Anti vegf

presented by dr. arvind kumar(g.r.m.c., gwalior, m.p.)

1. ANTI VEGFs IN OPHTHALMOLOGY BY Dr. A RVIND KUMAR

2. Vasculo endothelial growth factors are molecules produced by endothelial cells,pericytes,RPE,muller cells and glial cells to promote neovascularisation Also responsible for break in blood retinal barrier The future implications and indications of anti-vascular endothelial growth factor therapy in ophthalmic practice IJO WHAT ARE VEGFs

3. HYPOXIA VEGF ISOFORMS VEGF PROTIENS NEOVASCULARISATION RETINA ANTERIOR SEGMENT The future implications and indications of anti-vascular endothelial growth factor therapy in ophthalmic practice IJO

4. The antibodies which blocks the actions of VEGFs are anti VEGFs thus benefit the patients by decreasing the abnormal and harmful new blood vessels formation and by decreasing the leakage and swelling of the retina. This leads to stabilization of vision and even improvement in vision in many cases. The future implications and indications of anti-vascular endothelial growth factor therapy in ophthalmic practice IJO WHAT ARE ANTI VEGFs

5. ANTI VEGF PEGABTANIB RANIBIZUMAB BEVACIZUMAB MACUGEN LUCENTIS AVASTIN The future implications and indications of anti-vascular endothelial growth factor therapy in ophthalmic practice IJO COMMONLY USED ANTI VEGFs

6. Humanized monoclonal antibody Active against all isoforms of VEGFs Received its first approval in 2004 Rosenfield et al were the first ones to describe & publish the off label use of intravitreal Bevacizumab in 2005. MECHANISM OF ACTION: Bevacizumab ( Avastin ) binds directly to VEGF Forms protein complex Incapable of further binding to VEGF receptor sites which would initiate vessel growth effectively reducing available VEGF The future implications and indications of anti-vascular endothelial growth factor therapy in ophthalmic practice IJO BEVACIZUMAB

7. USE IN EYE DISEASE Off-label use as an intravitreal agent in the treatment of proliferative ( neovascular ) eye diseases Particularly for Choroidal neovascular membrane (CNV) in AMD. (not currently approved by the FDA for such use) The injection of 1.25-2.5 mg of –NO significant intraocular toxicity. Noted impressive results in the setting of: 1. CNV 2. Proliferative diabetic retinopathy 3. Neovascular glaucoma 4. Diabetic macular edema 5. Retinopathy of prematurity 6. Macular edema secondary to retinal vein occlusions.

8. ADMINISTRATION AND DOSAGE Typically given by transconjunctival intravitreal injections. Intravitreal injections for retinal pathologies are typically administered at 4-6 week intervals, although this varies widely based on disease and response. DOSE : Typical dose is 1.25mg in 0.05ml in adults, and half that dose in babies. COMBINATION THERAPY :  Photodynamic Therapy  Anti PDGF  Intravitreal Triamcinolone  Triple Therapy  Radiation BENEFITS:  Reduces frequency of injections  Reduces recurrence

9. BENEFITS: ADVERSE REACTIONS 1.High efficacy 2. Longer half life upto 20 days & thus fewer injections 3. Lack of preservative 4. Higher safety dose Retinal toxicity occurs at dosage > 3.5mg 5. Lower cost 6. Wide availability CNS: Headache, Dizziness, Sensory neuropath y CVS: HTN, Thrombo - embolsim Dermat : Alopecia (32%) GI: Abdominal pain, vomiting, anorexia Haemat : Bleeding, leukopenia , neutropenia Genitourinary: Proteinuria , vaginal haemorrhage RS: URTI, epistaxis

10. RANIBIZUMAB NON BINDING FRAGMENT Fab FRAGMENT MAKES IT HUMANISED MOUSE DERIVED LESS ANTIGENIC ACTIVE AGAINST ALL VEGF ISOFORMS HIGH AFFINITY BINDING SITE The future implications and indications of anti-vascular endothelial growth factor therapy in ophthalmic practice IJO RANIBIZUMAB

11. LUCENTIS Lucentis is an monoclonal antibody fragment ( Fab ) developed from the identical parent antibody as Avastin . Lucentis was approved for neovascular AMD in the U.S. in 2006 MECHANISM OF ACTION : Much smaller than the parent molecule and has been affinity stronger binding to VEGF-A. Anti- angiogenic property. Unlike the full length antibody, it penetrates the ILM and can gain access to the sub retinal space.

12. ADMINISTRATION AND DOSAGE Available as Injection, intravitreal 10 mg/ mL Dose: 0.5 mg/0.05 ml once every month PHARMACOKINETICS:  Vitreous t1/2 = 3 days (animals) 9 days (humans)  Serum concentrations upto 2000x lower than in the vitreous. Reduction in Ranibizumab clearance in renal impairment is considered clinically insignificant & dose adjustment is not expected to be needed. DRUG INTERACTIONS: Have not been studied. SAFETY PROFILE:  Serious ocular adverse events in 2 year MARINA study for ranibizumab 0.5 mg: 1. Endophthalmitis – 1.3% 2. Uveitis – 1.3% . 3. Retinal tear – 0.4% 4. Lens damage – 0.4% Serious ocular adverse events in 1 year ANCHOR study for ranibizumab 0.5 mg : 1. Endophthalmitis – 1.4 % 2. Uveitis – 0.7%  There was no increase in systemic adverse effects such as HTN, arterial thromboembolism in either study.

13. PEGABTANIN FIRST ANTI ANGIOGENIC AGENT 28 BASE RNA APTAMER SELECTIVELY BIND VEGF 165 NON IMMUNOGENIC DOEST NOT AFFECT NORMAL VASCULAR GROWTH PEGABTANIB

14. Pegylated Aptamer  Pegaptanib sodium injection (brand name Macugen ) is an anti- angiogenic medicine for the treatment of neovascular WET AMD. Discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals. Approval was granted U.S.(FDA) in Dec 2004. MECHANISM OF ACTION : Specifically binds to VEGF 165 ISOMER Protein that plays a critical role in angiogenesis (the formation of new blood vessels) Increased permeability (leakage from blood vessels) Two primary pathological processes responsible for vision loss associated with neovascular AMD.

15. ADMINISTRATION AND DOSAGE: Administered in a 0.3 mg dose once every six weeks by intravitreal injection. Marketed as a pre-filled syringe. CONTRAINDICATED ocular or periocular infections. PHARMACOKINETICS: (Not adequately studied in humans) Absorption  Very slow systemic absorption  Occurs within 1 to 4 days after 0.3 mg monocular dose. Metabolism & Excretion  By Endo & Exonucleases excreted by kidney.  DRUG INTERACTIONS: Not affected by Cytochrome P450 system.

16. BEVACIZUMAB RANIBIZUMAB FULL SIZED ANTIBODY ANTIBODY FRAGMENT 148 KILODALTONS 48 KILODALTONS HALF LIFE 20 DAYS HALF LIFE 3 DAYS SLOW CLEARANCE 100 TIMES FASTER COSTs LESS COSTLY COMPARISON Comparative role of intravitreal ranibizumab versus bevacizumab in choroidal neovascular membrane in age-related macular degeneration IJO

17. AFLIBERCEPT: EYLEA (NEW DRUG) Recombinant fusion protein consisting of VEGF- binding portions from the extracellular domains of human VEGF receptors 1 and 2, that are fused to the Fc portion of the human IgG1 immunoglobulin. INDICATIONS :1. Neovascular (Wet) ARMD Recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters ).  Administered by intravitreal injection every 4 weeks (monthly) for the first 12 weeks (3 months), followed by 2 mg (0.05 mL ) via intravitreal injection once every 8 weeks (2 months). Macular Edema Following CRVO  Recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters ).  Administered by intravitreal injection once every 4 weeks.   CONTRAINDICATIONS:  infections or active inflammations of or near the eye AFLIBERCEPT is moving through clinical trials for further intraocular and systemic indications.

18. TOPICAL ANAESTHESIA GIVEN PAINTING WITH BETADINE WITH INSTILLATION OF BETADINE IN CONJUNCTIVAL SAC DRUG TAKEN IN TUBERCULIN SYRINGE WITH 30G NEEDLE (1.25MG/0.05ML) ASK PATIENT TO LOOK DOWN FROM SUPEROTEMPORAL QUADRANT 4mm AWAY FROM LIMBUS NEEDLE IS INSERTED TOWARDS CENTRE OF GLOBE AND DRUG INJECTED INJECTION SITE PRESSED WITH COTTON BUD Comparative role of intravitreal ranibizumab versus bevacizumab in choroidal neovascular membrane in age-related macular degeneration IJO HOW TO GIVE

19. Injection volume : An injection volume of 0.05 mL is most commonly used. Safe volume to inject without preinjection paracentesis is believed to be 0.1 mL to 0.2 mL. Larger injection volumes are uncommon, exceptions: injection of gas for pneumatic retinopexy the injection of multiple intravitreal agents in one session.

20. Needle selection  Needle size varies according to the substance injected, with 27-gauge needles - triamcinolone acetonide and 30- gauge needles -anti-VEGF agents ranibizumab , bevacizumab , and aflibercept . Studies suggest that smaller, sharper needles require less force for penetration and result in less drug reflux.  Needle length between 0.5 and 0.62 inches (12.7 to 15.75 mm) is recommended, as longer needles may increase risk of retinal injury if the patient accidentally moves forward during the procedure. Injection site  The patient should be instructed to direct his or her gaze away from the site of needle entry.  The injection is placed 3 to 3.5 mm posterior to the limbus for an aphakic or pseudophakic eye, and 3.5 to 4 mm posterior to the limbus for a phakic eye.  Injection in the inferotemporal quadrant is common. Injection technique  Some guidelines suggest pulling the conjunctiva over the injection site with forceps or a sterile cotton swab to create a steplike entry path.  While this approach may, in theory, decrease reflux and risk of infection, a straight injection path is most commonly employed.  After the sclera is penetrated, the needle is advanced toward the center of the globe and the solution is gently injected into the midvitreous cavity. The needle is removed, and a sterile cotton swab is immediately placed over the injection site to prevent reflux.  IOP and CRA perfusion is assessed.  Topical Antibiotic is administered for one week.

21. Wet Age-Related Macular Degeneration Proliferative Diabetic Retinopathy Retinal Vein Occlusion CNVM Neovascular Glaucoma Macular Edema Vitreous Hmg Comparative role of intravitreal ranibizumab versus bevacizumab in choroidal neovascular membrane in age-related macular degeneration IJO USES

22. OTHER USES POSTERIOR SEGMENT ROP EALES disease Refractory post surgical CME. COATS disease ANTERIOR SEGMENT Iris neovascularization Before Keratoplasty to reduce to reduce corneal neovascularization ( 2.25mg IN 0.1ml near corneal vasc .) Pterygium ( 1.35mg/0.05m s /c) Trabeculectomy (to modulate wound healing

23. Raised IOP (13-17.6%) Cataract (0.07%) Endophthal mitis (0.1- 1%) Risk of ATE(4.6%)( decrease the synthesis of matrix metalloprote inases ) Rebound macular edema Immunoreac tivity (4.4- 6.3%) Retinal detatchment (0.08%) Central Retinal Artery Occlusion COMPLICATIONS

24. CONTRAINDICATIONS 1.Fibrovascular proliferation threatening the macula 2. Active ocular or periocular inflammation 3. Known hypersensitivity to drugs 4. Uncontrolled hypertension 5. Cardiovascular disease 6. Pregnancy and lactation 7. Pre pubescent children

25. For the treatment of patients with wet AMD, DME, RVO, or CNV due to PM, bevacizumab is the preferred initial anti-VEGF therapy, based on similar clinical effectiveness and lower cost compared with other anti-VEGF treatments . RECOMMENDATIONS

26. Ranibizumab or aflibercept can be used as alternative treatment options in patients who do not respond to bevacizumab or in patients who experience thromboembolism following the initiation of bevacizumab treatment or who are at a high risk of cardiovascular adverse events

27. The frequency and dose of intravitreal injections of the anti-VEGF drugs should be determined by the treating ophthalmologist dose should not exceed that recommended for a particular retinal condition by the product monograph (if available) or that used in randomized clinical trials . Comparative role of intravitreal ranibizumab versus bevacizumab in choroidal neovascular membrane in age-related macular degeneration IJO

28. Nowadays, anti-VEGF therapy has become one of the more frequently applied treatment modalities in ophthalmology. The indications for its usage have become wider and wider, but investigators still are looking for new drugs with more prolonged time of action or new forms of drugs delivery. CONCLUSIONS

29. M. Rajappa , P. Saxena , and J. Kaur , “Ocular angiogenesis: mechanisms and recent advances in therapy,” Advances in Clinical Chemistry, vol. 50, pp. 103–121, 2010 . PMLive , “Top Pharma list,” November 2014 J. G. Arroyo, “Towards a rational approach to combination therapy for neovascular age related macular degeneration,” The British Journal of Ophthalmology, vol. 91, no. 2, pp. 130–131, 2007. REFERENCES

30. J. W. Miller, A. P. Adamis , D. T. Shima et al., “Vascular endothelial growth factor/vascular permeability factor is temporally and spatially correlated with ocular angiogenesis in a primate model,” American Journal of Pathology, vol. 145, no. 3, pp. 574–584, 1994 L. P. Aiello, R. L. Avery, P. G. Arrigg et al., “Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders,” The New England Journal of Medicine, vol. 331, no. 22, pp. 1480–1487, 1994.

31. M. S. Gordon, K. Margolin , M. Talpaz et al., “Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer,” Journal of Clinical Oncology, vol. 19, no. 3, pp. 843–850, 2001 E. S. Gragoudas , A. P. Adamis , E. T. Cunningham Jr., M. Feinsod , and D. R. Guyer , “ Pegaptanib for neovascular age-related macular degeneration,” The New England Journal of Medicine, vol. 351, no. 27, pp. 2805–2816, 2004.

32. The era of anti-vascular endothelial growth factor (VEGF) drugs in ophthalmology, VEGF and anti-VEGF therapy Dorota Pożarowska 1  and  Piotr Pożarowski 2 Author information ►   Article notes ►   Copyright and License information ►   Disclaimer THANK YOU