Safety and Efficacy of Brolucizumab in the Treatment of Diabetic Macular Edema and Diabetic Retinopathy: A Systematic Review and Meta-Analysis

Figures & data

Figure 1. Shows PRISMA chart for selection of included articles.

Table 1. Summary of studies included in this review.

ID	Year	Country	Study design	Duration	Sample size	Age	Sex	Race	Quality
Brown et al.^Citation23	2022	USA	2 Randomized Controlled Clinical Trials	52 weeks	KESTREL (566)	<65	M: 355/F: 211	White (462), Black or African American (24),Asian (77), Japanese (62), Indian (10),Chinese (3), American Indian/Alaska Native (2), Native Hawaiian/Other Pacific Islander (2)	10
					KITE (360)	≥65	M: 235/F: 125	White (265), Black or African American (4),Asian (91), Indian (25), Chinese (30), Korean (19), Vietnamese (1)
Busch et al.^Citation29	2022	Germany	Cross-Sectional study	-	192 serum and 54 vitreous samples	-	M: 100/F: 92	-	10
Chakraborty et al.^Citation30	2022	UK	Retrospective, consecutive, interventional, uncontrolled, single-center study	24.6 ± 4.05 weeks	13	52.9 ± 4.6 years	M: 7/F: 6	-	9
Murray et al.^Citation31	2021	USA	Retrospective	3 months	98	34–95	M: 52/F: 46	Caucasian (51), Hispanic (42), African American (3), and Asian (2).	10
Chakraborty et al.^Citation32	2022	India	Case Report	4 weeks	1	48	M	Indian	7
Mahapatra et al.^Citation33		India	Case Series	6 months	3	case 1:54y/case 2:49/case 3:55	M/F/M	Indian	8
Hirano et al.^Citation34	2023	Japan	Case Report	unknown	1	68	F	Japanese	11
Chakraborty et al.^Citation35	2021	India	Case Series	16 weeks	3 eyes	Case 1: 56y Case 2: 37y case 3: 49 y	1: F 2: M 3: M	Indian	7

Table 2. Overview of BCVA changes after Brolucizumab across included studies.

TITLE	No. of patients	Baseline BCVA (ETDRS)	Mean Change in BCVA ± std	Post-treatment BCVA
Brown et al. (KESTREL)^Citation23	190	3 mg: 65.7 (11.09)	9.2 ± 0.57
	189	6mg: 66.6 (9.67)	7.3 ± 0.66
Brown et al. (KITE)^Citation23	179	66.0 (10.77)	10.6 ± 0.62
Chakraborty et al.^Citation32	13	58.74	78.48	65.10 4w
	13		78.48	65.54 8w
	13		78.48	65.54 12w
	13		82.93	61.14 16w
Chakraborty et al.^Citation32 Second dose	9	59.07	82.93	60.08 28w
Murray et al.^Citation31	98	40.53	76.19	50.05
Chakraborty et al.^Citation30	1	61.14 OD		OU: 69.94
		46.09 OS
Mahapatra et al.^Citation33	3	Case1: 45.03		Case1: 75.48
		Case2: 10.01		Case2: 25.06
		Case3: 10.01		Case3: +20.00
Hirano et al.^Citation34	1	74.79 OD		After two doses: 77.69 OD
				One month after 3rd dose: 74.79
Chakraborty et al.^Citation35	3	Case1: 61.14		80.15
		Case2: 69.94		80.15
		Case3: 69.94		80.15

Table 3. Summary of CST results in included studies.

TITLE	No. of patients	CSMT at baseline	CSMT post Tx	Mean CSMT ± std
Brown et al. (KESTREL)^Citation23	190	3mg: 456 ± 118	N/A	−167.1 ± 6.54
	189	6mg: 453 ± 123	N/A	−171.9 ± 6.18
Brown et al. (KITE)^Citation23	179	481 ± 132	N/A	−197 ± 6.3
Chakraborty et al.^Citation32	13	402 ± 60.1	273.33 ± 25.8 4w	−128.67 ± 65.4
	13		263.55 ± 22.01 8w	−138.45 ± 64
	13	419 ± 60.3	295.11 ± 13.38 12w	−106.89 ± 61.57
	13		378.3 ± 29.8 16w	−40.7 ± 67.26
Chakraborty et al.^Citation32 Second Dose	9	402 ± 60.1	295.1 ± 13.3	−106.9 ± 61.55
Murray et al.^Citation31	98	412.2 ± 77.83	340.7 ± 68.99	−71.5 ± 104.98
Chakraborty et al.^Citation30	1	321μm in OD	272μm in the OD
		637μm in OS	248μm in the OS
Mahapatra et al.^Citation33	3	Case1: 434	Case1: 180
		Case2: 298	Case2: 150
		Case3: 402	Case3: 167
Hirano et al.^Citation34	1	368μm	253μm
Chakraborty et al.^Citation35	3	Case 1: 621μm	Significant reduction at week 12 that recurrence at week 16
		Case 2: 645μm	Complete reduction at week 12 that recurrence at week 16
		Case 3: N/A	Complete resolve at week 12 that recur at week 16

Figure 2. Shows the meta-analysis of effect of Brolucizumab on BCVA across included articles.

Figure 3. Shows the meta-analysis of effect of Brolucizumab on CSMT across included articles.

Table 4. Safety of brolucizumab as observed by included studies.

TITLE	Dose	Type and number of events	Onset time (days)	Prognosis	Percentage of Ocular SAE
Brown et al. (KESTREL)^Citation23	3mg	Three cases of retinal vasculitis One case of Retinal vein thrombosis	(115, 96, 203) 291 days	- Mild to moderate - Resolved with routine clinical care without sequelae	3.7% of subjects in the brolucizumab 3 mg arm 1.1% of subjects in the brolucizumab 6 mg arm 2.1% of subjects in the aflibercept arm
	6mg	Two cases of retinal vasculitis progressing to RAO	114 days 136 days
Brown et al. (KITE)^Citation23	6mg	One case of RAO	N/A	Vision loss: −75 letters decline in visual acuity,
Busch et al.^Citation29	N/A	- Two patients with severe vision loss due to occlusive retinal vasculitis - One patient moderate IOI and signs of segmented blood flow	N/A	Full recovery on corticosteroids in the patient with IOI	In the vast majority of vitreous samples, brolucizumab ADA levels were obtained from patients who had never received brolucizumab.
Chakraborty et al.^Citation32		There was no evidence of inflammation, vasculitis, or any other ocular or systemic adverse effects in any of the eyes.
Murray et al.^Citation31		There was no evidence of inflammation, vasculitis, or any other ocular or systemic adverse effects in any of the eyes.
Chakraborty et al.^Citation30		There were no ocular or systemic adverse events after brolucizumab therapy.
Mahapatra et al.^Citation33		There were no ocular or systemic adverse events after brolucizumab therapy.
Hirano et al.^Citation34	3mg	OD retinal arterial occlusive vasculitis (Bilateral Injection)	1 month	Decline from 20/28 to 20/32, and after one year, BCVA reached 20/50	It is essential to detect IOI and subsequent retinal artery occlusive vasculitis at an early stage. Oral prednisolone is used to treat severe brolucizumab-associated IOI in patients with nAMD. However, due of the possibility of elevated blood glucose levels, oral prednisolone should be used with caution in patients with DME.

Abbreviations; ADA: Anti-Drug Antibodies, BCVA: Best Corrected Visual Acuity, DME: Diabetic Macular Edema, IOI: Intra-Ocular Inflammation, RAO: Retinal Artery Occlusion, SAE: Serious Adverse Events (Any adverse event that causes a >30 decrease in BCVA and lasts more than one hour),³⁷ nAMD: Neovascular Age-Related Macular Degeneration.

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. doi:10.1016/j.ajo.2022.01.004

 PubMed Web of Science ®Google Scholar

Busch M, Pfeil JM, Dähmcke M, et al. Anti-drug antibodies to brolucizumab and ranibizumab in serum and vitreous of patients with ocular disease. Acta Ophthalmol. 2022;100(8):903–910. doi:10.1111/aos.15124.

 PubMed Web of Science ®Google Scholar

Chakraborty D, Mondal S, Parachuri N, Kumar N, Sharma A. Brolucizumab—early experience with early extended interval regime in chronic centre involved diabetic macular oedema. Eye (Lond). 2022;36(2):358–360. doi:10.1038/s41433-021-01816-3.

 PubMed Web of Science ®Google Scholar

Murray JE, Gold AS, Latiff A, et al. Brolucizumab: evaluation of compassionate use of a complex anti-VEGF therapy. Clin Ophthalmol. 2021;15:4731–4738. doi:10.2147/OPTH.S339393

 PubMed Web of Science ®Google Scholar

Chakraborty S, Sheth JU, Campa C. Contralateral effect following intravitreal brolucizumab injection in diabetic macular Edema. Case Rep Ophthalmol Med. 2022;2022:1–4. doi:10.1155/2022/3755249.

 Web of Science ®Google Scholar

Mahapatra SK, Das A. Initial experience in off-label use of brolucizumab in diabetic macular ededama and retinal vein occlusion. Current Indian Eye Res J Ophthalmic Res Group. 2021;54(49):51.

 Google Scholar

Hirano T, Toriyama Y, Takahashi Y, et al. Retinal arterial occlusive vasculitis after multiple intravitreal brolucizumab injections for diabetic macular edema. Am J Ophthalmol Case Rep. 2023;29:101788. doi:10.1016/j.ajoc.2022.101788

 PubMedGoogle Scholar

Chakraborty D, Sheth JU, Boral S, et al. Off-label intravitreal brolucizumab for recalcitrant diabetic macular edema: a real-world case series. Am J Ophthalmol Case Rep. 2021;24:101197. doi:10.1016/j.ajoc.2021.101197

 PubMedGoogle Scholar

Table 25 , all ocular serious adverse events in the study eye (Safety Analysis Set). 2015.

 Google Scholar