HAWK and HARRIER

Abstract

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 ¼ 358), brolucizumab 6 mg (n ¼ 360), aflibercept 2 mg (n ¼ 360; HAWK) or 1:1 to brolucizumab 6 mg (n ¼ 370), aflibercept 2 mg (n ¼ 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 AE standard error) in BCVA from baseline to 96w in HAWK was 5.6AE0.79 Early Treatment Diabetic Retinopathy Study (ETDRS) letters for brolucizumab 3 mg, 5.90AE0.78 letters for brolucizumab 6 mg, and 5.3AE0.78 letters for aflibercept and in HARRIER was 6.1AE0.73 letters for brolucizumab 6 mg and 6.6 AE 0.73 letters for aflibercept. Greater central subfield thickness reductions were observed with brolucizumab 6 mg versus aflibercept in HAWK (LS mean, À174.8 mm vs. À148.7 mm; 95% confidence interval for treatment difference, e46.2 to e5.9 mm; P ¼ 0.0115) and HARRIER (LS mean, e197.7 mm vs. e155.1 mm; 95% confidence interval for treatment difference, e62.0 to e23.3 mm; P < 0.0001). The proportions of eyes with intraretinal fluid and/or subretinal fluid (IRF/SRF) at 96w in HAWK were 31% (P ¼ 0.0688) and 24% (P ¼ 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.

Inflammatory Complications of Intravitreal Anti-VEGF Injections

“…Underlying cardiovascular disease (e.g., hypertension, diabetes mellitus, cardiac arrhythmia) may be a risk factor for BARV. All patients who experience occlusive vasculitis in the HARRIER and HAWK trials had underlying cardiovascular disease, and the same is true for the majority of patients in another retrospective case series [57,63]. Otherwise, no pattern of medical history, ocular history, or medication allergy has been identified [54,57,59,60].…”

“…Despite the Novartis safety committee's report, the exact incidence of BARV remains unknown. The expanded 96-week safety outcomes from the HAWK and HARRIER trials found that six of the 730 brolucizumab patients (0.8%) experienced intraocular inflammation-associated retinal artery occlusion or thrombosis [63]. A review of ASRS data indicated that 14 cases (11 of which were occlusive) had been voluntarily reported by providers out of the 46,000 brolucizumab injections that were administered in the United States to that date, suggesting an incidence of 3.0 cases per 10,000 injections [58] Similarly, post-market data from Novartis suggested the incidence of occlusive retinal vasculitis was 4.7 per 10,000 brolucizumab injections [64].…”

Brolucizumab: A Newly Developed Anti-VEGF Molecule for the Treatment of Neovascular Age-Related Macular Degeneration

“…The pivotal trials achieved their primary end point, with BCVA gains from baseline of +6.6 and +6.8 ETDRS letters (HAWK) and +6.9 and +7.6 ETDRS letters (HARRIER) with brolucizumab and aflibercept, respectively (Table 1). These vision gains were sustained up to week 96 in an analysis of the 2-year outcomes from the pivotal trials [30].…”

“…The superior reductions in CST from baseline observed with brolucizumab at week 16 were maintained at week 48 [7] and 96 [30], despite less frequent injections in the brolucizumab group. This is an important result, as variation in retinal thickness during anti-VEGF treatment was found to be associated with worse BCVA outcomes and the development of fibrosis in a recent analysis [13].…”

CRISPR Technology for Ocular Angiogenesis

“…Later studies led to the approval of aflibercept, which has demonstrated non-inferiority to ranibizumab for most of these indications, with the exception of DME in which aflibercept showed better short-term visual outcomes in eyes with poor baseline vision (Heier et al, 2014;Korobelnik et al, 2014a,b;Clark et al, 2016). The most recently-approved brolucizumab is the smallest (28 kDa) in size, and may exhibit greater durability due to the higher achievable therapeutic molar dose, but may also trigger more intraocular inflammation that could limits its wide adoption (Baumal et al, 2020;Dugel et al, 2020). Other anti-angiogenic pharmacotherapies under investigation include pegylated anti-VEGF designed ankyrin repeat proteins (abicipar pegol), antibodies against Tie-2 receptor ligands (faricimab, nesvacumab, ARP-1536), and PDGF antagonists (ranucumab, X-82) (Shen et al, 2014;Frye et al, 2015;Callanan et al, 2018;Sahni et al, 2019;Cohen et al, 2020;Heier et al, 2020;Khanani et al, 2020).…”