Clinical Studies:
KITE/KESTREL
Citation: 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. 2022;238:157-172.
Key Points
- Brolucizumab provides comparable visual gains to aflibercept with fewer injections.
- Offers Q12W maintenance in a significant proportion of patients.
- Anatomical outcomes (CST/fluid) were superior with brolucizumab.
- Safety monitoring for IOI is essential during treatment.
Study Design
Phase III, multicenter, randomized, double-masked studies. 100 weeks. Comparators: Brolucizumab vs. aflibercept. Population: Patients with diabetic macular edema (DME).
Study Objectives and Endpoints
Primary Objective: Assess non-inferiority of brolucizumab to aflibercept in terms of visual acuity improvement.
Primary Endpoint: Mean change in best-corrected visual acuity (BCVA) from baseline to Week 52.
Key Secondary Endpoints: Proportion of eyes on 12-week dosing interval, change in central subfield thickness (CST), presence of intraretinal/subretinal fluid, safety outcomes.
Randomization Scheme and Interventions
Randomization:
- 1:1:1 ratio in KESTREL (6 mg brolucizumab, 3 mg brolucizumab, 2 mg aflibercept)
- 1:1 in KITE (6 mg brolucizumab vs. 2 mg aflibercept)
Dosing Regimens:
- Brolucizumab: 5 initial monthly loading doses → every 12 weeks (Q12W), with option to adjust to every 8 weeks (Q8W) based on disease activity.
- Aflibercept: 5 monthly loading doses → fixed Q8W dosing.
Study Subjects
- Total Participants: Over 1,200 across both studies.
- Inclusion: Treatment-naïve DME patients with visual impairment.
Study Eye Inclusion Criteria
- Central-involved DME in the study eye.
- BCVA between ~78 and 24 ETDRS letters (~20/32 to 20/320 Snellen equivalent).
- Central subfield thickness ≥ 300 µm.
Treatment
- Intravitreal injections of:
- Brolucizumab 6 mg (main investigational dose).
- Aflibercept 2 mg (comparator).
- Treatment interval adjustments in brolucizumab arms were disease activity–driven.
Assessment Methods
- Visual Acuity: ETDRS letter score.
- OCT Imaging: To assess CST and retinal fluid.
- Safety Monitoring: Adverse events including intraocular inflammation (IOI), retinal vasculitis, and vascular occlusion.
Results
- Visual acuity:
- At Week 52, brolucizumab 6 mg demonstrated noninferiority to aflibercept in mean change in BCVA from baseline. In KESTREL, the change was +9.2 letters for brolucizumab versus +10.5 letters for aflibercept. In KITE, the change was +10.6 letters for brolucizumab versus +9.4 letters for aflibercept.
- Efficacy:
- Brolucizumab demonstrated non-inferiority to aflibercept in BCVA gain at Week 52.
- A higher proportion of brolucizumab-treated eyes maintained Q12W dosing at week 52 following the loading doses (>50% of 6 mg treated eyes).
- Greater CST reduction and fluid resolution was seen with brolucizumab. In KESTREL, 60.3% of brolucizumab 6 mg patients had fluid at week 52 compared to 73.3% of aflibercept patients. In KITE, 54.2% of brolucizumab 6 mg patients had fluid compared to 72.9% of aflibercept patients.
- Safety:
- IOI-related adverse events were higher with brolucizumab. In KESTREL, the rates were 4.2% for brolucizumab 6 mg and 1.1% for aflibercept. In KITE, the rates were 2.2% for brolucizumab 6 mg and 1.7% for aflibercept.
- Retinal vasculitis rates were low, with 0.5% in KESTREL for brolucizumab 6 mg and no cases in KITE. Retinal vascular occlusion rates were 1.6% for brolucizumab 6 mg and 0.5% for aflibercept in KESTREL, and 0.6% for both treatment arms in KITE.
Conclusions
- Brolucizumab is an effective alternative to aflibercept for DME.
- Brolucizumab offers potential for extended dosing intervals (Q12W).
- Fluid resolution benefits are notable but must be weighed against safety profile.