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• Use of these slides is permitted only for the purpose of scientific and educational presentations.
• While every reasonable effort has been made to ensure accuracy of content, it is the responsibility of the
practitioner, relying on experience and knowledge of the patient, to determine the best treatment for each
individual patient. Bayer shall not be responsible or in any way liable for the continued accuracy &/or veracity of the
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arising from relying on the information contained in the presentation or otherwise.
• The data contained herein does not reflect the views or opinion of Bayer for use of product in indications in which it
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• Bayer shall not be responsible/ liable for miscommunication of this data if they are altered/ tampered in any
manner.
• Opinions expressed do not necessarily reflect the views of Bayer. Medical knowledge is constantly changing, so
standard safety precautions must be followed.
• For use of Registered Medical Practitioners only
• Eylea (Aflibercept) is approved in nAMD/PCV indications in India.
3. The ASRS has recently released several member updates on IOI and occlusive retinal vasculitis
following brolucizumab administration. The information contained herein provides an update on
relevant intraocular safety information following aflibercept injection and provides context for the
ASRS communications.
Hot topics deck: Intraocular safety of anti-VEGF agents
ASRS, American Society of Retina Specialists; IOI, intraocular inflammation; VEGF, vascular endothelial growth factor.
4. Aflibercept has a well-established safety profile across RCTs
supported by real-world pharmacovigilance monitoring
.
AE, adverse event; IOI, intraocular inflammation; RAO, retinal artery occlusion; RCT, randomized controlled trial.
1. Bayer. Data on file; April 2020. 2. Bayer AG. EYLEA – summary of product characteristics; May 2020. 3. Kitchens JW et al. Ophthalmology 2016; 123 (7): 1511–1520.
Aflibercept has over 4.8 million patient-years of exposure and more than 34 million vials have been sold since
its launch.1 It has a well-established ocular and systemic safety profile across clinical trials in multiple indications,
and real-world pharmacovigilance monitoring demonstrates that it is well tolerated in clinical practice.1–3
The post-marketing reporting rate of ocular (retinal) vasculitis after aflibercept is 0.00002%
(7 cases overall in more than 34 million vials sold)*,1
To date, there are no new safety concerns regarding the development of retinal vasculitis and/or
retinal vascular occlusion that may result in severe vision loss following intravitreal aflibercept injection
The rate of IOI with aflibercept in routine clinical practice has remained low at 0.012%
(1.2 cases per 10,000 vials sold)1
The rate of endophthalmitis / non-infectious endophthalmitis with aflibercept in routine clinical practice
has remained low at 0.007% (0.7 cases in 10,000 vials sold)1
5. In a comprehensive review of 8 RCTs across 4 indications, rates of ocular and
systemic AEs were low with aflibercept and similar to the control arm
*The uncontrolled trials CLEAR-IT 2 and VIEW 1 extension were included in order to maximize the aflibercept exposure in the study.
AE, adverse event; APTC, Antiplatelet Trialists’ Collaboration; ATE, arterial thromboembolic event; BRVO, branch retinal vein occlusion; CRVO, central retinal vein occlusion; DME, diabetic macular edema;
IOI, intraocular inflammation; ME, macular edema; MI, myocardial infarction; nAMD, neovascular age-related macular degeneration; RCT, randomized controlled trial; RR, rate ratio; SAE, serious adverse event.
Kitchens JW et al. Ophthalmology 2016; 123 (7): 1511–1520.
• Kitchens et al. performed a comprehensive
review of the rates of ocular and non-ocular
AEs with aflibercept and its respective
comparators (predominantly ranibizumab,
but also laser and sham)
• Data were pooled from eight RCTs (Phase II
and Phase III) and two uncontrolled trials*
o Review included 4,203 patients with follow-up
ranging from <6 months to >5 years
• Rates of ocular and non-ocular AEs across
indications either do not differ between
aflibercept and its comparator, or favor
aflibercept over its comparator
0 1 2 3 4 5
IOI
Endophthalmitis
Wound-healing complications
Hypertension
SAE
All APTC-defined ATEs
Non-fatal MI
Non-fatal stroke
Vascular death
Death
Rate ratios of intravitreal aflibercept injection vs. control for AEs across
nAMD, ME after CRVO, ME after BRVO, and DME
Favors treatment Favors control
RR
6. IOI is a well-known but rare ocular AE that has historically been observed at
comparably low rates across clinical trials with all anti-VEGF agents
*Included the following terms: anterior chamber cell, anterior chamber flare, aqueous fibrin, endophthalmitis, eye infection, eye inflammation, hypopyon, iridocyclitis, iritis, non-infectious endophthalmitis, uveitis, vitreal cells, and
vitritis. AE, adverse event; IOI, intraocular inflammation; VEGF, vascular endothelial growth factor.
Bayer. Data on file; Integrated analysis – Core RMP update for IOI.
In VIEW 1 and VIEW 2, the rates of any IOI-related AE in the study eye were low over 96 weeks:
0.41% per injection
(40 cases in 9,805 injections)
Ranibizumab 0.5 mg
0.28% per injection
(74 cases in 26,366 injections)
Aflibercept arms pooled
7. Endophthalmitis is a well-known but rare ocular AE that has historically been
observed at comparably low rates across clinical trials with all anti-VEGF agents
AE, adverse event; q4, every 4 weeks; q8, every 8 weeks, after 3 initial monthly doses; VEGF, vascular endothelial growth factor.
Schmidt-Erfurth U et al. Ophthalmology 2014; 121 (1): 193–201.
In VIEW 1 and VIEW 2, the rates of endophthalmitis in the study eye were low over 96 weeks:
VIEW 1/2 (n=595)
0.8%
Ranibizumab 0.5 mg Aflibercept 2 mg q8
VIEW 1/2 (n=610)
0%
Aflibercept 2 mg q4
VIEW 1/2 (n=613)
0.7%
8. Overall rates of serious ocular AEs, including endophthalmitis, were
low in Phase III RCTs of aflibercept across retinal disease indications
.
*2 mg q8 after 3 initial monthly doses. †2 mg q8 after 5 initial monthly doses. AE, adverse event; CRVO, central retinal vein occlusion; DME, diabetic macular edema; nAMD, neovascular age-related macular degeneration;
PRN, pro re nata (as needed); q4, every 4 weeks; q8, every 8 weeks; RCT, randomized controlled trial.
1. Schmidt-Erfurth U et al. Ophthalmology 2014; 121 (1): 193–201. 2. Kaiser PK et al. Ophthalmol Retina 2017; 1 (4): 304–313. 3. Heier JS et al. Ophthalmology 2016; 123 (11): 2376–2385.
4. Brown DM et al. Am J Ophthalmol 2013; 155 (3): 429–437. 5. Heier JS et al. Ophthalmology 2014; 121 (7): 1414–1420. 6. Ogura Y et al. Am J Ophthalmol 2014; 158 (5): 1032–1038.
Trial – indication
Follow-up period for ocular SAE reporting
Treatment (regimen) Endophthalmitis, %
VIEW 1 and VIEW 2 – nAMD1
Follow-up to Week 96
Ranibizumab (0.5 mg q4, then modified quarterly dosing from Week 52) 0.8 (n=5/595)
Aflibercept (2 mg q8*, 2 mg q4, or 0.5 mg q4, then modified quarterly dosing from Week 52) 0.3 (n=5/1,824)
VIEW 1 extension – nAMD2
Follow-up from Week 96 to Week 212
Aflibercept (2 mg, modified quarterly dosing) 0.9 (n=3/323)
VIVID and VISTA – DME3
Follow-up to Week 148
Laser 0 (n=0/287)
Aflibercept (2 mg q8† or 2 mg q4) 0.5 (n=3/578)
COPERNICUS – CRVO4,5
Follow-up to Week 24
Sham 0 (n=0/74)
Aflibercept (2 mg q4) 0.9 (n=1/114)
Follow-up from Week 24 to Week 100
Weeks 0–24: sham;
Weeks 24–100: aflibercept (2 mg PRN)
0 (n=0/60)
Weeks 0–24: aflibercept (2 mg q4);
Weeks 24–100: aflibercept (2 mg PRN)
0 (n=0/110)
GALILEO – CRVO6
Follow-up to Week 76
Weeks 0–48: sham;
Weeks 52–76: aflibercept (2 mg PRN)
0 (n=0/68)
Weeks 0–20: aflibercept (2 mg q4);
Weeks 24–76: aflibercept (2 mg PRN)
0 (n=0/104)
Follow-up from Week 52 to Week 76
Weeks 0–48: sham;
Weeks 52–76: aflibercept (2 mg PRN)
0 (n=0/52)
Weeks 0–20: aflibercept (2 mg q4);
Weeks 24–76: aflibercept (2 mg PRN)
0 (n=0/91)
9. What information is provided in the recent ASRS communications
relating to brolucizumab and what are the current recommendations?
Hot topics deck: Intraocular safety of anti-VEGF agents
ASRS, American Society of Retina Specialists; VEGF, vascular endothelial growth factor.
10. Summary of recent events, including ASRS member alerts, an ASRS special report,
and several case reports relating to IOI and RAO / occlusive retinal vasculitis
ASRS, American Society of Retina Specialists; FDA, Food and Drug Administration; IOI, intraocular inflammation; nAMD, neovascular age-related macular degeneration; RAO, retinal artery occlusion; SRC, Safety Review Committee.
1. Novartis Pharmaceuticals Corp. Beovu – prescribing information; October 2019. 2. ASRS member communication; January 2020. 3. ASRS member communication; February 2020. 4. Safety of Beovu® (brolucizumab). Available at: https://www.brolucizumab.info. Accessed
June 2020. 5. ASRS member communication; March 2020. 6. Haug SJ et al. Am J Ophthalmol Case Rep 2020; 18: 100680. 7. Jain A et al. Am J Ophthalmol Case Rep 2020; 18: 100687. 8. Baumal CR et al. Ophthalmology 2020; Epub ahead of print (DOI: 10.1016/
j.ophtha.2020.04.017). 9. ASRS Special Report: Occlusive retinal vasculitis following intravitreal brolucizumab: An ASRS Research and Safety in Therapeutics (ReST) Committee Report; Spring 2020. 10. Safety of Beovu® (brolucizumab). Available at:
https://www.brolucizumab.info/. Accessed June 2020. 11. Rosenfeld PJ et al. Am J Ophthalmol 2020; doi: 10.1016/j.ajo.2020.05.012. 12. Retinal Physician. Editorial Calls for Halting Use of Beovu. Available at: https://www.retinalphysician.com/issues/2020/june-2020/editorial-
calls-for-halting-use-of-Beovu. Accessed June 2020. 13. ASRS member communication; June 2020. 14. Novartis. US FDA approves updated Novartis Beovu® label, to include additional safety information. Available at: https://www.novartis.com/news/media-releases/us-fda-
approves-updated-novartis-beovu-label-include-additional-safety-information. Accessed June 2020.
ASRS Special Report
Comprehensive report with updated information on cases
and numbers. Overall, 26 eyes from 25 patients were reported as
having retinal vasculitis, of which 22 eyes were designated occlusive.9
Oct
2019
Jan
2020
Mar
2020
Feb
2020
Apr
2020
Brolucizumab approved
for the treatment of
nAMD in the USA.1
ASRS member communication
Alert released to raise awareness of the
incidence of potential occlusive retinal
vasculitis with brolucizumab. Overall, 14
cases of retinal vasculitis were reported,
of which 11 were designated occlusive.3
First published case reports
• Retinal arterial occlusive vasculitis following
intravitreal brolucizumab administration.6
• Severe vision loss secondary to retinal
arteriolar occlusions after multiple intravitreal
brolucizumab administrations.7
• Retinal vasculitis and intraocular inflammation
after intravitreal injection of brolucizumab.8
Novartis confirms safety
signal with brolucizumab10
Launch of www.brolucizumab.info
Website providing updates on the safety
profile of brolucizumab.4
ASRS member communication
The ASRS warned physicians that it had begun
to receive physician reports of IOI following
administration of brolucizumab.2
ASRS member communication
Update released providing details on reports of vasculopathy,
including occlusive retinal vasculitis, with brolucizumab.5
May
2020
Jun
2020
Editorial article calls for
halting use of brolucizumab11
Two US clinicians provided their
perspective on the response of the
medical community to reports of IOI
following brolucizumab. This was
followed by a response from Novartis on
June 1 in Retinal Physician.12
ASRS member communication
Update released detailing the findings of the
Novartis-commissioned SRC review of safety data
from the Phase III HAWK and HARRIER trials.13
FDA approved updated
brolucizumab label
that includes additional
safety information14
11. HAWK and HARRIER: Patients receiving brolucizumab experienced
higher rates of serious ocular AEs compared with aflibercept
*Results focus on the safety database from HAWK and HARRIER, with supportive safety data provided from OSPREY, OWL, SHRIKE, and SEE. A brolucizumab 3 mg treatment group was included in HAWK only. †Uveitis = preferred
terms; uveitis, anterior chamber inflammation, and vitritis. A subject with multiple occurrences of a SAE for a preferred term is counted only once for that preferred term. ‡No explanation was provided as to why uveitis was reported
twice in this summary of SAEs. SAEs occurring in 1 subject in any treatment group: cataract subcapsular, dry AMD, macular hole, anterior chamber inflammation, blindness, cataract, cataract – traumatic, dacryocystitis, retinal artery
embolism, retinal depigmentation, retinopathy proliferative, vitritis.
AE, adverse events; AMD, age-related macular degeneration; FDA, Food and Drug Administration; EMA, European Medicines Agency IOI, intraocular inflammation; SAE, serious adverse events; VA, visual acuity.
1. FDA drug approval package: BEOVU (brolucizumab-dbII); Clinical review(s). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/761125Orig1s000MedR.pdf. Accessed June 2020.
2. Beovu – European public assessment report. Available at: https://www.ema.europa.eu/en/documents/assessment-report/beovu-epar-public-assessment-report_en.pdf. Accessed June 2020.
Serious ocular AEs occurring in ≥1 subjects in any treatment group
HAWK Pooled HAWK and HARRIER*
Brolucizumab 3 mg
(n=358)
Brolucizumab 6 mg
(n=730)
Aflibercept 2 mg
(n=729)
Subjects with ≥1 SAE, n (%) 6 (1.7) 25 (3.4) 11 (1.5)
AEs occurring in ≥1 subjects in any
treatment group, n (%)
Uveitis† 1 (0.3) 7 (1.0) 0
Endophthalmitis 3 (0.8) 4 (0.5) 1 (0.1)
Retinal artery occlusion 3 (0.8) 0 1 (0.1)
Uveitis‡ 1 (0.3) 5 (0.7) 0
VA reduced 0 2 (0.3) 3 (0.4)
Retinal detachment 1 (0.3) 2 (0.3) 2 (0.3)
Retinal artery thrombosis 0 2 (0.3) 0
Retinal pigment epithelial tear 0 2 (0.3) 0
Retinal tear 0 2 (0.3) 1 (0.1)
Both the FDA and EMA acknowledged more patients in the pooled brolucizumab
6 mg groups experienced serious ocular AEs than the pooled aflibercept groups1,2
12. • Aflibercept has a well-established safety profile across RCTs supported by real-world pharmacovigilance monitoring.
• The rate of IOI with aflibercept in routine clinical practice has remained low at 0.012% (1.2 cases per 10,000 vials
sold)
• The rate of endophthalmitis / non-infectious endophthalmitis with aflibercept in routine clinical practice
has remained low at 0.007% (0.7 cases in 10,000 vials sold)
• The post-marketing reporting rate of ocular (retinal) vasculitis after aflibercept is 0.00002%
(7 cases overall in more than 34 million vials sold)
• In a comprehensive review of 8 RCTs across 4 indications, rates of ocular and systemic AEs were low with aflibercept
and similar to the control arm.
• HAWK and HARRIER: Both the FDA and EMA acknowledged more patients in the pooled Brolucizumab
6 mg groups experienced serious ocular AEs than the pooled Aflibercept groups.
• Rates of IOI were 5-fold higher among patients who received Brolucizumab 6 mg compared with patients who
received aflibercept (4.4% [95%CI: 2.30–7.08] vs 0.8% [95%CI 0.14–1.63], respectively)
• The EMA noted a signal for increased IOI risk with Brolucizumab compared with aflibercept, with a risk difference of
3.6% (95% CI: 1.08–6.53) between the treatment groups in favour of aflibercept.
• The ASRS has recently released several member updates on IOI and occlusive retinal vasculitis following Brolucizumab
administration
Summary
13. HAWK and HARRIER: Patients receiving brolucizumab experienced numerically higher
rates of IOI, including more cases of endophthalmitis, than those receiving aflibercept
AEs with a start date on or after the date of first study drug administration are counted. AEs with a start date on or after the start date of treatment with an alternative anti-VEGF are not included. *Results focus on the safety database
from HAWK and HARRIER, with supportive safety data provided from OSPREY, OWL, SHRIKE, and SEE. A brolucizumab 3 mg treatment group was included in HAWK only. †Preferred term: retinopathy hypertensive. ‡Preferred term:
contusion. AE, adverse event; CI, confidence interval; EMA, European Medicines Agency; FDA, Food and Drug Administration; IOI, intraocular inflammation; IOP, intraocular pressure; VEGF, vascular endothelial growth factor.
1. FDA drug approval package: BEOVU (brolucizumab-dbII); Clinical review(s). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/761125Orig1s000MedR.pdf. Accessed June 2020.
2. Beovu – European public assessment report. Available at: https://www.ema.europa.eu/en/documents/assessment-report/beovu-epar-public-assessment-report_en.pdf. Accessed June 2020.
Preferred term, n (%) [eyes]
HAWK Pooled HAWK and HARRIER*
Brolucizumab 3 mg
(n=358)
Brolucizumab 6 mg
(n=730)
Aflibercept 2 mg
(n=729)
Subjects with ≥1 AE 59 (16.5) [96] 105 (14.4) [161] 86 (11.8) [110]
IOI 16 (4.5) [25] 32 (4.4) [44] 6 (0.8) [10]
Endophthalmitis 4 (1.1) [4] 5 (0.7) [5] 1 (0.1) [1]
IOP increased 18 (5.0) [33] 28 (3.8) [4.1] 33 (4.5) [44]
Hypersensitivity 11 (3.1) [11] 18 (2.5) [22] 19 (2.6) [20]
Retinal pigment epithelial tear 5 (1.4) [6] 20 (2.7) [20] 8 (1.1) [9]
Glaucoma 5 (1.4) [5] 4 (0.5) [4] 9 (1.2) [9]
Arterial thromboembolic events 4 (1.1) [5] 9 (1.2) [9] 3 (0.4) [3]
Retinal arterial occlusive events 4 (1.1) [5] 6 (0.8) [6] 1 (0.1) [1]
Venous thromboembolic events 3 (0.8) [3] 0 0
Vitreous hemorrhage 1 (0.3) [1] 1 (0.1) [1] 3 (0.4) [3]
Hypertension† 1 (0.3) [1] 0 0
Non-ocular hemorrhage‡ 0 0 2 (0.3) [2]
Traumatic cataract 0 1 (0.1) [1] 0
Ocular AEs in the study eye potentially related to intravitreal anti-VEGF1
Both the FDA and the EMA highlighted that the rate of IOI was higher in the pooled
brolucizumab 6 mg groups compared with the pooled aflibercept groups at Week 961,2
• Rates of IOI were 5-fold higher among patients who received brolucizumab 6 mg compared with patients
who received aflibercept (4.4% [95%CI: 2.30–7.08] vs 0.8% [95%CI 0.14–1.63], respectively)1,2
• The EMA noted a signal for increased IOI risk with brolucizumab compared with aflibercept, with a risk
difference of 3.6% (95% CI: 1.08–6.53) between the treatment groups in favor of aflibercept2
14. January 22, 2020: The ASRS issued a member alert highlighting
first reports of IOI following use of brolucizumab in clinical practice
AE, adverse event; ASRS, American Society of Retina Specialists; FDA, Food and Drug Administration; IOI, intraocular inflammation; ReST, Research and Safety in Therapeutics.
ASRS member communication; January 2020.
The ASRS encouraged practitioners to report
all drug- and device-related AEs and reminded
members that administration of brolucizumab and
aflibercept is contraindicated in the setting of
active IOI (drug-related or otherwise), according to
their FDA labels.
[Brolucizumab] update for ASRS members
“The ASRS ReST Committee has begun to receive physician reports
of intraocular inflammation following administration of Beovu.
In the pivotal Phase III trials, inflammation was noted in up to
4% of Beovu patients as indicated on the FDA label.
The ASRS encourages practitioners to report all drug- and
device-related adverse events. Particularly in the setting of a newly
approved dug or device, such reports are critical in defining our
real-world experienced through analysis of the aggregate of
collected reports. We remind members that administration of Beovu
and Eylea is contraindicated in the setting of active intraocular
inflammation (drug-related or otherwise), according to their FDA
labels.”
15. February 23, 2020: The ASRS issued a member alert highlighting
cases of occlusive vasculitis following brolucizumab administration
ASRS, American Society of Retina Specialists; FDA, Food and Drug Administration; IOI, intraocular inflammation; VEGF, vascular endothelial growth factor.
ASRS member communication; February 2020.
• An ASRS member update was released to
raise awareness of the incidence of potential
occlusive retinal vasculitis within the
ophthalmology community and to encourage
close monitoring for IOI following brolucizumab
treatment
• In addition to cases of mild to moderate IOI,
these reports included 14 cases of vasculitis,
of which 11 were designated as occlusive
retinal vasculitis
• The ASRS urged clinicians to carefully inspect
the eye for any IOI immediately prior to
injection of brolucizumab and to defer anti-
VEGF administration when any concerning
signs of inflammation are present
[Brolucizumab] update for ASRS members
“Since FDA approval of Beovu on [October 7, 2019], the ASRS has received reports
of intraocular inflammation following Beovu administration. In addition to cases
of mild–moderate intraocular inflammation, these reports have included 14 cases
of vasculitis, of which 11 were designated as occlusive retinal vasculitis by the
reporting provider. Novartis estimates that approximately 46,000 injections have
been administered to date in the US. The etiology of these events is unclear. Long-
term outcomes and optimal treatment strategies are not defined at this time…
In the setting of Beovu-associated inflammation, the ASRS encourages close follow
up and appropriate imaging, as some cases of occlusive vasculitis may initially be
subtle or present in a delayed fashion.
Current, and future, informed consent should appropriately discuss and
document potential risks.
We urge vigilance and reporting of any adverse treatment-related events,
regardless of agent, by all practitioners. The ASRS will continue to track these
events and update the retina community as further information
becomes available.”
16. March 30, 2020: The ASRS issued a member update detailing post-approval
cases of occlusive retinal vasculitis reported with brolucizumab1
AMD, age-related macular degeneration; ASRS, American Society of Retina Specialists; FDA, Food and Drug Administration; ReST, Research and Safety in Therapeutics.
1. ASRS member communication; March 2020. 2. ASRS Special Report. Occlusive retinal vasculitis following intravitreal brolucizumab: An ASRS Research and Safety in Therapeutics (ReST) Committee Report; Spring 2020.
3. ASRS member communication; February 2020.
• Key findings from a safety analysis by the
ASRS ReST Committee were reported in this
update and later highlighted in an ASRS Special
Report (April 7, 2020)2
• This update included reports of vasculopathy
including occlusive vasculitis following
brolucizumab from 25 eyes of 24 patients, an
increase on the 14 cases report in an earlier
member update (February 23, 2020)1–3
• The ASRS notified its members that Novartis has
appointed an independent Safety Review
Committee (SRC) to review inflammation-related
safety events in the post-marketing setting as
well as in the HAWK and HARRIER trials1
[Brolucizumab] update for ASRS members1
“Since the October 7, 2019 FDA approval of Beovu for treatment of neovascular
AMD (with permanent J-code effective on 1/1/2020), the ASRS Research and
Safety in Therapeutics (ReST) Committee has received reports of vasculopathy
including occlusive vasculitis following intravitreal injection of the drug.
From these reports, the ASRS has reviewed detailed clinical data from
25 eyes (of 24 patients) including imaging from 23 eyes…
…The ASRS will continue to follow these cases. Additionally, Novartis has
appointed an independent Safety Review Committee to review these events both
in the post-marketing setting as well as in HAWK/HARRIER. This committee
consists of both academic and private practice members, including uveitis and
imaging specialists, from around the world, and we expect that this committee
will present their findings to the retina community separately.
The ASRS will continue to keep the retina community updated with available
information and asks physicians to report any Beovu-related adverse events to
the ASRS, FDA, and Novartis. As always, the ASRS encourages active vigilance
and reporting of all drug- and device-related adverse events.”
17. • The ASRS published a Special Report detailing post-approval cases of retinal vasculitis reported
with brolucizumab
o Data from 26 eyes of 25 patients with retinal vasculitis after receiving brolucizumab were collected:
April 7, 2020: The ASRS ReST Committee concluded that intravitreal brolucizumab injection
appears to be associated with retinochoroidal vasculopathy (including occlusive vasculitis)
AE, adverse event; ASRS, American Society of Retina Specialists; ETDRS, Early Treatment Diabetic Retinopathy Study; IOI, intraocular inflammation; ReST, Research and Safety in Therapeutics; VA, visual acuity;
VEGF, vascular endothelial growth factor.
ASRS Special Report. Occlusive retinal vasculitis following intravitreal brolucizumab: An ASRS Research and Safety in Therapeutics (ReST) Committee Report; Spring 2020.
• No eyes had a history of anti-VEGF associated inflammation,
and only 1 patient had a history of iritis
• 22 of 26 eyes (85%) with retinal vasculitis were reported as
having occlusive vasculitis
• Overall, a mean vision loss of approximately 37 ETDRS letters
(between 6 and 7 lines) from baseline was recorded at the
most recent follow-up visit
• 88% of reported cases occurred in women
• All AEs arose after 1 (11 eyes, 44%), 2 (11 eyes, 44%), or
3 (4 eyes, 12%) brolucizumab injections, though it is unlikely
that a meaningful number of patients received more than
3 injections by the time of this analysis
• Mean time to presentation was 25.5 days (range 3–63 days)
from the most recent brolucizumab injection
VA parameter Snellen (approx. ETDRS letters)
All eyes (N=26)
Mean VA at baseline 20/45 (67.5)
Mean VA at most recent brolucizumab injection 20/52 (64.5)
Mean VA at AE onset 20/151 (41)
Mean worst VA 20/397 (20)
Mean VA at most recent follow-up 20/243 (31)
Eyes with >60 days of follow-up (n=8)
Mean VA at baseline 20/52 (64.5)
Mean VA at AE onset 20/145 (42)
Mean worst VA 20/512 (14.5)
Mean VA at most recent follow-up 20/214 (33.5)
18. Of the 8 eyes that were re-treated with a different anti-VEGF agent after diagnosis of an AE related to brolucizumab:1
The ASRS Special Report included information on 8 eyes that were re-treated with
a different anti-VEGF agent after diagnosis of an AE related to brolucizumab
AE, adverse event; ASRS, American Society of Retina Specialists; ReST, Research and Safety in Therapeutics; VEGF, vascular endothelial growth factor.
1. ASRS Special Report. Occlusive retinal vasculitis following intravitreal brolucizumab: An ASRS Research and Safety in Therapeutics (ReST) Committee Report; Spring 2020. 2. Bayer AG. EYLEA – summary of product characteristics;
May 2020. 3. Novartis Pharmaceuticals Corp. Beovu – prescribing information; October 2019. 4. Novartis Pharmaceuticals Corp. Lucentis – summary of product characteristics; January 2020.
• Overall, 4 of these eyes received aflibercept once inflammation had
resolved, and there was no recurrence of inflammation in those eyes
• In another 2 eyes, there was persistent posterior-only inflammation
at the time of retreatment with aflibercept, but there was no
worsening of inflammation after aflibercept injection
• In the last 2 eyes, onset of occlusive vasculitis was noted to follow
injection of anti-VEGF medication (one received aflibercept and the
other received ranibizumab) in the setting of pre-existing, active
brolucizumab-associated inflammation
If considering switching a patient experiencing brolucizumab-associated inflammation back to aflibercept, it is important
to note that intravitreal administration of any anti-VEGF agent is contraindicated in patients with active inflammation.2–4
Anti-VEGF agents should not be administered while a patient is presenting with signs of an ongoing inflammation.
19. Several case reports of patients who experienced RAO and severe vision loss
after intravitreal brolucizumab injections have now been published1–3
RAO, retinal artery occlusion; VA, visual acuity; VEGF, vascular endothelial growth factor.
1. Haug SJ et al. Am J Ophthalmol Case Rep 2020; 18: 100680. 2. Jain A et al. Am J Ophthalmol Case Rep 2020; 18: 100687. 3. Baumal C et al. Ophthalmology 2020: doi: https://doi.org/10.1016/ j.ophtha.2020.04.017.
A total of 18 eyes were included
across all published case reports, all of
which were previously treated with
other anti-VEGF agents, including
aflibercept, without any inflammatory
response prior to switching to
brolucizumab. After switching to
brolucizumab, several patients
experienced life-impacting vision loss,
and their VA did not return to baseline
(i.e. before the switch) after cessation
of brolucizumab treatment.3
20. Novartis concluded there is a confirmed safety signal of rare AEs of “retinal vasculitis and/or retinal
vascular occlusion that may result in severe vision loss” after intravitreal brolucizumab injection
*Event rates are discrete; there is no duplication between categories. †Includes reports of retinal artery occlusion, retinal artery thrombosis, retinal artery embolism, retinal ischemia, arterial occlusive disease, and retinal vascular
occlusion. AE, adverse event; IOI, intraocular inflammation; SAE, serious adverse event.
1. ASRS Special Report: Occlusive retinal vasculitis following intravitreal brolucizumab: An ASRS Research and Safety in Therapeutics (ReST) Committee Report; Spring 2020.
2. Safety of Beovu® (brolucizumab). Available at: https://www.brolucizumab.info. Accessed June 2020.
It is estimated that 70,000 brolucizumab vials have been used post-marketing in 37,000 unique patients.1
AE* Post-marketing AE rates
Total of three events of interest 6.99 per 10,000 injections
Retinal vasculitis 1.69 per 10,000 injections
Retinal vascular occlusion
†
1.57 per 10,000 injections
Retinal vasculitis and retinal vascular occlusion* 3.73 per 10,000 injections
The SRC also conducted an unmasked review of a subset of imaging data from HAWK and HARRIER and indicated that
they saw some of the same AEs in the trials. They found that these events occurred on a spectrum ranging from IOI to
vasculitis to occlusive events that sometimes resulted in vision loss. The SRC continues to review safety data from the
HAWK and HARRIER trials and is expected to publish its independent review in the coming months.2
Current safety data from the brolucizumab information website (as of May 8, 2020)2
Brolucizumab
21. Post-marketing reporting rates of “retinal vasculitis and/or retinal
vascular occlusion” with aflibercept remain low since its launch
*Event rates are discrete; there is no duplication between categories. †Includes reports of retinal vasculitis, ocular vasculitis, hemorrhagic vasculitis (upon review = ocular occurrence). ‡Includes reports of RAO, retinal artery
embolism, retinal artery stenosis, retinal artery thrombosis, retinal artery spasm, retinal ischemia, retinal vascular occlusion, retinal vascular thrombosis. §Includes one case where aflibercept was injected in active IOI/vitritis
following brolucizumab and the patient developed hemorrhagic vasculitis and RAO, and one case reported as occlusive vasculitis that was deemed appropriate for the combination category.
AE, adverse event; IOI, intraocular inflammation; RAO, retinal artery occlusion.
Bayer. Data on file; April 2020.
As of March 31, 2020 more than 34 million aflibercept vials had been sold globally.
AE* Post-marketing AE rates
Total of three events of interest 0.03 per 10,000 sold vials
Retinal vasculitis
†
0.001 per 10,000 sold vials
Retinal vascular occlusion
‡
0.03 per 10,000 sold vials
Retinal vasculitis and retinal vascular occlusion
§
0.0006 per 10,000 sold vials
Safety data for aflibercept information website (case data as of April 30; exposure as of March 31, 2020)
Aflibercept
22. Across clinical trials and real-world pharmacovigilance monitoring,
retinal vasculitis has not been a safety signal with aflibercept
*Includes one case where aflibercept was injected in active IOI/vitritis following brolucizumab and developed hemorrhagic vasculitis and RAO. This patient had previously received 40 aflibercept injections and was switched because
of residual SRF, but then had vitritis at the next visit and was switched back to aflibercept immediately.
IOI, intraocular inflammation; RAO, retinal artery occlusion; SRF, subretinal fluid; VEGF, vascular endothelial growth factor.
1. Bayer. Data on file; January 2020. 2. Bayer. Data on file; April 2020. 3. Bayer AG. EYLEA – summary of product characteristics; May 2020. 4. Novartis Pharmaceuticals Corp. Beovu – prescribing information; October 2019.
5. Novartis Pharmaceuticals Corp. Lucentis – summary of product characteristics; January 2020.
None of the reported cases of retinal vasculitis were
deemed as occlusive across all Phase III trials of aflibercept.1
Post-marketing cases of vasculitis as of April 30, 20202
Ocular (retinal) vasculitis* 0.002 per 10,000 vials sold
Systemic vasculitis 0.0003 per 10,000 vials sold
Any vasculitis 0.002 per 10,000 vials sold
The post-marketing reporting rate of ocular (retinal) vasculitis after
aflibercept is 0.00002% (7 cases overall in 34 million vials sold).
One of these cases is a patient switched to aflibercept in the setting of
active inflammation / vitritis following brolucizumab administration.2
If considering switching patients back to aflibercept, it is important to
remember that aflibercept (or any anti-VEGF agent) is contraindicated
in patients with active inflammation and should not be administered
while a patient is presenting with signs of an ongoing inflammation.3–5
Rate of retinal vasculitis across pivotal
Phase III clinical trials (N=3,236)1
Rate of retinal vasculitis 0.06% (n=2)
Aflibercept
23. In May 2020, an editorial article provided the perspective of two US clinicians on the
response of the medical community to reports of IOI following brolucizumab
AE, adverse event; AMD, age-related macular degeneration; FDA, Food and Drug Administration; IOI, intraocular inflammation; nAMD, neovascular age-related macular degeneration.
1. Rosenfeld PJ et al. Am J Ophthalmol 2020; doi: 10.1016/j.ajo.2020.05.012.
2. Retinal Physician. Editorial Calls for Halting Use of Beovu. Available at: https://www.retinalphysician.com/issues/2020/june-2020/editorial-calls-for-halting-use-of-Beovu. Accessed June 2020.
• The authors praised the fast response of the ophthalmic community
in identifying cases of inflammation following brolucizumab injection
and reporting them to the appropriate authorities1
• While investigations into the causes of inflammation-related AEs
with brolucizumab are ongoing, the authors concluded that use of
brolucizumab is unwarranted since other agents are available for the
treatment of nAMD1
o Notably, they recommended that brolucizumab injections should be
stopped until further investigations are concluded and remedies
implemented, and that this should be made official by the relevant
ophthalmological societies and the FDA1
On June 1, Novartis issued a response to the editorial:
“…While we respect individual perspectives, we believe [brolucizumab]
continues to represent an important treatment option, addressing unmet needs
for patients with wet AMD, with an overall favorable benefit-risk profile.”2
24. Novartis has issued guidance for physicians around IOI-related AEs with brolucizumab
and managing patients with these events after intravitreal injection
AE, adverse event; IOI, intraocular inflammation; VA, visual acuity; VEGF, vascular endothelial growth factor.
Safety of Beovu® (brolucizumab). Available at: https://www.brolucizumab.info/. Accessed June 2020.
• Post-marketing reports of IOI-related AEs suggest that these events can occur as early as the first or second
injection of brolucizumab, with patients reporting changes in vision, such as significant increase in floaters or
blurry vision, within 1–2 weeks of treatment
• As such, Novartis provided general guidance for physicians on the www.brolucizumab.info website as follows:
• Before injecting look for signs of IOI; this may involve
examination by slit lamp or posterior segment imaging
• If active IOI is present, you must not perform an intraocular
injection and should treat the IOI according to medical practice
• Instruct your patients to contact you immediately if they notice
any changes in VA or any signs of inflammation, such as eye pain,
floaters, discomfort, or ocular hyperemia
• As a reminder, all anti-VEGF agents are contraindicated in patients
with ocular or periocular infections, active IOI, or known
hypersensitivity to any of the excipients
25. June 4, 2020: The ASRS issued a member update detailing the findings of the
Novartis-commissioned SRC review of safety data from HAWK and HARRIER
ASRS, American Society of Retina Specialists; IOI, intraocular inflammation; ReST, Research and Safety in Therapeutics; SRC, Safety Review Committee; VEGF, vascular endothelial growth factor.
ASRS member communication; June 2020.
• The occurrence of IOI in association with retinal vasculitis and
retinal vascular occlusion is a new safety signal that appears
to be specific to brolucizumab.
• 23 treatment-naive patients (2.1%) treated with
brolucizumab developed IOI with concomitant retinal
vasculitis and vascular occlusion, while just 1 patient (0.1%)
treated with aflibercept was found to have “probable” IOI
with retinal vasculitis and retinal vascular occlusion.
• It is difficult to predict when inflammation events will occur
after brolucizumab injection. In cases where a patient has
tolerated brolucizumab treatment for a period of time, they
may still be at risk of experiencing inflammation events after
brolucizumab injection.
• The ASRS ReST Committee did not provide a conclusive
statement on the risk–benefit profile of brolucizumab,
instead recommending that the risk–benefit profile should be
determined by the treating physician on a case-by-case basis.
[Brolucizumab] update for ASRS members
• “Post-marketing reports have highlighted the occurrence of IOI in association
with retinal vasculitis and retinal vascular occlusion with brolucizumab, which
differs from the common experience with other approved anti-VEGF agents.”
• “IOI of any form was identified in 4.6% (50/1,088) of study patients.
Of those, 36 subjects had concomitant retinal vasculitis for an overall rate of
3.3% (36/1,088). Of the 36 subjects with IOI and vasculitis, 23 subjects had
concomitant vascular occlusion for an overall rate of 2.1% (23/1,088).”
• “…although the SRC identified that the majority of inflammation events
presented within the first 6 months of brolucizumab initiation (74%, 37/50),
some events presented between 12–18 months (12%, 6/50).”
• “The ReST Committee believes that this risk–benefit assessment at the
individual patient level is best determined by the judgment of the
treating provider.”
26. June 10, 2020: The FDA approved updates to the US Prescribing Information for
brolucizumab to include the new safety signal under ‘Warnings and Precautions’1,2
AE, adverse event; FDA, Food and Drug Administration; IOI, intraocular inflammation.
1. Novartis. US FDA approves updated Novartis Beovu® label, to include additional safety information. Available at: https://www.novartis.com/news/media-releases/us-fda-approves-updated-novartis-beovu-label-include-additional-
safety-information. Accessed June 2020. 2. Novartis Pharmaceuticals Corp. Beovu – prescribing information; June 2020.
The update to the US label includes characterization of
retinal vasculitis and retinal vascular occlusion as part of
the spectrum of IOI-related AEs observed in HAWK and
HARRIER, and includes the addition of a sub-section
dedicated to retinal vasculitis and/or retinal vascular
occlusion under ‘Warnings and Precautions’ (Section 5
of the US Prescribing Information).1
“Retinal vasculitis and/or retinal vascular occlusion,
typically in the presence of intraocular inflammation,
have been reported with the use of [brolucizumab].
Patients should be instructed to report any
change in vision without delay.” 2
27. Aflibercept has a well-established safety profile across RCTs
supported by real-world pharmacovigilance monitoring
*Includes one case where aflibercept was injected in active IOI/vitritis following brolucizumab and the patient developed hemorrhagic vasculitis and RAO. This patient had previously received 40 aflibercept injections and was
switched because of residual SRF, but then had vitritis at the next visit and was switched back to aflibercept immediately.
AE, adverse event; IOI, intraocular inflammation; RAO, retinal artery occlusion; RCT, randomized controlled trial.
1. Bayer. Data on file; April 2020. 2. Bayer AG. EYLEA – summary of product characteristics; May 2020. 3. Kitchens JW et al. Ophthalmology 2016; 123 (7): 1511–1520.
Aflibercept has over 4.8 million patient-years of exposure and more than 34 million vials have been sold since
its launch.1 It has a well-established ocular and systemic safety profile across clinical trials in multiple indications,
and real-world pharmacovigilance monitoring demonstrates that it is well tolerated in clinical practice.1–3
The post-marketing reporting rate of ocular (retinal) vasculitis after aflibercept is 0.00002%
(7 cases overall in more than 34 million vials sold)*,1
To date, there are no new safety concerns regarding the development of retinal vasculitis and/or
retinal vascular occlusion that may result in severe vision loss following intravitreal aflibercept injection
The rate of IOI with aflibercept in routine clinical practice has remained low at 0.012%
(1.2 cases per 10,000 vials sold)1
The rate of endophthalmitis / non-infectious endophthalmitis with aflibercept in routine clinical practice
has remained low at 0.007% (0.7 cases in 10,000 vials sold)1
28. Levels of ADAs increased with exposure to brolucizumab –
why have the EMA and FDA highlighted this finding?
Hot topics deck: Intraocular safety of anti-VEGF agents
ADA, anti-drug-antibodies; EMA, European medicines agency; FDA, Food and Drug Administration; VEGF, vascular endothelial growth factor.
29. HAWK and HARRIER: Anti-drug antibodies (ADAs) increased with
brolucizumab exposure
ADA, anti-drug antibodies; FDA, Food and Drug Administration; nAb, neutralizing antibodies; SPC, summary of product characteristics.
1. FDA drug approval package: BEOVU (brolucizumab-dbII); Clinical pharmacology review(s). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/761125Orig1s000ClinPharmR.pdf. Accessed June 2020.
2. Regeneron Pharmaceuticals. EYLEA – prescribing information; December 2011. 3. Bayer AG. EYLEA – summary of product characteristics; May 2020.
HAWK
(n=360)
HARRIER
(n=369)
Total
(N=729)
Baseline ADA+ 128 (36%) 193 (52%) 321 (44%)
≥1 sample ADA+ 241 (67%) 281 (76%) 522 (72%)
Baseline nAb+ 15 (4%) 105 (29%) 120 (17%)
≥1 sample nAb+ 81 (23%) 151 (41%) 232 (32%)
Neutralizing antibodies were detected in 23–41%
patients receiving brolucizumab 6 mg
Immunogenicity status of patients receiving brolucizumab 6 mg in the safety population1
ADAs were detected in
the pre-treatment serum
sample of up to half of
treatment-naive patients
After initiation of dosing,
the presence of
ADAs increased
In the US prescribing information for aflibercept, pre-treatment incidence of ADAs to
aflibercept was 1–3%. After dosing with aflibercept for 24–100 weeks, ADAs did not increase.2
The EU SPC for aflibercept does not include reference to incidence of ADAs.3
Brolucizumab
Aflibercept
30. HAWK
(n=360)
HARRIER
(n=369)
Total
(N=729)
Baseline ADA+ 128 (36%) 193 (52%) 321 (44%)
≥1 sample ADA+ 241 (67%) 281 (76%) 522 (72%)
Baseline nAb+ 15 (4%) 105 (29%) 120 (17%)
≥1 sample nAb+ 81 (23%) 151 (41%) 232 (32%)
Immunogenicity status of patients receiving brolucizumab 6 mg in the safety population1
HAWK and HARRIER: Anti-drug antibodies (ADAs) increased with
brolucizumab exposure
ADA, anti-drug antibodies; EMA, European Medicines Agency; FDA, Food and Drug Administration; IOI, intraocular inflammation; nAb, neutralizing antibodies.
1. FDA drug approval package: BEOVU (brolucizumab-dbII); Clinical pharmacology review(s). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/761125Orig1s000ClinPharmR.pdf. Accessed June 2020.
2. Beovu – European public assessment report. Available at: https://www.ema.europa.eu/en/documents/assessment-report/beovu-epar-public-assessment-report_en.pdf. Accessed June 2020. 3. Novartis Pharmaceuticals
Corp. Beovu – prescribing information; October 2019,
• The EMA highlighted the potential for an immune response in patients treated with brolucizumab; among
patients with treatment-emergent ADAs, a higher number of IOI adverse reactions were observed2
• The FDA also highlighted that IOI was observed in 6% of patients with treatment-emergent antibodies
(and in 2% patients without positive antibodies)3
• Both the EMA and FDA noted that the clinical relevance of the impact of ADAs on safety remains unclear2,3
Brolucizumab
31. Summary: Intraocular safety of anti-VEGF agents
ADA, anti-drug antibody; AE, adverse event; CI, confidence interval; EMA, European Medicines Agency; FDA, Food and Drug Administration; IOI, intraocular inflammation; SRC, safety review committee; VEGF, vascular endothelial growth factor.
1. FDA drug approval package: BEOVU (brolucizumab-dbII); Clinical review(s). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/761125Orig1s000MedR.pdf. Accessed June 2020. 2. Beovu – European public assessment report. Available
at: https://www.ema.europa.eu/en/documents/assessment-report/beovu-epar-public-assessment-report_en.pdf. Accessed June 2020. 3. Novartis Pharmaceuticals Corp. Beovu – prescribing information; October 2019. 4. Bayer. Data on file; April 2020. 5. Bayer
AG. EYLEA – summary of product characteristics; May 2020.6. Kitchens JW et al. Ophthalmology 2016; 123 (7): 1511–1520. 7. ASRS Special Report: Occlusive retinal vasculitis following intravitreal brolucizumab: An ASRS Research and Safety in Therapeutics
(ReST) Committee Report; Spring 2020. 8. Safety of Beovu® (brolucizumab). Available at: https://www.brolucizumab.info/. Accessed June 2020. 9. Novartis Pharmaceuticals Corp. Lucentis – summary of product characteristics; January 2020.
10. FDA drug approval package: BEOVU (brolucizumab-dbII); Clinical pharmacology review(s). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/761125Orig1s000ClinPharmR.pdf. Accessed June 2020. 11. Regeneron Pharmaceuticals.
EYLEA – prescribing information; December 2011.
The rate of serious ocular AEs was numerically higher with brolucizumab than with aflibercept in HAWK and HARRIER, and
the rate of IOI with brolucizumab was 5-fold that with aflibercept. The EMA noted a signal for increased IOI risk with
brolucizumab, with a risk difference of 3.6% (95% CI: 1.08–6.53) between the treatment groups in favor of aflibercept.1–3
• Aflibercept has over 4.8 million patient-years of exposure and more than 34 million vials have been sold since its launch.3 It has a
well-established ocular and systemic safety profile across clinical trials in multiple indications, and real-world pharmacovigilance
monitoring demonstrates that it is well tolerated in clinical practice.4–6
Novartis and an independent external SRC concluded that there is a confirmed safety signal of rare AEs of “retinal vasculitis
and/or retinal vascular occlusion that may result in severe vision loss” after intravitreal brolucizumab injection.7,8
• To date, there are no new safety concerns regarding the development of retinal vasculitis and/or retinal vascular occlusion that may result
in severe vision loss following intravitreal aflibercept injection.
• If considering switching patients back to aflibercept, it is important to remember that intravitreal administration of aflibercept (or any
anti-VEGF agent) is contraindicated in patients with active inflammation. Therefore, anti-VEGF agents should not be administered while
a patient is presenting with signs of an ongoing inflammation.3,5,9
The brolucizumab US label highlights that ADAs increased with brolucizumab exposure, and that IOI was observed in 6% of
patients with treatment-emergent antibodies in HAWK and HARRIER.10
• In contrast, the US prescribing information aflibercept states that after dosing with aflibercept for 24–100 weeks, ADAs did not increase;
however, the clinical relevance of the impact of ADAs on vision and safety remains unclear.10,11
