Brolucizumab shows robust visual gains and anatomical improvements in patients with DME: AJO
Diabetic macular edema (DME) is a common microvascularcomplication in patients with diabetes, and has become the leading cause ofvision loss in the adult working population. In the diabetic retina,hyperglycemia and oxidative stress trigger an upregulation of vascularendothelial growth factor (VEGF), leading to a breakdown of the innerblood-retinal barrier and increased vascular permeability. Subsequent fluidleakage into the intraretinal layers causes swelling or thickening of themacula characteristic of DME and compromises visual function.
Despite the overall anatomical and functional improvementsachieved with anti-VEGF treatment, some patients continue to have persistentDME, despite continuous therapy. With the currently available anti-VEGFs,intensive treatment is often required to dry the macula as far as possible andachieve optimal treatment outcomes. However, patients with DME often experiencea high medical burden due to multiple comorbidities and real-world evidenceshows that this can result in high rates of noncompliance, under-treatment forDME and, in turn, lower visual gains.
Brolucizumab is a single-chain antibody fragment (scFv) thathas a high affinity for VEGF. Its low molecular weight (26 kDa) enablesdelivery of more drug per injection compared with other available anti-VEGFsand offers the potential for more effective tissue penetration and increasedduration of action.
The current study by David M. Brown and team reported theprimary 52-week outcomes of KESTREL and KITE studies to evaluate the efficacyand safety of brolucizumab in the treatment of patients with visual impairmentdue to DME.
They carried a double-masked, 100-week, multicenter, active-controlled,randomized trial. Subjects were randomized 1:1:1 to brolucizumab 3 mg/6 mg oraflibercept 2 mg in KESTREL (n = 566) or 1:1 to brolucizumab 6 mg oraflibercept 2 mg in KITE (n = 360). Brolucizumab groups received 5 loadingdoses every 6 weeks (q6w) followed by 12- week (q12w) dosing, with optionaladjustment to every 8 weeks (q8w) if disease activity was identified atpredefined assessment visits; aflibercept groups received 5 doses every 4 weeks(q4w) followed by fixed q8w dosing. The primary endpoint was best-correctedvisual acuity (BCVA) change from baseline at Week 52; secondary end pointsincluded the proportion of subjects maintained on q12w dosing, change inDiabetic Retinopathy Severity Scale score, and anatomical and safety outcomes.
At Week 52, brolucizumab 6 mg was noninferior (NI margin 4letters) to aflibercept in mean change in BCVA from baseline (KESTREL: +9.2letters vs +10.5 letters; KITE: +10.6 letters vs +9.4 letters; P < .001),more subjects achieved central subfield thickness (CSFT)< 280 µm, and fewerhad persisting subretinal and/or intraretinal fluid vs aflibercept, with morethan half of brolucizumab 6 mg subjects maintained on q12w dosing afterloading.
In KITE, brolucizumab 6 mg showed superior improvements inchange of CSFT from baseline over Week 40 to Week 52 vs aflibercept (P = .001).
The incidence of ocular serious adverse events was 3.7%(brolucizumab 3 mg), 1.1% (brolucizumab 6 mg), and 2.1% (aflibercept) inKESTREL; and 2.2% (brolucizumab 6 mg) and 1.7% (aflibercept) in KITE.
KESTREL and KITE met the primary endpoint of noninferiorityin BCVA change from baseline at Week 52 of brolucizumab 6 mg vs aflibercept,with >50% of brolucizumab 6 mg subjects being maintained on a q12w intervalthrough Week 52. Moreover, anatomical outcomes, as determined by CSFT reductionand retinal fluid resolution, favored brolucizumab 6 mg over aflibercept. Theincidence of ocular SAEs and AEs of special interest associated withbrolucizumab 6 mg were low in both studies, although the overall risk of IOI,retinal vasculitis, and retinal vascular occlusion were higher in brolucizumab treatedeyes compared with aflibercept-treated eyes.
Focusing on anatomical outcomes, lower proportions ofsubjects with retinal fluid were observed for brolucizumab compared withaflibercept at Week 32 and Week 52 in both studies. At Week 52, 13% to 18%fewer subjects had SRF and/or IRF in the brolucizumab 6 mg arm, which wasachieved with a median of 7 injections compared with 9 in the aflibercept arms.Already at Week 32, 8 weeks after an active injection in all treatment arms, areduction in the proportion of subjects with SRF and/or IRF in the brolucizumabarm was apparent, with 1 less injection
In summary, the brolucizumab 52-week results in the KESTRELand KITE studies demonstrate clinically meaningful visual acuity gains andexcellent anatomic improvements with an overall favorable benefit/risk profile;therefore, brolucizumab could provide an additional therapeutic option in DMEthat reduces the burden on patients, physicians, and the health care system.
Source: DAVID M. BROWN, ANDRÉS EMANUELLI, FRANCESCO BANDELLO;Am J Ophthalmol 2022;238: 157–172 https://doi.org/10.1016/j.ajo.2022.01.004
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