This document provides an overview of newer anti-VEGF therapies for treating retinal diseases involving abnormal blood vessel growth (neovascularization). It discusses the mechanisms and indications of established therapies like bevacizumab, ranibizumab, and aflibercept. It then summarizes several newer anti-VEGF agents currently in clinical trials, including conbercept, brolucizumab, abicipar pegol, and faricimab. These newer therapies aim to provide improved efficacy compared to existing options through mechanisms like inhibiting additional growth factors or requiring less frequent dosing. Ongoing clinical trials are evaluating their safety and ability to improve vision outcomes in conditions like wet age-related macular degeneration and diabetic

1. NEWER ANTI-VEGFS
DR. POONAM JUNEJA
RESIDENT
DEPARTMENT OF OPHTHALMOLOGY
SMCH, GHAZIABAD

2. HISTORY
• In 1948, MICHAELSON proposed FACTOR X which was responsible for iris and retinal
neovascularization seen in ischemic retinopathies.
• In 1989, Leung at al isolated endothelial mitogen from pituitary follicular cells,
termed it vascular endothelial growth factor(VEGF)
• Elevated levels of VEGF was seen in ocular fluids in patients with active neovascular
ocular disease when compared with ocular fluids with no neovascularization.

3. WHAT ARE VEGFS??
• VEGF is a member of the platelet-derived growth factor (PDGF) family.
• The VEGF gene family is constituted of VEGF-A, VEGF-B, VEGF-C, VEGF-D and placenta
growth factor (PlGF), located on chromosome 6p12.
• Hypoxia has been shown to be a major inducer of VEGF gene transcription.
• As a response to metabolic distress, the retinal pigment epithelium (RPE) and the
retina produce various factors, particularly VEGF, which induce new vessels
proliferation.

4. 1.
• VEGF bind to its receptors on endothelial cells
2. • Promotes metalloproteinases production by endothelial cells
3.
• leads to endothelial cell proliferation
4.
• new blood vessel growth
5. • thus plays a key role in angiogenesis
6. • powerful agonist of vascular permeability
7.
• causes vascular leakage by formation of fenestrations in microvascular
endothelium
8.
• leading to macular edema
Thus, inhibition of VEGF activity is key to treatment of macular edema and prevention of progressive
capillary non-perfusion, especially in diabetic retinopathy and retinal vein occlusions.

5. INDICATIONS OF ANTIVEGF
• Wet ARMD
• Diabetic macular edema
• Proliferative diabetic retinopathy
• Retinal vein occlusion
• Myopic choroidal neovascularization
• Retinopathy of prematurity
• Neovascular glaucoma
• Central serous retinopathy
• Ocular tumors
• Corneal neovascularization

6. BEVACIZUMAB
• In 1997, trial was initiated by Genetech for development of AntiVEGF AVASTIN
(BEVACIZUMAB), which got FDA approval in February2004 for treatment of COLON
CANCER in combination with chemotherapy.
• Bevacizumab is FDA approved for use in non-squamous non-small cell lung cancer
• Bevacizumab has a FDA indication for glioblastoma(Brian cancer)
• Bevacizumab use in ophthalmology is off-label, meaning it is not FDA approved for
ocular use
MECHANISM OF ACTION - Bevacizumab binds to soluble VEGF and inhibits the
binding of VEGF molecules to its receptors on the surface of endothelial cells
• Reduction in activity of VEGF inhibits angiogenesis and vascular permeability.

7. DOSAGE
• Intravitreal injections for retinal pathologies are typically administered at 4-6 week
intervals, although this varies widely based on disease and response
• The typical dose is 1.25mg in 0.05ml in adults,and half that dose in babies
• It is supplied in 100 mg and 400 mg preservative-free, single-use vials with a volume
volume of 4 mL or 16 mL of bevacizumab (25 mg/mL).

8. RANIBIZUMAB
• Genetech generated LUCENTIS which was proven effective by 2 trials –
MARINA (MINIMALLY OCCULT/CLASSIC TRIAL OF AntiVEGF ANTIBODY RANIBIZUMAB
IN THE TREATMENT OF NEOVASCULAR AMD)
ANCHOR (AntiVEGF antibody for treatment of predominantly classic choroidal
neovascularization in AMD)
• Trials proved ranibizumab to be effective in improving VA in all forms of choroidal
neovascularization.
• It was approved by FDA in 2006.

9. MECHANISM OF ACTION
• Ranibizumab binds to the receptor-binding site on VEGF-A, which inhibits
the binding of VEGF molecules to their receptors on the surface of
endothelial cells.
DOSAGE
• The approved dose of intravitreal ranibizumab injection is either 0.3 or 0.5
mg in 0.05 ml once a month for up to 3 months.
• Dosing recommendations vary according to indications.

10. AFLIBERCEPT
• It was approved by FDA in November 2011 based on VIEW STUDY.
MECHANISM OF ACTION
• Aflibercept is a soluble decoy receptor that binds vascular endothelial growth
factor-A (VEGF-A), VEGF-B and placental growth factor (PIGF).
• It is called a decoy receptor as VEGF does not bind to its original receptors and
mistakenly binds with aflibercept, thereby reducing VEGF's activity.
DOSAGE
The approved dose of intravitreal aflibercept injection (IAI) is 2.0mg in 0.05ml.

11. PEGAPTANIB
• FDA approved MACUGEN for treatment of ARMD, which became first
Antiangiogeneic theapy for ocular neovascularization.
MECHANISM OF ACTION
Pegaptanib specifically binds to the 165 isoform of VEGF, a protein that plays a critical
role in angiogenesis and increased permeability
DOSAGE
Pegaptanib is administered in a 0.3 mg dose once every six weeks
by intravitreal injection.

12. Anti VEGF Brand name Type Action Dose Vitreous
half-life
Pregatanib Macugen Aptamer Binds to VEGF 165 isomer 0.3mg/0.05ml 2.73 days
Bevacizumab Avastin Humanized
monoclonal
antibody
Forms protein complex by
binding directly to VEGF
1.25-2.5mg /
0.05ml
4.9 days
Ranibizumab Lucentis Monoclonal
antibody fragment
Stronger binding to VEGF-A
( 140 times more than
Bevacizumab)
Can penetrate internal
limiting membrane and
access the subretinal space
0.5mg / 0.05ml 9 days
Aflibercept Eyelea Recombinant fusion
protein
Contains VEGF binding
portions of the extracellular
domains of VEGFR-1 and
VEGFR-2, fused to the Fc
portion of human
immunoglobulin G
2mg / 0.05ml 3.63 days
(rabbit)

13. COMPLICATIONS OF ANTIVEGF
• Endophthalmitis
• Retinal pigment epithelial tear
• Retinal detachment
• Elevated intraocular pressure
• Subconjunctival hemorrhage
• Corneal abrasion
• Vitreous hemorrhage
• Cataract formation
• inflammation

14. NEXT GENERATION THERAPEUTICS
• Conbercept
• Brolicuzumab
• Abicipar pegol
• Faricimab
• KSI-301
• OPT 302
• X-82
• Ranibizumab port delivery system
• Gene therapy delivery

15. CONBERCEPT
• A recombinant VEGF receptor protein used for treatment of wetARMD.
• It inhibit activity of all VEGF isoforms and PIGF.
• PANDA-1 and PANDA-2phase III trails compared
AIM – To compare mean change in BCVA at end of 36weeks.
However the study could not meet its primary aim.
0.5mg CONBERCEPT every 12weeks
1mg CONBERCEPT every 12weeks
2mg AFLIBERCEPT every 8weeks

16. • Study done by Cui and Lu compared conbercept for AMD treatment –
• AIM – To measure BCVA and central retinal thickness
• Conclusion – Conbercept shows more effects on long term BCVA in AMD patients then
Triamcinolone(after 3 months)
TTT (after 6 months)
Therapeutic effect of conbercept was similar to ranibizumab
• Conbercept reduces concentration of serumVEGF during period of treatment(1month)
ranibizumab triamcinolone
bevacizumab
TTT(traditional
transpupillary
thermotherapy)

17. • PHOENIX STUDY done by Liu et all –
• At 3months, BCVA improved in conbercept group than in sham group.
CONCLUSION - 3 montly dose of conbercept followed by quarterly dosage was highly
effective in AMD.
0.5mg of CONBERCEPT
once montly for first
3months
Once quarterly until
12th month
CONBERCEPT
GROUP
SHAM GROUP
0.5mg of SHAM once
montly for first 3months
Once quarterly until
12th month

18. BROLUCIZUMAB
• Single chain antibody fragment that inhibits all isoforms of VEGF-A
• Smallest AntiVEGF with molecular weight of 26kDa.
• Small size leads to fast systemic clearnce, lower systemic exposure, better tissue
penetration and a much higher molar dose in same volume can be delivered.
• HAWK AND HARRIER STUDY – 2 years randomized study
AIM – compare efficacy of brolucizumab with aflibercept in neovascular AMD
DOSING –
HAWK HARRIER
TWO DOSES OF BROLUCIZUMAB (3MG
and 6mg) with 2mg aflibercept
6mg brolucizumab with
2mg aflibercept

19. • Primary endpoint – mean BCVA change at week 48.
• Secondary endpoint – change in BCVA and central sub field thickness(CSFT), intra
and sub retinal fluid and disease activity at week16.
RESULTS – In HAWK STUDY, brolucizumab was found to be noninferior.
Decrease disease activity at week 16, with 6mg of brolucizumab
than with aflibercept.
• In HARRIER STUDY, Decrease disease activity at week 16, with 6mg of
brolucizumab than with aflibercept.
CONCLUSION – Brolucizumab offers less frequent intravitreal injections in eyes
treated for neovascular AMD.

20. ABICIPAR PEGOL
• It’s a ankyrin repeat protein which inhibits all isoforms of VEGF-A
• SEQUOIA AND CEDAR STUDY – Patients with neovascular AMD were divided into
3groups –
CONCLUSION- Abicipar demonstrated non-inferiority compared to ranibizumab with
less frequent injections in terms of improving BCVA.
3monthy abicipar 2mg
injections, followed by
every 8weeks
Montly ranibizumab
injections
2montly abicipar 2mg
injections, followed by
every 12weeks

21. • THE MAPLE STUDY –
• Modified formulation of 2mg abicipar was used in this study.
• 123 neovascular AMD patients were randomized to treatment by 2MG ABICIPAR or
SHAM.
RESULTS – Modification of abicipar decreased rate of imflammation to 8.9%.

22. • THE REACH STUDY –
• It was a multicentre RCT in patients with newly diagnosed neovascular AMD
BCVA and CRT were similar in abicipar groups when compared with ranibizumab.
Abicipar 1mg ranibizumab
Abicipar 2mg

23. FARICIMAB
• It’s a bispecific antibody which targets two factors :
VEGF
Angiopoietin-2
• PHASE I CLINICAL TRAIL –
24 patients of neovascular AMD refractory to 3 or more AntiVEGF injection in past
6months were included in the study.
RESULT - overall favourable safety profile with evidence of BCVA and anatomical
improvement was seen.

24. • THE AVENUE TRAIL –
273 patients of newly diagnosed nAMD were included in this study.
Ranibizumab 0.5mg
every 4 weeks
Faricimab
6mg/ranibizumab
0.5mg combination
Faricimab 6mg
every 8 weeks
Faricimab 6mg
every 4weeks
Faricimab 1.5mg
every 6weeks

25. • BOULEVARD TRIAL – A 36week RCT with 229 patients of DME.
Newly diagnosed
patients(168)
Previously treated
patients(61)
6mg of
FARICIMAB
1.5mg of
FARICIMAB
0.3mg of
RANIBIZUMAB
0.3mg of
RANIBIZUMAB
6mg of
FARICIMAB

26. RESULT – 6mg of faricimab was superior to 0.3mg ranibizumab in terms of VA, greater
central subfoveal thickness reduction and diabetic retinopathy severity score
improvement.

27. KSI-301
• It’s a humanized AntiVEGF antibody (similar to ranibizumab)
• It is by far the largest AntiVEGF drug. Its size and clinical dose creates an equivalent
molar dose seven times that of ranibizumab.
DAZZLE STUDY – Currently a phase IIB/III study is investigating efficacy and safety of
repeated injections in 368 patients with nAMD given at 12, 16, 20 week interval
following initial 3 loading doses.
It was compared to aflibercept at 8week intervals following 3loading montly doses.

28. OPT-302
• It targets VEGF-C and VEGF-D to play a role in nAMD pathogenesis.
• A phase1/2a study showed in newly diagnosed patients, i.v injections of both OPT-
302 (2mg) and ranibizumab (0.5mg) given every 4weeks resulted in VA gain and
reduction in macular thickness when compared to ranibizumab alone.

29. X-82
• It’s a ORAL antiPDGF and VEGF-A inhibitor.
• A phase 2 APEX STUDY tested x-82 at 50mg, 100mg and 200mg doses compared to
placebo.
• Change in VA from baseline to 52weeks was the primary outcome.
• Study showed that patients who received 200mg had better improvement in VA
than the placebo group.

30. RANIBIZUMAB PORT DELIVERY SYSTEM
• It is a permanent, surgically implanted intraocular device which may be refilled.
• It is currently approved for WetAMD and has ongoing clinical trails for DME and DR.
• It contain high concentration ranibizumab formulation(100mg/ml) which slowly
diffuses to vitreous at appropriate intervals and for extended treatment duration.

31. • LADDER TRIAL – The visual and anatomical results were comparable between
ranibizumab PDS and traditional intravitreal injections.
• ARCHWAY TRIAL – PDS was non-inferior with 100mg/ml surgical implant compared
to montly ranibizumab injections.
COMPLICATIONS – Vitreous haemorrhage

32. GENE THERAPY DELIVERY
• There are many active gene therapy trials going on –
REGENxBIO has multiple gene therapy trials for wetAMD.
It is modified adenoviral vector containing genetic package, which through process of
transfection, enables RPE cells to produce modified ranibizumab like molecule.
It has reduced the number of AntiVEGF injections required.
ADVERUM BIOTECHNOLOGIES using viral vector intravitreally for expression of
Aflibercept with positive phase I results, now moving to Phase II.

33. REFERENCES
• DOS Times, volume28,July-august2022
• American Academy Of Ophthalmology
• Yanoff Ophthalmology
THANK YOU