HAWK and HARRIER
Citation: Dugel PU, Singh RP, Koh A, et al. Hawk and Harrier: Ninety-six-week outcomes from the phase 3 trials of brolucizumab for neovascular age-related macular degeneration. Ophthalmology. 2021;128(1):89-99.
- HAWK and HARRIER, sponsored by Alcon Research, was designed to compare intravitreal brolucizumab, with an adjustable dosing interval of 12 or 8 weeks, and intravitreal aflibercept, with a fixed dosing interval of 8 weeks, for the treatment of vision loss from neovascularization from age-related macular degeneration.
- Participants were randomized 1:1:1 to brolucizumab 3 mg, brolucizumab 6 mg, or aflibercept 2 mg (HAWK); and 1:1 to brolucizumab 6 mg or aflibercept 2 mg (HARRIER), being followed every 4 weeks for up to 96 weeks.
- Patients treated with intravitreal brolucizumab demonstrated noninferior change in best-corrected visual acuity (BCVA) and improved anatomic outcomes compared with those treated with intravitreal aflibercept at 96 weeks.
- Both brolucizumab and aflibercept were well tolerated with similar safety profiles except for increased incidence of intraocular inflammation with or without retinal vasculitis in eyes treated with brolucizumab.
To determine whether intravitreal brolucizumab at doses of 3 mg or 6 mg produces noninferior visual benefit and similar safety profile compared with intravitreal aflibercept 2 mg for the treatment of neovascular age-related macular degeneration (nAMD).
*In the FOCUS trial, all patients received PDT (no ranibizumab-only arm)
Two similarly designed, phase 3, multicenter, prospective, randomized, double-masked, interventional clinical trials
- Patients aged ≥ 50 years with treatment-naïve, active, central-subfield involving choroidal neovascularization lesions due to age-related macular degeneration with best corrected ETDRS visual acuity ≤ 78 (approximate Snellen equivalent, 20/32 or worse) and ≥ 23 (20/400 or better)
- Prior treatment for nAMD, central-subfield fibrosis or geographic atrophy, other visually significant ocular condition (e.g., infection, other retinal disease, uncontrolled glaucoma), vitreous hemorrhage within 4 weeks, recent surgery or panretinal photocoagulation, aphakia, uncontrolled hypertension, recent stroke or myocardial infarction.
RANDOMIZATION SCHEME AND INTERVENTIONS:
- Patients were randomized 1:1:1 to brolucizumab 3 mg, brolucizumab 6 mg, or aflibercept 2 mg (HAWK); or 1:1 to brolucizumab 6 mg or aflibercept 2 mg (HARRIER).
- Patients received a loading dose of either brolucizumab or aflibercept over a period of 3 months. Afterward, patients receiving brolucizumab were injected every 12-weeks and adjusted to every 8 weeks if they had active disease, while patients receiving aflibercept were injected every 8 weeks.
MAIN OUTCOME MEASURE:
- Demonstrate noninferior change in BCVA from baseline in response to intravitreal brolucizumab compared to intravitreal aflibercept.
- 1078 patients (HAWK) and 739 patients (HARRIER) with treatment-naïve nAMD.
- Participants were followed at 4-week intervals through week 96.
- A similar proportion of patients receiving brolucizumab 3 mg, brolucizumab 6 mg, and aflibercept 2 mg injections completed study treatment up to week 96.
- At 96 weeks, the mean change in BCVA from baseline was a gain of 5.6 ETDRS letters for brolucizumab 3 mg, 5.9 letters for brolucizumab 6 mg, and 5.3 letters for aflibercept 2 mg in HAWK; in HARRIER, the gain was 6.1 letters for brolucizumab 6 mg, and 6.6 letters for aflibercept 2 mg. These results demonstrate a noninferior mean change in BCVA amongst the brolucizumab group compared with the aflibercept group.
- In both HAWK and HARRIER, eyes treated with brolucizumab had greater central subfield thickness reductions and decreased proportion of ongoing intraretinal or subretinal fluid compared with eyes treated with aflibercept at 96 weeks.
- In HAWK and HARRIER, 45% and 39% of patients receiving brolucizumab 6 mg, respectively, were successfully maintained on the 12-week treatment regimen through week 92.
- The most common reported adverse event was conjunctival hemorrhage for brolucizumab 3 mg (11%), brolucizumab 6 mg (8%), and aflibercept 2 mg (9%) in HAWK; and reduced visual acuity for brolucizumab 6 mg (9%) and cataract for aflibercept 2 mg (12%) in HARRIER.
- Overall rates of adverse events was similar between brolucizumab and aflibercept treated eyes except for higher rates of intraocular inflammation (IOI), including iritis and uveitis, in eyes treated with brolucizumab (5%) compared with aflibercept (1%). The rate for IOI in HARRIER was <1% for both brolucizumab and aflibercept groups. Post hoc analyses of HAWK and HARRIER clinical trials by Monés et al. (Ophthalmology, 2020) found an incidence of 5% of IOI, 3% of IOI with vasculitis, and 2% of IOI with vasculitis and occlusion in brolucizumab treated eyes (compared with 1% incidence of IOI in aflibercept-treated eyes).
- In pooled HAWK and HARRIER analyses, about half of all IOI events occurred within the first 12 weeks of treatment in both brolucizumab and aflibercept treated eyes.
- A case series published by Baumal et al. (Ophthalmology, 2020) evaluated features of 15 eyes from 12 patients with evidence of IOI or retinal vasculitis following treatment with intravitreal brolucizumab 6 mg. All eyes had IOI with varying findings including segmental sheathing and discontinuity of both small and large retinal arteries, sclerosis of arteries, cotton-wool spots, and focal phlebitis. Fluorescein angiography (FA) demonstrated delayed retinal arterial filling, retinal vascular nonperfusion, and dye leakage from affected areas. Mean VA was reduced from a baseline of 0.426 logMAR (Snellen equivalent 20/53) to 0.833 logMAR (Snellen equivalent 20/136) after a mean follow-up of 25 days.
- A subsequent article by Baumal et al. (Ophthalmology Retina, 2020) provides recommendations for managing IOI, retinal vasculitis, and retinal occlusion following treatment with intravitreal brolucizumab, including early patient education regarding potential signs of IOI and use of multimodal imaging to assist in confirming the diagnosis (OCT, FA, widefield imaging). This article recommends immediate discontinuation of brolucizumab therapy and initiation of potent corticosteroids for confirmed IOI.
- In these randomized clinical trials, intravitreal brolucizumab was shown to be noninferior to intravitreal aflibercept for the treatment of vision loss from neovascularization in AMD. Nearly one-half of patients treated with brolucizumab were successfully maintained on a 12-week dosing interval, decreasing their burden of treatment. While brolucizumab was tolerated well with similar rates of adverse events compared with intravitreal aflibercept, patients treated with brolucizumab may be at increased risk of IOI, retinal vasculitis, and retinal occlusion; these patients should be monitored closely for these events, especially within the first few months of treatment.