Findings from a pair of phase 3 trials suggest that the new VEGF inhibitor brolucizumab is more effective than aflibercept at resolving retinal fluid in patients with wet AMD.
Study design
The authors describe 2 double-masked, multicenter, active-controlled, randomized trials, dubbed HAWK and HARRIER, comparing intravitreal brolucizumab 3 mg, brolucizumab 6 mg or aflibercept 2 mg in 1,817 patients with untreated, active choroidal neovascularization due to AMD.
After 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 at 12 weeks.
Aflibercept-treated eyes received q8w dosing throughout the study. The study was designed to test noninferiority in mean BCVA changes from baseline to week 48. The authors also tracked central foveal thickness and determined the percentage of patients who maintained q12w dosing through week 48.
The masked investigator assessed disease activity to identify eyes that required more frequent treatment at a q8w interval in the brolucizumab groups.
Outcomes
Brolucizumab was noninferior to aflibercept with regards to the average change in BCVA from baseline to week 48. In the HAWK trial, eyes treated with brolucizumab 3 mg or brolucizumab 6 mg gained 6.1 and 6.6 letters, respectively, compared with 6.8 letters among aflibercept-treated eyes (P<0.001 for all). In the HARRIER trial, eyes treated with brolucizumab 6 mg gained 6.9 letters, compared with 7.6 letters among aflibercept-treated eyes (P<0.001).
The proportion of study eyes that gained at least 15 letters of vision by week 48 was 25.2% (brolucizumab 3 mg), 33.6% (brolucizumab 6 mg) and 25.4% (aflibercept 2 mg) in the HAWK trial, and 29.3% and 29.9% (brolucizumab 6 mg and aflibercept 2 mg, respectively) in the HARRIER trial.
In brolucizumab-treated eyes, the likelihood of exclusively maintaining q12w dosing after loading through week 48 was 49.4% for 3 mg and 55.6% for 6 mg in the HAWK trial, and 51.0% for 6 mg in the HARRIER trial. Among eyes without disease activity during the first q12w interval, the probabilities for remaining on q12w dosing until week 48 increased to 80.9% (3 mg), 85.4% (6 mg in HAWK) and 81.7% (6 mg in HARRIER).
Greater central subfield thickness (CST) reductions from baseline to week 16 were observed among eyes treated with brolucizumab 6 mg versus aflibercept in both the HAWK (−161 vs −134 µm, P<0.001) and HARRIER (−174 vs −134 µm, P<0.001) trials; similar results were observed at week 48 in the HAWK (−173 vs −144 µm, P=0.001) and HARRIER (−194 vs −144 µm, P<0.001) trials.
Limitations
The studies do not directly compare aflibercept q12w dosing with brolucizumab q12w dosing.
Clinical significance
These studies reveal a noninferior improvement in visual acuity and a favorable anatomic response in treatment-naive patients with neovascular AMD who were treated with 8-week to 12-week dosing intervals of brolucizumab, compared with 8-week dosing intervals of aflibercept.
Only 49% to 56% of patients were able to maintain q12w dosing. However, 81% to -85% of those who initially achieved no disease activity after their first q12w dose were able to continue q12w dosing. The treatment is not currently FDA approved. Further studies comparing q12 week dosing of brolucizumab versus other currently available treatments will help assess brolucizumab's potential to decrease treatment burden.