Various anti vegf structure usage indication and their future

3. Ranibizumab Aflibercept Bevacizumab
Company Genentech/Novartis Regeneron/Bayer Genentech/Roche
MOA /class
Anti-VEGF-A antibody fragment
[targets all VEGF-A isoforms]1
Anti-VEGF-A/PIGF/VEGF-B
recombinant fusion protein
[targets all VEGF-A isoforms,
VEGF-B and PIGF]4
Anti-VEGF-A
full-length antibody
[targets all VEGF-A isoforms]8
Molecular weight 48 kDa2 97–115 kDa4 149 kDa8
Half-life in the
rabbit eye
2.88 days3 4.79 days5 4.32 days3
Half-life in the
human eye
3.2 days1 4.8days 6.7 days9
Systemic elimination
half-life
~2 hours2 4–5 days6.7 20 days8
Licensed
indications
Wet AMD, visual impairment
due to DME, visual impairment due to ME
secondary to RVO (BRVO and CRVO)1
Wet AMD in the USA, Australia,
Colombia and Japan4; CRVO in
the USA; metastatic colorectal
cancer in the USA
Metastatic colorectal cancer, non-
small cell lung cancer, glioblastoma,
metastatic kidney cancer8
Formulation/
administration
Intravitreal injection
from a single-use vial1
Intravitreal injection
from a single-use vial (US and
Australia)4, or pre-filled syringe
(Australia); intravenous infusion
For licensed indications: intravenous
infusion from a single-use vial8
3
1. Novartis Europharm Ltd. Lucentis SmPC. September 2011; 2. www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/0007 15/WC500043550.pdf; 3. Bakri SJ et al. Ophthalmology
2007;114:2179–82; 4. Regeneron Pharmaceuticals, Inc. EYLEA® prescribing information. November 2011; 5. Regeneron Pharmaceuticals, unpublished data; 6. Dixon JA et al. Expert Opin Investig Drugs 2009;18:1573–80;
7. Tew et al. Clin Cancer Res 2010;16:358–66; 8. Genentech, Inc. Avastin® prescribing information. September 2011; 9. Zhu Q et al. Ophthalmology 2008;115:1750–1755; e1.
VEGF, vascular endothelial growth factor; PIGF, placental growth factor; AMD, age-related macular degeneration; DME, diabetic macular edema; ME, macular edema; RVO, retinal vein occlusion; BRVO, branch RVO;
CRVO, central RVO

4. Fc portion of Human
immunoglobin G1
Aflibercept is a recombinant protein consisting of sequences
derived from human vascular endothelial growth factor
(VEGF)

5. 5
1. Novartis Europharm Ltd. Lucentis SmPC. September 2011
2. www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000715/WC500043550.pdf
3. Regeneron Pharmaceuticals, Inc. EYLEA® prescribing information. November 2011
4. Genentech, Inc. Avastin® prescribing information. September 2011
VEGF, vascular endothelial growth factor; PIGF, placental growth factor
Ranibizumab Aflibercept Bevacizumab
Structure
Fab
Fc portion Fc portion

6. 1. Mackenzie F and Ruhrberg C. Development. 2012; 139(8): 1371-1380; 2. Takahashi H and Shibuya M. Clin Sci
(Lond). 2005; 109(3): 227-241; 3. Schmidt-Erfurth U, et al. Ophthalmology. 2014; 121(1): 193-201.
VEGFR-1 VEGFR-2
VEGF
-A
VEGF
-A
VEGF
-B
PlGF
Clinical evidence suggests that inhibition of VEGFR-1 by VEGF-B and PlGF
inhibitors provides no additional benefit
VEGF-A is the main regulator of neovascularization in the eye1; it activates
both VEGFR-1 and VEGFR-22
Ranibizumab
Aflibercept
bevacizumab
Aflibercept
T Aflibercept
T
Ranibizumab
Aflibercept
T

7. 1. Kim H, et al. Mol Vis. 2009; 15: 2803-2812;
2. Andersen JT, et al. J Biol Chem. 2011; 286(7): 5234-5241; 3. LUCENTIS® SmPC; April 2016.
Full-chain antibody
(aflibercept)
Fc portion
Fab fragment Fc receptor
(upregulated in nAMD)
Fc binding
Fc transport
to systemic
circulation
Blood–retinal barrier
Eye Blood
Fab fragment, no Fc portion
(ranibizumab)
No Fc binding
Systemic exposure
Full-length antibodies
are recycled by cells
and released back into
the blood instead of
being broken down,
prolonging systemic
exposure

9. SAFETY AND EFFICACY OF
RANIBIZUMAB,AFLIBERCEPT AND
BEVACIZUMAB IN DME
CONCLUSION
 ranibizumab ,aflibercept and bevacizumab all
improves vision in center involved DME but relative
effect based on baseline visual acuity
 when visual loss is MILD there is no apparent
difference
 when loss is SEVERE less than 20/50 aflibercept
has superior 2 year visual compared with
bevacizumab
Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema.Diabetic Retinopathy Clinical
Research Network., Wells JA, Glassman AR, Ayala AR, Jampol LM, Aiello LP, Antoszyk AN, Arnold-
Bush B, Baker CW, Bressler NM, Browning DJ, Elman MJ, Ferris FL, Friedman SM, Melia M, Pieramici
DJ, Sun JK, Beck RW

10. RESULT
 the two-year primary endpoint, ranibizumab was
non-inferior to PRP with a mean gain of +2.8 letters
vs. +0.2 letters in the PRP group
 Among pt treated with ranibizumab results In visual
acuity were not worse than PRP at 2 years
although long term follow up is required

11.  CONCLUSION:
In the treatment of retinal vein occlusion,
bevacizumab and ranibizumab have similar
effects on reducing macular thickness and
improving visual acuity
Ophthalmic Surg Lasers Imaging Retina. 2015 Sep;46(8):844-50. doi: 10.3928/23258160-20150909-09

12.  Ranibizumab and bevacizumab had similar effects on
visual acuity over a 2-year period.
 There were no differences between drugs in rates of
death or arteriothrombotic events.
 Switching from monthly to as-needed treatment
resulted in greater mean decrease in vision during year
2
Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Maguire
MG, Martin DF, et al. Five-Year Outcomes with Anti-Vascular Endothelial Growth Factor Treatment of
Neovascular Age-Related Macular Degeneration: The Comparison of Age-Related Macular Degeneration
Treatments Trials. Ophthalmology. 2016;123(8):1751–1761. doi:10.1016/j.ophtha.2016.03.045

13.  AT the end and during trial more patients
originally assigned to ranibizumab had
arteriothrombotic events than patients assigned
to bevacizumab (7.6% versus 4.5%).
 During the 2 years of the clinical trial, the
proportion of patient with these events was
nearly equal with 4.7% of ranibizumab-treated
patients and 5.0% of bevacizumab-treated
patients having an event
Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group,
Maguire MG, Martin DF, et al. Five-Year Outcomes with Anti-Vascular Endothelial Growth
Factor Treatment of Neovascular Age-Related Macular Degeneration: The Comparison of Age-
Related Macular Degeneration Treatments Trials. Ophthalmology. 2016;123(8):1751–1761.
doi:10.1016/j.ophtha.2016.03.045

15. CONBERCEPT
FARICIMAB
SUSTAINED RELEASE: RANIBIZUMAB
PORT DELIVERY SYSTEM
BROLUCIZUMAB
NEW AGENTS

16.  Conbercept is a genetically engineered
homodimeric protein that inhibits the activity of
VEGF-family proteins.
 Conbercept (also named KH902)
 Its a recombinant, soluble, VEGF-receptor
protein that was designed as a receptor decoy
composed of the second Ig domain of VEGFR-
1, and the third and fourth Ig domains of
VEGFR-2, and the constant region (Fc) of the
human IgG1.
Safety and efficacy of conbercept in neovascular age-related macular degeneration: results from a 12-month randomized
phase 2 study: AURORA study.Li X, Xu G, Wang Y, Xu X, Liu X, Tang S, Zhang F, Zhang J, Tang L, Wu Q, Luo D, Ke X,
AURORA Study Group.
Ophthalmology. 2014 Sep; 121(9):1740-7.

18.  Conbercept binds to and neutralizes VEGF-A
and all its isoforms, which results in a
binding affinity that is higher than that of
ranibizumab.
 Conbercept shows a higher PlGF-binding
activity compared with ranibizumab.
A phase 1 study of KH902, a vascular endothelial growth factor receptor decoy, for exudative age-related macular degeneration.Zhang M,
Zhang J, Yan M, Luo D, Zhu W, Kaiser PK, Yu DC, KH902 Phase 1 Study Group.
Ophthalmology. 2011 Apr; 118(4):672-8
The LIM domain protein FHL1C interacts with tight junction protein ZO-1 contributing to the epithelial-mesenchymal transition (EMT) of a
breast adenocarcinoma cell line.Zhao JL, Liang SQ, Fu W, Zhu BK, Li SZ, Han H, Qin HY
Gene. 2014 Jun 1; 542(2):182-9.

19.  It is produced by Chinese hamster ovary cell
lines
 Intravitreous half-life of conbercept in
humans has not been reported. However, it
is 4.2 days in rabbit eye
Safety and efficacy of conbercept in neovascular age-related macular degeneration: results from a 12-month
randomized phase 2 study: AURORA study.Li X, Xu G, Wang Y, Xu X, Liu X, Tang S, Zhang F, Zhang J, Tang L, Wu Q,
Luo D, Ke X, AURORA Study Group.
Ophthalmology. 2014 Sep; 121(9):1740-7.

20.  VEGF-A belongs to the VEGF family, which
includes six isoforms: VEGF-A, PlGF1,
PIGF2, VEGF-B, VEGF-C, and VEGF-D.
 Each of these isoforms can bind to a specific
combination of three vascular endothelial
growth factor receptors of VEGFR-1, -2, and
-3

21. Conbercept vs other control clinical
methods for AMD treatment. Ranibizumab,
triamcinolone, and traditional transpupillary
thermotherapy (TTT).
Cui, C., & Lu, H. (2017). Clinical observations on the use of new anti-VEGF drug, conbercept, in age-related macular
degeneration therapy: a meta-analysis. Clinical interventions in aging, 13, 51–62. doi:10.2147/CIA.S151225
Continue…

22.  No differences were found in the BCVA and
CRT improvement between the groups
treated with conbercept and ranibizumab.
 the conbercept group had a lower serum
VEGF level.
 After 3 months of treatment, conbercept led
to a more significant BCVA and CRT
improvement than triamcinolone.

24.  At month 12, the mean BCVA letter score improved by
9.3 ± 5.2 with conbercept, and by 8.9 ± 4.4 with
ranibizumab, the mean CRT reduction was
138.4 ± 97.7 μm and 145.2 ± 72.5 μm, respectively.
 Both conbercept and ranibizumab are effective in the
treatment of DME, achieving the similar clinical efficacy.
In comparison to ranibizumab, conbercept shows a
longer treatment interval and fewer intravitreal
conbercept injections are needed.
BMC Ophthalmol.2017 Aug 25;17(1):158. doi: 10.1186/s12886-017-0554-
8.

25.  No significant differences in improvement of
BCVA (p > 0.05, t-test) or reduction of CMT (p >
0.05, t-test) were noted in either group
Fengjiao Li, Ming Sun, Jianlian Guo, Aihua Ma & Bojun Zhao (2017) Comparison of Conbercept with
Ranibizumab for the Treatment of Macular Edema Secondary to Branch Retinal Vein Occlusion, Current Eye
Research, 42:8, 1174-1178, DOI: 10.1080/02713683.2017.1285943

26.  Bispecific monoclonal antibody that is being
investigated for diabetic macular edema

27. Ang2 levels are elevated in retinal vascular diseases, including nAMD, DR,
proliferative DR, and RVO

28.  Ang2 upregulate inflammation via a
mechanism of inducing endothelial cells to
become more sensitive to the effect of tumor
necrosis factor-alpha (TNFα).
 Ang2 is believed to be stored within endothelial
cells, released under the influence of
angiogenic, inflammatory, and other cytokines
Regula JT, von Leithner PL, Foxton R, et al. Targeting key angiogenic
pathways with a bispecific CrossMAb optimized for neovascular eye
diseases. EMBO Mol Med. 2016;8(11):1265-1288

29.  THE BOULEVARD STUDY established the
superior efficacy and durability of faricimab in
patients with DME compared to monthly
ranibizumab.
 THE STAIRWAY STUDY confirmed extended
durability of faricimab in patients with nAMD
compared to monthly ranibizumab.
 YOSEMITE/RHINE STUDIES are ongoing and
are evaluating efficacy and durability of
faricimab in patients with DME compared to
aflibercept.

30.  The ranibizumab port delivery system is a
refillable implant that is placed beneath the
conjunctiva and is designed to provide
sustained release of ranibizumab into the
vitreous

31. https://doi.org/10.1016/j.ophtha.2019.03.036

32.  The implant is placed in the superotemporal
quadrant of the pars plana about 4 mm posterior to
the limbus done in an operating room under local
anesthesia with sedation.
 Surgeons make a small, full-thickness scleral
cutdown and photocoagulate the uvea once it is
exposed. The vitreous is entered with a 3.2- mm
blade, and the filled device is then inserted followed
by suturing of conjunctiva and Tenon’s capsule to
provide good coverage of the implant flange

33.  Assess the safety and efficacy of
ranibizumab delivered via the port delivery
system (PDS) compared with intravitreal
injections of ranibizumab
 In the Ladder trial, the PDS was tested with
3 customized ranibizumab formulations (10
mg/ml, 40 mg/ml, and 100 mg/ml)
https://doi.org/10.1016/j.ophtha.2019.03.036

34.  Results for the PDS 100 mg/ml were the most
promising, with a median time to first implant refill of
15.0 months and 79.8% of patients who went 6
months or more without meeting implant refill
criteria.
 Treatment with PDS also successfully reduced the
overall treatment burden for patients
 PDS patients receiving approximately 80% fewer
ranibizumab treatments than patients in the monthly
intravitreal ranibizumab 0.5-mg injection treatment.
https://doi.org/10.1016/j.ophtha.2019.03.036

35.  ARCHWAY, a phase III study comparing
PDS 100 mg/mL refilled every 24 weeks with
monthly intravitreal ranibizumab 0.5 mg, was
launched in September 2018

36.  ADVERSE EFFECTS was vitreous
hemorrhage, occurring in 7 patients (3.9%)
in the overall PDS-treated population.

37.  Developed by grafting complementarity-
determining regions of anti–VEGF-A antibody to
a human Single-chain antibody fragments
(scFv)
 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, designed to
increase duration.

39.  Brolucizumab (RTH258) is a single-chain
antibody fragment that inhibits all isoforms of
VEGF-A.
Holz FG, Dugel PU, Weissgerber G, et al. Single-chain antibody fragment VEGF inhibitor rth258 for
neovascular age-related macular degeneration: A randomized controlled study. Ophthalmology.
2016;123(5):1080–1089. doi:10.1016/j.ophtha.2015.12.030

41.  Comparison of the q8w treatment regimen
between brolucizumab 6 mg and aflibercept
2 mg showed anatomic advantages with
brolucizumab while reaching noninferiority in
best-corrected visual acuity (BCVA).
P.U. Dugel, G.J. Jaffe, P. Sallstig, et al.Brolucizumab versus aflibercept in participants with
neovascular age-related macular degeneration: a randomized trial
Ophthalmology, 124 (2017), pp. 1296-1304

42.  In HAWK brolucizumab 3 mg vs brolucizumab 6
mg,
 In HARRIER brolucizumab 6 mg vs aflibercept
2 mg
 brolucizumab (q12w/q8w) is non-inferior to
fixed-dose AFLIBERCEPT with respect to the
change in BCVA from baseline to Week 48.
https://doi.org/10.1016/j.ophtha.2019.04.017

43.  Abicipar pegol (MP0112) is a 34-kDa
Designed Ankyrin Repeat Protein (DARPin)
that also inhibits all isoforms of VEGF-A
 Patients were more likely to experience
inflammatory events with Abicipar Pegol at
more than 15% compared to less than 1%
with ranibizumab
Souied EH, Devin F, Mauget-Faÿsse M, et al. Treatment of exudative age-related macular degeneration with a designed
ankyrin repeat protein that binds vascular endothelial growth factor: A phase I/II study. Am J Ophthalmol. 2014;158(4):724–
732. doi:10.1016/j.ajo.2014.05.037

44.  phase 3 trials, nAMD eyes were randomized
to either 0.5 mg ranibizumab monthly, 2.0
mg abicipar pegol every 8 weeks after 3
initial monthly doses

45.  52 week results: Higher clearance of SRF,
IRF and absence of all fluids were observed
with abicipar versus ranibizumab. ~91% of
patients maintained stable vision, ~15%
experienced Intra ocular inflammation.
 ABICIPAR had 6 times higher rate of
endophthalmitis compared to ranibizumab
(1.3% vs. 0.2%)

46.  Antibody bio conjugate polymer
 Phase 1 First-In-Human 12 week study
results: Demonstrated safety and rapid onset
of durable response with single dose
administration
 no drug related adverse effect or intraocular
inflammation were observed
 950 kDA
Authors Affiliation: Sunil S Patel – University of Texas Southwestern Medical
Center

47.  Mitochondria targeted drug, (Stealth
BioTherapeutics)
 Reduce production of toxic reactive oxygen
species and stabilizes cardiolipin

48.  Phase 1 study evaluate safety, tolerability
and efficacy of Elamipretide 40mg
Subcutaneous in non-study eyes with
quiescent NV AMD
 May improve visual function in both
treatment eye and fellow eye, (non-study
eyes with NV AMD)

49.  TOPICAL EYE DROP Formulation for
potential use in nAMD. The rationale was
that, through inhibition of VEGF receptors
2/3,
 Regorafenib targets the same pathway as
that of the currently used intravitreally
injected biologics that bind and neutralize the
ligand

50.  The Developing Regorafenib Eye drops
for neovascular Age‐related Macular
degeneration (DREAM) study: an
open‐label phase II trial
 The programme was TERMINATED after
because efficacy was lower than with current
nAMD treatments.

51.  lampalizumab, a selective complement factor
D inhibitor,
 Did not reduce the enlargement of GA
lesions vs sham
 TERMINATED

52.  Integrins are cell surface receptors that mediate
cell-to-cell interaction with further downstream
kinase signaling and are upregulated in times of
oxidative stress
 LIFITEGRAST (SHIRE), a compound with the
potential to treat ocular surface inflammation
 ALG-1001 RISUTEGANIB (Luminate, Allegro
Ophthalmics), which has retinal indications

53.  Integrins are cell surface receptors involved in
angiogenesis and inflammation
 ALG-1001 inhibits all three receptors associated
with angiogenesis
 ALG-1001 is an oligopeptide that targets four
different integrin receptor sites It has two
distinct mechanisms of action, antiangiogenesis
and vitreolysis,

55.  It blocks two members of the vascular
endothelial growth factor family, namely
VEGF-C and VEGF-D, which cause blood
vessels to grow and leak.

58.  Its never Ending ……
DREAM BIG
Associate ophthalmologist

59.  Intravitreal aflibercept dosed monthly or every 2 months
after 3 initial monthly doses produced similar efficacy
and safety outcomes as monthly ranibizumab.
 These studies demonstrate that aflibercept is an
effective treatment for AMD, with the every-2-monthly
reduces the risk from monthly intravitreal injections and
the burden of monthly monitoring.

60. Conclusions
 Intravitreal injections of 2.0 mg ranibizumab
led to statistically significant VA gains and
anatomic improvement in patients with
persistent intraretinal, subretinal, or
subretinal pigment epithelial fluid during a
previous regimen of chronic monthly 0.5-mg
ranibizumab injections.
https://doi.org/10.1016/j.ophtha.2012.08.008
Volume 120, Issue 2, February 2013, Pages 349-354

61.  Analyses from the PIER and EXCITE studies have shown
that visual and anatomic response during and for the 12
weeks after the loading phase are associated with visual
acuity outcomes over the remainder of the first year of
treatment.
 the EXCITE study have shown that patients who lose
vision during the initial loading phase will have better
visual outcomes with more frequent treatment versus
patients who follow an every 12 weeks (q12w) treatment
regimen.26 Analyses from CATT and EXCITE have shown
that new IRF/intraretinal cysts, and to a lesser degree
central subfield thickness (CST) increase, are associated
with later visual acuity decline

62.  In the BOULEVARD study, treatment-naive patients
with DME were treated with 0.3 mg ranibizumab
(Lucentis; Genentech), 1.5 mg faricimab, and 6.0
mg faricimab.9 The primary objective of the
BOULEVARD study was to assess the efficacy of
faricimab compared with ranibizumab in anti-VEGF
treatment-naïve patients at week 24. This study
showed faricimab demonstrated robust BCVA gains
in patients at 6 months, with mean of +13.9 letters
gained from baseline. Secondly, it demonstrated
statistically significant BCVA gains over
ranibizumab at 6 months
Khanani AM. Anti-VEGF/anti-angiopoietin-2 bispecific antibody RG7716 in
diabetic macular edema: results from the phase 2 BOULEVARD clinical trial.
Paper presented at the World Ophthalmology Congress, Barcelona, Spain,
June 18, 2018

63.  patients were treated with faricimab 6.0 mg
every 16 weeks (Q16W), 6.0 mg every 12
weeks (Q12W), and ranibizumab 0.5 mg every
4 weeks (Q4W).10 The results showed 65% of
faricimab-treated patients had no disease
activity 12 weeks after the loading injections.
BCVA outcomes for patients receiving faricimab
every 16 weeks and every 12 weeks were
comparable to those receiving ranibizumab
every 4 weeks.
Khanani AM. Simultaneous inhibition of VEGF and Ang2 with faricimab in neovascular AMD: STAIRWAY phase
2 results. Paper presented at the Retina Subspecialty Day, American Academy of Ophthalmology Meeting,
Chicago, Illinois, October 26, 2018.

64. During a span of 6 months, RBZ injections by
the current protocol had significantly better
visual outcome than focal/grid laser
treatment in patients with DME
Intraocular injections of RBZ provided benefit
for patients with DME for at least 2 years,
and when combined with focal or grid laser
treatments.

65. RBZ monotherapy and combined with laser
provided superior visual acuity gain over
standard laser in patients with visual
impairment due to DME.
At 1 year, no differences were detected
between the RBZ and RBZ + laser arms.
RBZ
monotherapy and combined with laser had a
safety profile in DME similar to that in age-
related macular degeneration.

66.  Intravitreal VEGF aflibercept Trap-Eye
produced a statistically significant and
clinically relevant improvement in visual
acuity when compared with macular laser
photocoagulation in patients with DME.