2. Unmet needs from the physicians’ perspective
Physicians still identify treatment and monitoring burden as key unmet
needs in nAMD management despite flexible dosing
0 10 20 30 40 50 60 70 80 90
Improved efficacy
Reduced treatment
burden
Improved safety
Long acting/
sustained delivery
New treatment
mechanisms of action
US 37.0%
Intl 37.1%
US 56.3%
Intl 70.6%
US 73.2%
Intl 66.1%
US 6.3%
Intl 13.6%
US 31.9%
Intl 37.1%
What are the greatest unmet needs regarding nAMD treatment?a
ASRS Preferences and Trends (PAT)
membership survey 20183
aData gathered from 1029 retina specialists; 1. Holz FG, et al. Br J Ophthalmol. 2015;99:220-226; 2. Mantel I. Trans Vis Sci Tech. 2015;4:6;
3. ASRS Preferences and Trends (PAT) membership survey 2018. ASRS, American Society of Retina Specialists; Intl, international; US, United States
“Indeed,........monitoring visits are the
most time- and resource-consuming
part of patient care with anti-VEGF
therapy for individuals with nAMD”
- Mantel I. Trans Vis Sci Tech 20152
3. Stressed clinic capacity may impact timely
treatment
Adoption of flexible regimens, particularly T&E, to increase
individualization and reduce the burden on healthcare resources4-7
However, this may result in delays in detection of
recurrences and suboptimal
treatment frequency8,9
Why do you believe discontinuous anti-VEGF treatment for nAMD is
retina specialists’ most common regimen?a
0 10 20 30 40 50 60
US 17.1%
Intl 22.9%
US 23.1%
Intl 21.8%
US 2.7%
Intl 3.4%
US 48.3%
Intl 44.0%
US 8.8%
Intl 7.8%
A. Vision is the same with continuous
and discontinuous treatment
B. Patients prefer fewer shots, even if
they lose some vision
C. Physicians prefer fewer shots, even
if patients lose some vision
Combination of B and C
Other
In the ASRS PAT survey,
many retina specialists believed that discontinuous anti-
VEGF treatment is used as a result of physician or patient
preference, even if this results in some vision loss4
. Amoaku W, et al. Eye. 2012;26(suppl 1):S2-S21; 2. Amoaku W. https://www.rcophth.ac.uk/wp-content/uploads/2014/12/2013-SCI-302-Maximising-Capacity-in-AMD-Services-July-2013.pdf. Accessed May 4, 2017; 3. Samalia P, et al. N
Z Med J. 2016;129:32-8; 4. ASRS Preferences and Trends (PAT) membership survey 2016; 5. Boyer DS, et al. Ophthalmology. 2009;116:1731-1739; 6. Busbee BG, et al. Ophthalmology. 2013;120:1046-56; 7. Regillo CD, et al. Am J
Ophthalmol. 2008;145:239-48; 8. Wong WL, et al. Lancet Glob Health. 2014;2:e106-e116; 9. Finger RP, et al. Acta Ophthalmol. 2013;91:540-6.
4. An ongoing challenge is to maintain nAMD treatment
efficacy while reducing clinic visits.
. Freund KB, Mrejen S, Gallego-Pinazo R. An update on the pharmacotherapy of neovascular age-related macular degeneration. Expert Opin Pharmacother. 2013;14: 1017e1028.
. Holz FG, Schmitz-Valckenberg S, Fleckenstein M. Recent developments in the treatment of age-related macular degeneration. J Clin Invest. 2014;124:1430e1438.
5. What is a single-chain antibody fragment
(scFv)?
An scFv represents the smallest functional unit of an antibody that still retains full
binding capacity to its target1
Single-chain antibody fragments (scFv) are the smallest functional unit of
an antibody, allowing delivery of a greater molar dose compared with
larger molecules and the potential for more effective tissue
penetration,attributes designed to increase duration
Brolucizumab
. Ophthalmology 2016;123:1080-1089
6. HAWK and HARRIER
HAWK and HARRIER are 2 similarly designed phase 3 trials comparing
Brolucizumab with Aflibercept to treat nAMD.
Ophthalmology 2020;127:72-84
Dugel PU, Singh RP, Koh A, Ogura Y, Weissgerber G, Gedif K, Jaffe GJ, Tadayoni R, Schmidt-Erfurth U, Holz FG, HAWK and HARRIER: 96-Week outcomes from the phase trials of brolucizumab for neovascular age-related macular degeneration,
Ophthalmology (2020),
7. Take home messages from Hawk and
Harrier
RETINA / OPHTHALMOLOGY
RETINA / OPHTHALMOLOGY
8. 8
Disease Assesment at Week 16 decided the treatment criteria
post loading 3 doses
• If any time during the trial,
the patient had any disease
activity, the patient was
shifted to q8w dosing and
continued till the end of the
trial
• 50% patients
maintained q12w dosing till
the end of the trial
Dugel PU, et al. Ophthalmology 2020;127(1):72–84;
In Brolucizumab arm of the H&H trial
9. 9
Potential for q12w dosing
~80% patients
who received q12w dose till week48 , continued on
q12w until week 96
In Brolucizumab arm of the H&H trial
~50% patients
who had no DA after loading dose , maintained
q12w dosing till week 48
Dugel PU, et al. Ophthalmology 2020;127(1):72–84;
10. 10
Sub-RPE fluid resolved
In Brolucizumab arm of the H&H trial
~more than 30%
patients
had the Sub-RPE fluid resolved
indicating better penetrative power of the drug
(as compared to Aflibercept arm)
Dugel PU, et al. Ophthalmology 2020;127(1):72–84;
11. 11
IRF and SRF fluid resolved
In Brolucizumab arm of the H&H trial
~more than 35%
patients
had no fluid(No IRF Neither SRF) in the retina
indicating better pK and pD of the drug
(as compared to Aflibercept arm)
Dugel PU, et al. Ophthalmology 2020;127(1):72–84;
12. 12
Stable CST reduction
In Brolucizumab arm of the H&H trial
Dugel PU, et al. Ophthalmology 2020;127(1):72–84;
Graphs showing the central subfield thickness
(CST) change from baseline to week 96 in the
Brolucizumab and Aflibercept treatment groups
in the
13. 13
PREDICTABILITY
Successful completion of the q12w at Week 48
(>50%) was predictive of continuing on a q12w
interval until week 96 (≥75%)
Successful completion of the first q12w interval was
predictive (≥80%) of continuing on a q12w interval
until Week 48*;
VISUAL OUTCOMES
The BCVA achieved by brolucizumab at
Week 48 (primary endpoint) was
maintained at Week 96*
DISEASE ACTIVITY
Significantly fewer brolucizumab 6 mg
patients showed disease activity at
week 16*
ANATOMICAL OUTCOMES
The superior anatomic results
seen for brolucizumab at Weeks
16 and 48 were reaffirmed at
Week 96*
q12w TREATMENT INTERVAL
Over 50% of brolucizumab 6 mg
patients were maintained on a
q12w dosing interval immediately
following a loading dose until Week
48*
14. Case of serendipity
LE pretreated
80 yr male, High myopic, Le CNV-TYPE2
LE- Cf1 m
RE-6/6 N6
One RANIBIZUMAB
One BROLUCIZUMAB
Cf5 m
PATH
27. PED WHICH GOT FATTER AND FLATTER
64 year lady with occult CNV large PED- IPCV
Past Interventions:
24 Ranibizumab
5 Aflibercept
FIRST Brolucizumab Injected on 30-10 -20
SECOND Brolucizumab injected a month later
THIRD BROLUCIZUMZAB AFTER 2.5 MONTH
MIR
32. 4. Hyper-reflective Foci
• Particularly adjacent to fluid lesions
• Migrating RPE cells, Pigment-laden macrophages, Micro-exudates
of lipid, fibrin or activated microglia
• In early AMD, hyper-reflective foci are a risk factor for progression
to advanced disease
1. Ritter M, et al. Br J Ophthalmol 2014;98:1629–1635
2. Yun H et al. Graefe's Archive for Clinical and Experimental
Ophthalmology 08:2019
32
38. 7. Pigment Epithelial Detachment
• PED was present in 54%-80% of patients at the time of enrolment in CATT, EXCITE, and VIEW
• A course of three monthly anti-VEGF injections generally reduces the rate of PED by about 25%, in contrast
to a 70% - 80% resolution of sub- and intraretinal fluid
Ross H et al. Springer 10.1038: 09; 2019 38
In the VIEW studies, patients received continuous
anti-VEGF therapy during the first 48 weeks. At 52
weeks, a discontinuous, “as-needed” dosing regimen
was introduced. Only eyes with pigment-epithelial
detachments developing secondary intraretinal
cystoid fluid
60. Clinical Implications
• Patients with nAMD should be diagnosed and treated early
• Patients presenting with extensive foveal cystoid fluid may be
counselled that, though they are likely to experience some gain in
VA, even aggressive treatment may not provide similar levels of
functional benefit as in the average patient without such
morphologic changes
• Anti-VEGF treatment may be stopped for cystic degeneration
(“degenerative IRC”) overlying RPE atrophy or scarring due to the
limited responsiveness of such fluid
Lai TT et al. Scientific reports. 2019 Jan 24;9(1):529 60
61. Differentiation of IRF is most important
• Degenerative – small with underlying RPE atrophy scarring
or atrophy, poor response to anti VEGF, need aggressive
therapy and modification of treatment modalities
• Exudative – large, ovoid shaped, quick and good response to
anti VEGF, less frequent follow up and can have more flexible
regimen
61
Lai TT et al. Scientific reports. 2019 Jan 24;9(1):529.
62. CASE who bled comes WITH COVID
• 79 YR MALE
• RE occult CNV since 2017 -6/12
• Multiple Ranibizumab monthly then PRN-2 monthly
• PED with subretinal haemorrage –GAS + RANIBIZUMAB
• Switch to Aflibercept and Dex- implant
• NO FOLLOW UP 6 MONTHS
• Now back with intraretinal and subretinal fluid-PED
• CF 2m –brolucizumab given on 30th Nov 2020
MITR
69. 5. Subretinal Hyperreflective material and Fibrous scarring
• Particularly in Type II (classic) CNV, new vessels from the choroidal neovascular complex typically
proliferate directly in the subretinal space after initially penetrating Bruch's membrane
• Usually associated with an active CNV lesion, including subretinal haemorrhage and lipid or fluid
exudation
1. Vinnie P et al RETINA 34:1281–1288, 2014
2. Erfurth U et al. Progress in Retinal and Eye Research 50 (2016) 1-24 69
Baseline presentation of patient
with nAMD
SHRM
Presentation following long term VEGF
inhibition
SHRM and
PED have
condensed
into a spindle
shaped fibrous
scar
76. CASE of too many injections over 11 yrs
• 80 YRS FEMALE
• RE OCCULT CNV -6/12 –CONICAL PED –IPCV, PACHYCHOROID
• 80 RANIBIZUMAB OVER 10 YRS STARTING 2010
• LE SCARRED CNV- AMD -6/60
• POST LOCKDOWN 9 MONTHS VA DROPPED 6/60 BOTH EYES
• RE- IRF ,PED-MULTILAYER,SHREM
• LE- PED
• BE BROLUCIZUMAB
• DAY 1 PT FEELS BETTER- FLUID LESS
Kar
96. CASE of bilateral multiple injections(pahalaj)
• 80 YR LADY
• DRY AMD -5 YRS
• CONVERSION TO WET -BILATERAL
• SUDDENLY ONE FINE DAY
• 25 RANIBIZUMAB EACH EYE SINCE 2017
• SWITCH TO BROLUCIZUMAB
• VISION 6/24 6/36
• 2nd dose at 3 months
111. CASE of double hump camel
• 80 YR MALE
• RE –CF 2M LE -6/18
• BE OCCULT CNV WITH PED RE 2010 LE 2018
• BE- MULIPLE Bevacizumab, Aflibercept, Ranibizumab
• LE- Brolucizumab -2dec 20 For Occult Double PED
FEDL
121. Post-Hoc Analysis Conclusions
• Brolucizumab 6 mg is associated with greater and sustained reduction
in SHRM and PED compared with aflibercept .
• Although the majority of patients treated with brolucizumab achieve
complete drying of IRF, SRF, and Sub RPE fluid ,most still demonstrate
residual Type1 MNV.
• A Maximum reduction in SHRM with persistence of a PED without
exudation may be the preferred anatomic configuration for the
optimal long-term visual outcomes.
• As this is the post-hoc analysis, observations needs to be confirmed in
future long-term prospective studies.
122. NOV 20-OPHTHALMOLOGY
• SAFETY REVIEW COMMITTEE
• HAWK HARRIER POST ANALYSIS
• 1817 EYES
• IOI -4.6%(VASCULITIS-3.3%;OCCLUSION-2.1%)
• MODERATE VISION LOSS-0.74%
• IOI FIRST EVENT WITHIN 3 MONTHS OF FIRST INJECTION
123. AAO 20-BROLUCIZUMAB
• IRIS REGISTRY 1200 PATIENTS OF BROLUCIZUMAB
• RETINAL VASCULITIS- RV AND RETINAL VASCULAR OCCLUSION-RO
• HIGHEST RISK IN 6 MONTHS -
1. INTRAOCULAR INFAMMATION-IOI
2. PRIOR RO IN 12 MONTHS BEFORE FIRST BROLUCIZUMAB
• OVERALL RISK OF RV OR RO -0.46%
• INCREASED TO 3.97% -PRIOR IOI OR RO
124. AAO 20 -BROLUCIZUMAB
• 50% WET AMD-UNRESOLVED FLUID
• 1/3 RD NEED MONTHLY INJECTIONS
• UNMET NEED IN WET AMD FOR BEOVUE
• HAWK HARRIER DATA-INCREASED RV/RO IN EYES WITH TREATMENT
EMERGENT-BOOSTED /INDUCED-ANTI DRUG ANTIBODIES-ADAs
• GREATER AND SUSTAINED REDUCTION IN PED AND SUBRETINAL
HYPER-REFLECTIVE MATERIAL VS AFLIBERCEPT
• FIRST SINGLE CHAIN ANTIBODY FRAGMENT –SMALLER SIZE 26
KDA,TISSUE PENETRATION,RAPID CLEARANCE,HIGHER
CONCENTRATION 6 MG,MORE ACTIVE BINDING TO VEGF RECEPTORS
125. Summary
• Brolucizumab is an potent addition to our treatment armamentarium
for patients with Neovascular AMD.
• Appears to have superior drying and consequently superior durability
over other currently available agents.
• Severe intraocular inflammation and occlusive retinal vasculitis with
vision loss, is uncommon (prob<1/100), but requires comprehensive
discussion with the patient prior to use ,weighing this risk against the
risk of vision loss with persistent activity.
129. Take home message
• When to use BROLUCIZUMAB
In case of recalcitrant patients
In De-novo patients
In non responsive / Chronic patients
130. Take home message
• When to switch to BROLUCIZUMAB
Non Responders
Tachyphylactic
131. Take home message
• When to avoid using BROLUCIZUMAB
• (in which type of patients)?
H/O Old Thrombosis
H/O of IOI
Any Ocular surgery / Interventions
132. Take home message
• Advantages of BROLUCIZUMAB
Long acting drug (3Months)
Small molecule better penetrative power
Excellent Drying
133. Case of Dr Sherlock Holmes
• 83 YR DOCTOR OF A FAMILY OF DOCTORS
• HIGH MYOPE
• DV BOTH EYES FEW WEEKS
• TOLD OPHTHALMOLOGIST HE FELT HE HAD AMD
• CAME TO US BOTH EYES CNV
• RE CF 3M SUBFOVEAL CNV
• LE 6/9 JUXTAFOVEAL CNV
• BE BROLUCIZUMAB -LE FIRST
• 2nd dose at 1 month vision improvement in left eye 6/6 p N8
138. Naïve TYPE 1 CNV case-who bled to blindness
• 82 yr male
• Be glaucoma –cup0.9
• LE MASSIVE SUBRETINAL HAEM WITH CNV
• BROLUCIZUMAB GIVEN
• ZERO PROGNOSIS
• 1WEEK FLATTENING AND DRYING
142. CASE with big bumps
• 76 YR Female
• BE CNV
• RE SCARRRED -CFCF
• LE 6/12 OCCULT CNV WITH RED PED AND EXUDATES
• 3 RANIBIZUMAB
• NOW Brolucizumab
• DAY1 -6/9
• PED REDUCTION BY 200µ
Dham
154. 5. Outer Retinal Tubulations
Hyporeflective, branching tubular structure surrounded by a
hyperreflective ring, located in the outer nuclear layer of the retina and
often overlying fibrous scarring
Outer retinal tubulation may be misdiagnosed as intraretinal or
subretinal fluid, which lacks the hyperreflective border
1. Karen B et al. RETINA 35:1339–
1350, 2015
2. Erfurth U et al. Progress in Retinal
and Eye Research 50 (2016) 1-24
154
ORT
Open ORT (An
ovoid cross-section
lacking
hyperreflectivity on
its outer
aspect (adjacent to
the scar)
157. CASE who didn’t budge
• 78 YR Male
• BE SOFT DRUSENIOD PED 6/6
• Diminishing Vision for last 15 DAYS 6/12
• LARGE PED
• BROLUCIZUMAB DONE
• NO CHANGE IN 1 WEEK
• ? SOLID PED
IRA
159. 9. Condition of the Vitreomacular Interface
Studies report that the rate of posterior vitreous detachment in eyes with neovascular
AMD ranges from 60% to 74%
Patients with both posterior vitreous detachment and SRF at baseline demonstrated
very stable visual acuity benefits even with infrequent treatment
Eyes without vitreomacular adhesion demonstrated less need for retreatment in a PRN
protocol in CATT
Clinical Implications
Patients with complete posterior vitreous detachment, such patients may be
recommended a treat and extend regimen, particularly if SRF is also present at
baseline
On the other hand, patients without a complete posterior vitreous detachment should be
treated intensively and aggressively to avoid possible functional losses with infrequent
therapy
Mantel I, et al. Retina 2109:39:906–917
Erfurth U et al. Progress in Retinal and Eye Research 50 (2016) 1-24
167. CASE OF CRYSTALS
• 45 YR MALE
• BILATERAL CNV
• BIETTE’S CRYSTALLINE RETINAL DEGENERATION
• MULTIPLE INJ OF RANIBIZUMAB AND AFLIBERCEPT -10 YRS
• VISION OD-6/60, OS- CF 5 M
• ? OS BROLUCIZUMAB
MALK
168.
169. Case OF AN NRI
55 year male
RE 6/9
CNV
4 RANIBIZUMAB
OCT-INTRARETINAL SPLIT AT EZ ELM
Last BROLUCIZUMAB
DUB
179. Basic Succinct Statement
PAGENAX®
Presentation: Solution for injection. Each vial contains 27.6 mg of brolucizumab in 0.23 mL solution.
Indications: Pagenax is indicated for the treatment of neovascular (wet) age-related macular degeneration (AMD).
Dosage regimen and administration:
Single-use vial for intravitreal use only. Each vial should only be used for the treatment of a single eye. Pagenax must be administered by a qualified physician.
Adults: The recommended dose for Pagenax is 6 mg (0.05 mL) administered by intravitreal injection every 4 weeks (monthly) for the first three doses. Thereafter, Pagenax is administered every 12 weeks (3 months). The physician may individualize treatment intervals based on disease activity as assessed by visual acuity and/or
anatomical parameters. The treatment interval could be as frequent as every 8 weeks (2 months).
Special populations: ♦Renal impairment: No dose adjustment is required. ♦Hepatic impairment: No dose adjustment is required. ♦Geriatric patients: No dose adjustment is required. ♦Pediatric patients: Safety and efficacy have not been established.
Contraindications: ♦Hypersensitivity to the active substance or to any of the excipients. ♦Active or suspected ocular or periocular infection. ♦Active intraocular inflammation.
Warnings and precautions: ♦Endophthalmitis, retinal detachment, retinal vasculitis and/or retinal vascular occlusion: Intravitreal injections, including those with Pagenax, have been associated with endophthalmitis and retinal detachment. Proper aseptic injection techniques must always be used when administering Pagenax.
Retinal vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular inflammation, have been reported with the use of Pagenax. Patients should be instructed to report any symptoms suggestive of the above mentioned events without delay. ♦Intraocular pressure increases: Transient increases in intraocular
pressure have been seen within 30 minutes of injection, similar to those observed with intravitreal administration of other VEGF inhibitors. Sustained intraocular pressure increases have also been reported. Both intraocular pressure and perfusion of the optic nerve head must be monitored and managed appropriately. ♦Driving and
using machines: Patients may experience temporary visual disturbances after an intravitreal injection with Pagenax and the associated eye examination. Advise patients not to drive or use machinery until visual function has recovered sufficiently.
Pregnancy, lactation, females and males of reproductive potential
Pregnancy: The potential risk of use of Pagenax in pregnancy is unknown. However, based on the anti-VEGF mechanism of action, brolucizumab must be regarded as potentially teratogenic and embryo/fetotoxic. Therefore, Pagenax should not be used during pregnancy unless the expected benefits outweighs the potential risks to the
fetus.
Lactation: Breast-feeding is not recommended during treatment and for at least one month after the last dose when stopping treatment with Pagenax.
Females and males of reproductive potential: Women of reproductive potential should use effective contraception (methods that result in less than 1% pregnancy rates) during treatment with Pagenax and for at least one month after the last dose when stopping treatment with Pagenax.
Adverse drug reactions:
Common (1 to 10%): Visual acuity reduced, retinal haemorrhage, uveitis, iritis, vitreous detachment, retinal tear, cataracts, conjunctival haemorrhage, vitreous floaters, eye pain, intraocular pressure increase, conjunctivitis, retinal pigment epithelial tear, vision blurred, corneal abrasion, punctate keratitis, hypersensitivity.
Uncommon (<1%): Endophthalmitis, blindness, retinal artery occlusion, retinal detachment, conjunctival hyperaemia, lacrimation increased, abnormal sensation in eye, detachment of retinal pigment epithelium, vitritis, anterior chamber inflammation, irirodyclitis, anterior chamber flare, corneal oedema, vitreous haemorrhage.
Frequency not known: Retinal vasculitis, retinal vascular occlusion.
Interactions: No formal interaction studies have been performed.
Packs: One 0.23 ml vial, one filter needle
Before prescribing, please consult full prescribing information available from Novartis Healthcare Private Limited, Inspire BKC, Part of 601 & 701, Bandra Kurla Complex, Bandra (East), Mumbai – 400 051, Maharashtra, India. Tel +91 22 50243335/36, Fax +91 22 50243010.
To be sold by retail on the prescription of an Ophthalmologist only.
India BSS dated 6 Jul 2020 based on International BSS dtd 30 Apr 2020 effective from 23 Jul 2020.
