HAWK and HARRIER: Phase 3, Multicenter, Randomized, Double-Masked Trials of Brolucizumab for Neovascular Age-Related Macular Degeneration.

PURPOSE: Two similarly designed phase 3 trials (HAWK and HARRIER) compared brolucizumab, a single-chain antibody fragment that inhibits vascular endothelial growth factor-A, with aflibercept to treat neovascular age-related macular degeneration (nAMD). DESIGN: Double-masked, multicenter, active-controlled, randomized trials. PARTICIPANTS: Patients (N = 1817) with untreated, active choroidal neovascularization due to age-related macular degeneration in the study eye. INTERVENTION: Patients were randomized to intravitreal brolucizumab 3 mg (HAWK only) or 6 mg or aflibercept 2 mg. After loading with 3 monthly injections, brolucizumab-treated eyes received an injection every 12 weeks (q12w) and were interval adjusted to every 8 weeks (q8w) if disease activity was present; aflibercept-treated eyes received q8w dosing. MAIN OUTCOME MEASURES: The primary hypothesis was noninferiority in mean best-corrected visual acuity (BCVA) change from baseline to Week 48 (margin: 4 letters). Other key end points included the percentage of patients who maintained q12w dosing through Week 48 and anatomic outcomes. RESULTS: At Week 48, each brolucizumab arm demonstrated noninferiority to aflibercept in BCVA change from baseline (least squares [LS] mean, +6.6 [6 mg] and +6.1 [3 mg] letters with brolucizumab vs. +6.8 letters with aflibercept [HAWK]; +6.9 [brolucizumab 6 mg] vs. +7.6 [aflibercept] letters [HARRIER]; P < 0.001 for each comparison). Greater than 50% of brolucizumab 6 mg-treated eyes were maintained on q12w dosing through Week 48 (56% [HAWK] and 51% [HARRIER]). At Week 16, after identical treatment exposure, fewer brolucizumab 6 mg-treated eyes had disease activity versus aflibercept in HAWK (24.0% vs. 34.5%; P = 0.001) and HARRIER (22.7% vs. 32.2%; P = 0.002). Greater central subfield thickness reductions from baseline to Week 48 were observed with brolucizumab 6 mg versus aflibercept in HAWK (LS mean -172.8 µm vs. -143.7 µm; P = 0.001) and HARRIER (LS mean -193.8 µm vs. -143.9 µm; P < 0.001). Anatomic retinal fluid outcomes favored brolucizumab over aflibercept. Overall, adverse event rates were generally similar with brolucizumab and aflibercept. CONCLUSIONS: Brolucizumab was noninferior to aflibercept in visual function at Week 48, and >50% of brolucizumab 6 mg-treated eyes were maintained on q12w dosing interval through Week 48. Anatomic outcomes favored brolucizumab over aflibercept. Overall safety with brolucizumab was similar to aflibercept (ClinicalTrials.gov; NCT02307682, NCT02434328).

Expanding the Phenotypic and Genotypic Spectrum of Bietti Crystalline Dystrophy.

The rare form of retinal dystrophy, Bietti crystalline dystrophy, is associated with variations in CYP4V2, a member of the cytochrome P450 family. This study reports patients affected by typical and atypical Bietti crystalline dystrophy, expanding the spectrum of this disease. This is an observational case series of patients with a clinical and molecular diagnosis of Bietti crystalline dystrophy that underwent multimodal imaging. Four unrelated patients are described with two known variants, c.802-8_810del17insGC and c.518T > G (p.Leu173Trp), and one novel missense variant, c.1169G > T (p.Arg390Leu). The patient with the novel homozygous variant had the most severe phenotype resulting in macular hole formation and retinal detachment in both eyes. To the best of our knowledge, there is no association of these features with Bietti crystalline dystrophy. Patient 1 was the youngest patient and had the mildest phenotype with crystals in the retina without chorioretinal atrophy and visual complaints. Patients 2 and 3 presented with fewer crystals and chorioretinal atrophy. These three patients presented a classic phenotype. The fourth patient presented with an atypical and severe phenotype. This study reveals a new genotype and new phenotype associated with this disorder.