aflibercept dosing. Anatomical outcomes favoured brolucizumab over aflibercept, with 76% of brolucizumab participants maintained on q12w dosing after loading to week 48.

HAWK and HARRIER: Ninety-Six-Week Outcomes from the Phase 3 Trials of Brolucizumab for Neovascular Age-Related Macular Degeneration.

PURPOSE: To report the 96-week outcomes from HAWK and HARRIER. DESIGN: Phase 3, prospective, randomized, double-masked, multicenter studies comparing efficacy and safety of brolucizumab 3 mg (HAWK only) and 6 mg with aflibercept 2 mg in eyes with neovascular age-related macular degeneration (nAMD). PARTICIPANTS: Treatment-naïve eyes with nAMD were randomized 1:1:1 to brolucizumab 3 mg (n = 358), brolucizumab 6 mg (n = 360), aflibercept 2 mg (n = 360; HAWK) or 1:1 to brolucizumab 6 mg (n = 370), aflibercept 2 mg (n = 369; HARRIER). METHODS: After 3 monthly loading doses, brolucizumab patients received every (q)-12-week (w) dosing, possibly adjusting to q8w dosing if disease activity was present at predefined disease activity assessment (DAA) visits. Aflibercept was dosed in a fixed q8w regimen. Visual and anatomic parameters were assessed throughout. Primary end point was at week 48 (48w), confirmed at 96w. MAIN OUTCOME MEASURES: Mean best-corrected visual acuity (BCVA) change from baseline, proportion of patients on an q12w regimen, retinal thickness, retinal fluid changes, and safety, all to 96w. RESULTS: Mean change (least squares [LS] mean ± standard error) in BCVA from baseline to 96w in HAWK was 5.6±0.79 Early Treatment Diabetic Retinopathy Study (ETDRS) letters for brolucizumab 3 mg, 5.90±0.78 letters for brolucizumab 6 mg, and 5.3±0.78 letters for aflibercept and in HARRIER was 6.1±0.73 letters for brolucizumab 6 mg and 6.6 ± 0.73 letters for aflibercept. Greater central subfield thickness reductions were observed with brolucizumab 6 mg versus aflibercept in HAWK (LS mean, -174.8 µm vs. -148.7 µm; 95% confidence interval for treatment difference, -46.2 to -5.9 µm; P = 0.0115) and HARRIER (LS mean, -197.7 µm vs. -155.1 µm; 95% confidence interval for treatment difference, -62.0 to -23.3 µm; P < 0.0001). The proportions of eyes with intraretinal fluid and/or subretinal fluid (IRF/SRF) at 96w in HAWK were 31% (P = 0.0688) and 24% (P = 0.0002) for brolucizumab 3 mg and 6 mg and 37% for aflibercept, whereas in HARRIER, they were 24% for brolucizumab 6 mg (P < 0.0001) and 39% for aflibercept. At 92w (last DAA), a 45.4% and 38.6% probability was observed for brolucizumab 6 mg patients of maintaining an q12w treatment regimen in HAWK and HARRIER, respectively. Brolucizumab exhibited an overall well-tolerated safety profile. CONCLUSIONS: Visual outcomes from 48w to 96w confirm the efficacy achieved at 48w. Brolucizumab demonstrated greater fluid resolution compared with aflibercept. The q12w potential for brolucizumab observed at 48w was maintained to 96w.

Pharmacokinetics and Safety of Travoprost 0.004% Ophthalmic Solution Preserved with Polyquad in Pediatric Patients with Glaucoma.

PURPOSE: To evaluate the systemic pharmacokinetics (PKs) of travoprost 0.004% preserved with Polyquad® (TRAVATAN®) in pediatric patients with glaucoma or ocular hypertension. METHODS: This was a phase 1, open-label, multicenter clinical study of patients aged ≥2 months to <18 years. Patients received daily administration of travoprost 0.004% preserved with Polyquad in both eyes for 7 days. Plasma samples were collected 30 min before the final dose and at 10, 20, 40, and 80 min postdose. The main outcome measure was maximum concentration of travoprost free acid in plasma (Cmax). RESULTS: Included in the PK analysis were 24 patients (average age 9.6 ± 4.9 years). At least 1 sample with quantifiable levels of travoprost free acid was collected for 11 patients. The mean Cmax was 0.0471 ± 0.0105 ng/mL for patients aged 2 months to <3 years; 0.0258 ± 0.0128 ng/mL for ages 3 to <12 years; and 0.0109 ± 0.0005 ng/mL for ages 12 to <18 years. Travoprost was undetectable in samples collected predose from pediatric patients. Treatment-related adverse events (AEs) included hyperemia, eye pain, and eye pruritus (n = 1 each). There were no discontinuations or drug-related serious AEs. CONCLUSIONS: Travoprost free acid concentration in plasma was low in pediatric patients, detectable in only 11 of 24 patients. There was no accumulation of travoprost over the course of treatment. No clear relationship was observed between age/body surface area and Cmax. No increased risk was identified for the use of travoprost 0.004% preserved with Polyquad in patients <18 years of age.