Two factors in the treatment of diabetic macular edema (DME) are widely known; persistence of fluid can reduce visual acuity outcomes, and monthly intravitreal injections are challenging for patients with multiple comorbidities. The promise of brolucizumab is that, with its low molecular weight, it can be given at 6 mg dosage, and so may act effectively in longer therapy intervals.
Prior studies show brolucizumab was comparable to aflibercept in reducing retinal fluid for patients with neovascular age-related macular degeneration (nAMD). Now, data published in the American Journal of Ophthalmology shows results of a multi-center phase III trial which demonstrates its efficacy at 52 weeks for the treatment of DME.
Two 100-week trials began mid-2018; KESTREL is taking place at 118 centers (ClinicalTrials.gov Identifier: NCT03481634), and KITE at 79 sites (ClinicalTrials.gov Identifier: NCT03481660), both conducted internationally.
The 566 KESTREL participants were randomized 1:1:1 into 3 arms: brolucizumab 3 mg, brolucizumab 6 mg, or aflibercept 2 mg, and 360 individuals in KITE were assigned 1:1 to brolucizumab 6 mg or aflibercept 2 mg. After 5 loading doses 6 weeks apart for brolucizumab and 4 weeks for aflibercept, a masked investigator assessed participants at weeks 32, 36, and 48. Aflibercept injections followed a fixed 8-week maintenance schedule, and brolucizumab a 12-week target, unless the disease activity assessment indicated an earlier 8-week need.
More than 50% of those treated with brolucizumab 6 mg in either trial were effectively managed on a 12-week maintenance regimen for one year. The resulting median number of injections across 52 weeks was 7 in brolucizumab arms, and 9 for aflibercept fixed-interval groups.
At 52 weeks, KESTREL patients receiving brolucizumab 6 mg displayed best corrected visual acuity (BCVA), least squares mean estimate of +9.2 letters compared with +10.5 letters for aflibercept, and KITE participants undergoing brolucizumab had gains of +10.6 letters compared with aflibercept attaining +9.4 letters, after adjusting for baseline BCVA and age. Data for the 2 studies were pooled to compare diabetic retinopathy severity scale (DRSS) scores. Using a 10% non-inferiority margin, brolucizumab 6 mg was noninferior to aflibercept for the proportion of individuals reaching a ≥2 step-better DRSS score at 52 weeks (P <.001).
Structural results for the 2 anti-VEGFs showed a treatment difference of 13.4% in favor of brolucizumab 6 mg for maintaining central subfield thickness (CST) <280 μm in KESTREL, and 16.3% in KITE. Further, a treatment difference for participants with intra- or subretinal fluid was -13.2% in KESTREL’s brolucizumab 6 mg arm, and -18.4% in KITE’s brolucizumab cohort.
Serious ocular adverse events arose in KESTREL for 1.1% with brolucizumab 6 mg and 2.1% aflibercept, and in KITE, for 2.2% with brolucizumab and 1.7% aflibercept. AEs specifically scrutinized — intraocular inflammation (IOI), retinal vascular occlusion, or endophthalmitis occurred for 0% to 1.7% in each group, except mild to moderate IOI was experienced by 3.7% in the KESTREL brolucizumab 6 mg cohort, and 4.7% in the 3 mg set. Most IOI cases were mild to moderate and treated with no resulting sequelae.
The trials did not allow for adjustment between 8- and 12-week dosing schedules that would produce a “head-to-head” comparison of the two biologics, which is a limitation of the design. Strengths included masked image graders at a central reading center, and the first time a 6-week initial loading phase has been compared with other DME-prescribed anti-VEGFs’ typical protocol of 4 weeks.
Disclosures: The study was sponsored by Novartis AG. Several study authors disclosed affiliations with the biotech, pharmaceutical, and/or medical device industries. Please see the original reference for a full list of authors’ disclosures.
Brown DM, Emanuelli A, Bandello F, et al. KESTREL and KITE: 52-week results from two phase III pivotal trials of brolucizumab for diabetic macular edema. Am J Ophthalmol. Published online January 13, 2022. doi:10.1016/j.ajo.2022.01.004