BROLUCIZUMAB
Nil Financial Interest

VEGF: INTRODUCTION
• VEGF (Vascular Endothelial Growth Factor,) which is responsible for
growth of blood vessels.
• It is also responsible for many retinal diseases by causing new
vessels growth and by increasing leakage and thus causing retinal
swelling

BROLUCIZUMAB
• Humanized monoclonal single-chain variable fragment (scFv) that binds and inhibits
vascular endothelial growth factor A (VEGF-A)
• Single-chain fragment variable is the smallest functional unit of an antibody, the Fv
region
• Molecular weight - 26 Kd
• Half-life of 3.0 days

ADVANTAGES
• Being small fragments, they are able to penetrate tissue more rapidly and
evenly
• Brolucizumab binds VEGF-A in a 2:1
• Higher binding affinity to VEGF-A isoforms than bevacizumab or
ranibizumab
• Radily penetrate to the choroid and RPE while having minimal serum
concentrations
• FDA-approved for treatment of wet ARMD
• Longer interval between injections

DOSAGE
• Recommended dosage is 6 mg (0.05 mL of solution that is 120 mg/mL)
• Once per month for the first 3 doses as loading doses
• Dosing interval after is recommended 8 to 12 weeks based on clinician assessment
of disease
• 30-gauge transconjunctival intravitreal injection via the pars plana

INDICATIONS
CNVM, PCV

INDICATIONS
DME

LITERATURE
HAWK and HARRIER
Purpose- To compare Brolucizumab with Aflibercept in treatment
neovascular ARMD
Study Design: Double-masked, active-controlled, randomized trials
Participants: Patients (N = 1817) with untreated, active choroidal
neovascularization due to ARMD in the study eye
Reference- Dugel PU, Koh A, Ogura Y, Jaffe GJ, Schmidt-Erfurth U, Brown DM, Gomes AV, Warburton J,
Weichselberger A, Holz FG; HAWK and HARRIER Study Investigators. HAWK and HARRIER: Phase 3, Multicenter,
Randomized, Double-Masked Trials of Brolucizumab for Neovascular Age-Related Macular Degeneration.
Ophthalmology. 2020 Jan;127(1):72-84.

Materials and Methods:
• Patients were randomized 1:1:1 to receive brolucizumab 3 mg or 6 mg or
aflibercept 2 mg (HAWK) or 1:1 to receive brolucizumab 6 mg or aflibercept 2
mg (HARRIER)
• After loading with 3 monthly injections, brolucizumab-treated eyes received an
injection every 12 weeks (q12w) and were interval adjusted to every 8 weeks
(q8w) if disease activity was present; aflibercept-treated eyes received q8w
dosing
Main outcome measures: The primary hypothesis was noninferiority in mean best-
corrected visual acuity (BCVA) change from baseline to Week 48. Other key end
points included the percentage of patients who maintained q12w dosing through
Week 48 and anatomic outcomes.

RESULTS
• BCVA-The mean change in BCVA from baseline at week 48 (primary end
point) in brolucizumab-treated eyes was noninferior to that in aflibercept-
treated eyes, and these visual gains were maintained to week 96
• Central Subfield Thickness- At week 96, greater CST reductions were
observed with brolucizumab 3 mg and 6 mg versus aflibercept in and with
brolucizumab 6 mg versus aflibercept in HARRIER
• IRF/SRF- In both HAWK and HARRIER, significantly fewer eyes treated
with brolucizumab showed IRF or SRF at weeks 16 and 48, and this
difference was maintained to week 96. The proportion of eyes with IRF or
SRF at week 96 in HAWK was 31% for brolucizumab 3mg, 24% for
brolucizumab 6 mg and 37% for aflibercept whereas in HARRIER, it was
24% for brolucizumab 6 mg and 39% for aflibercept

RESULTS
• Sub RPE fluid-At week 96, the proportions of eyes with sub-RPE fluid in
HAWK were 14% and 11% for brolucizumab 3 mg and 6 mg,
respectively, compared with 15% for aflibercept. In HARRIER, the
proportion of eyes with sub-RPE fluid was 17% for brolucizumab 6 mg
compared with 22% for aflibercept

CONCLUSION
• Brolucizumab was noninferior to aflibercept in visual function
• Anatomic outcomes favoured brolucizumab over aflibercept resulting in
fewer eyes with intra-retinal fluid (IRF), sub-retinal fluid (SRF), or sub-RPE
fluid and an increased reduction in central subfield thickness (CST) on OCT
• Overall safety with brolucizumab was similar to aflibercept
• Combined intraocular inflammation (IOI) (iritis and uveitis) was higher in
the brolucizumab 6 mg group of HAWK compared with the aflibercept
group

KITE AND KESTREL STUDY FOR DME
Purpose: To compare the efficacy and safety of brolucizumab with aflibercept in
patients with diabetic macular edema (DME)
Design: Double-masked, 100-week, multicenter, active-controlled, randomized
trials
Reference-Brown DM, Emanuelli A, Bandello F, Barranco JJE, Figueira J, Souied E, Wolf S, Gupta V, Ngah NF,
Liew G, Tuli R, Tadayoni R, Dhoot D, Wang L, Bouillaud E, Wang Y, Kovacic L, Guerard N, Garweg JG.
KESTREL and KITE: 52-Week Results From Two Phase III Pivotal Trials of Brolucizumab for Diabetic Macular
Edema. Am J Ophthalmol. 2022 Jun;238:157-172.

Methods:
• Subjects were randomized 1:1:1 to brolucizumab 3 mg/6 mg or aflibercept 2 mg
in KESTREL (n = 566) or 1:1 to brolucizumab 6 mg or aflibercept 2 mg in
KITE (n = 360)
• Brolucizumab groups received 5 loading doses every 6 weeks (q6w) followed
by 12-week (q12w) dosing, with optional adjustment to every 8 weeks (q8w) if
disease activity was identified at predefined assessment visits
• aflibercept groups received 5 doses every 4 weeks (q4w) followed by fixed q8w
dosing

RESULTS
• At Week 52, brolucizumab 6 mg was noninferior to aflibercept in mean change in
BCVA from baseline (KESTREL: +9.2 letters vs +10.5 letters; KITE: +10.6 letters vs +9.4 letters; P < .001)
• More subjects achieved central subfield thickness (CSFT) <280 µm, and fewer had
persisting subretinal and/or intraretinal fluid vs aflibercept, with more than half of
brolucizumab 6 mg subjects maintained on q12w dosing after loading
• In KITE, brolucizumab 6 mg showed superior improvements in change of CSFT
from baseline over Week 40 to Week 52 vs aflibercept
• The incidence of ocular serious adverse events was 3.7% (brolucizumab 3 mg),
1.1% (brolucizumab 6 mg), and 2.1% (aflibercept) in KESTREL; and 2.2%
(brolucizumab 6 mg) and 1.7% (aflibercept) in KITE.

CONCLUSION
• Brolucizumab 6 mg showed robust visual gains and anatomical
improvements with an overall favourable benefit/risk profile in patients
with DME

BROLICIZUMAB FOR CRVO INDUCED
RECALCITRANT MACULAR EDEMA
• A series of 2 patients involving treatment of eyes with
recalcitrant macular edema due to CRVO treated with
brolicizumab
• Patient treated with 10 ranibizumab, 2 bevacizumab, 2
aflibercept and 1 dexamethasone implant
• Other patient treated with 12 ranibizumab
• Improvement in BCVA following brolicizumab
Reference- Chakraborty et al, Brolicizumab in Recalcitrant macular edema. Current eye
research, 2021

RISK OF INFLAMMATION AND RETINAL OCCLUSION-RELATED
EVENTS WITH BROLUCIZUMAB
• Fifty brolucizumab-treated eyes were considered to have definite/probable drug-related
events within the spectrum of IOI, retinal vasculitis, and/or vascular occlusion. On the
basis of these cases, incidence of definite/probable IOI was 4.6% (IOI + vasculitis, 3.3%;
IOI + vasculitis + occlusion, 2.1%
• There were 8 cases of at least moderate visual acuity loss (≥15 ETDRS letters) in eyes
with IOI (7 in eyes with IOI + vasculitis + occlusion)
• Of the 8 cases, 5 experienced their first IOI-related event within 3 months of the first
brolucizumab injection
• Incidence of IOI in aflibercept-treated eyes was 1.1%, with at least moderate visual
acuity loss in 0.14%.
Reference- Monés J, Srivastava SK, Jaffe GJ, Tadayoni R, Albini TA, Kaiser PK, Holz FG, Korobelnik JF, Kim IK, Pruente C, Murray TG, Heier JS. Risk of Inflammation,

• Retrospective study on 21 PCV eyes. The median pretreatment vision was 0.6
logMAR and improved to 0.3 logMAR whereas the mean macular thickness
improved from 443 ± 60 μm at baseline to 289 ± 25 μm at the last follow-up
period
• None of the eyes experienced any intraocular inflammation across 48 injection
sessions.
• Brolucizumab is safe and effective in controlling PCV disease in both treatment-
resistant and treatment-naïve eyes
Reference- chakraborty D, Maiti A, Sengupta S, Mondal S, Nandi K, Chakraborty S. Initial experience in treating polypoidal choroidal vasculopathy with
brolucizumab in Indian eyes - A multicenter retrospective study. Indian J Ophthalmol. 2022 Apr;70(4):1295-1299

• Immediate onset of sterile endophthalmitis with hypopyon after intravitreal
Brolucizumab
• Vitrectomy biopsy with intravitreal ceftazidime and vancomycin
• Microbiological testing of the vitreous fluid did not show any organism on
smear, and there was no growth on culture
• Polymerase chain reaction for Eubacteria was negative
Reference- Narayanan, Raja; Tyagi, Mudit; Gupta, Shashank R1; Nayaka, Ashraya2; Jayadev, Chaitra3. Immediate onset of sterile endophthalmitis with
hypopyon after intravitreal Brolucizumab in a case of polypoidal choroidal vasculopathy. Indian Journal of Ophthalmology: February 2021 - Volume 69 - Issue
2 - p 469-470

• A female patient diagnosed with PCV with IMC-NS 2
• LE BCVA 6/12
• LE S/P Accentrix 5 injections
• Advised LE Brolicuzumab
• Post injection decrease in size of polyp and IRF

PCV

• A patient came with BCVA 6/9P
• OCT LE- FVPED with SRF. Diagnosis- LE CNVM
• S/P injection Accentrix 3, Avastin 1
• Advised LE Brolicuzumab
• Post injection decrease in FVPED with resolution of SRF

CNVM

THANK YOU