Anti VEGF in Ophthalmology

This presentation outlines the use of Anti VEGF injections in Ophthalmology.

1. Anti VEGF’s & their uses

2. VEGF: Introduction VEGF is a short form for Vascular Endothelial Growth Factor, which is responsible for growth of blood vessels. Besides having a role in normal vascular growth, VEGF is also responsible for many retinal diseases by causing new vessels growth and by increasing leakage and thus causing retinal swelling

3. VEGF: Family

4. VEGF: Role in Humans Br J Ophthalmol . 2006 Dec; 90(12): 1542–1547.

5. VEGF: Role in Pathology Macular Edema Neovascular AMD Proliferative Retinopathies Tumours

6. Pathological VEGF-A secreted by RPE Hypoxia Accumulation of lipid metabolic byproducts Oxidative stress to Retina & RPE Alterations in Bruch’s membrane Drusen ( Reduction in the choriocapillaries blood flow and block diffusion of oxygen and nutrients to RPE and photoreceptors) VEGF in Eye: Initiating Stimuli Witmer et al, Prog Retin Eye Res, 2003; Ferrara et al, Nat Med , 2003 .

7. VEGF & The Angiogenic Cascade Proliferation Migration Proteolysis VEGF FGF Other Angiogenic Growth Factors Vascular Endothelial Cell Migrating endothelial cells form new blood vessels in formerly avascular space Hypoxia Basement Membrane Enzymes break the basement membrane Activated endothelial cells proliferate, migrate, and release proteases VEGF and other angiogenic factors bind to endothelial cells of nearby capillaries and activate them Hypoxia stimulates production of VEGF and other angiogenic growth factors in the subretinal space

8. VEGF induced new vessels show: Endothelial cell hyperplasia Leaky, friable vessels Loss of pericytes Increased tortuosity More propensity for hemorrhage and leakage

9. Anti VEGF Therapy: Agents

10. PEGAPTANIB ( MACUGEN ) First Anti Angiogenic Agent 28 Base RNA Aptamer NON-IMMUNOGENIC NATURE Selectively binds extra cellular VEGFA 165 DOES NOT EFFECT NORMAL VASCUALR GROWTH

11. PEGAPTANIB FDA approved for the treatment of neovascular (wet) age-related macular degeneration(AMD) Pegaptanib is a  pegylated  anti-vascular endothelial growth factor (VEGF)  aptamer , a single strand of nucleic acid Pegaptanib specifically binds to the 165 isoform of VEGF A

12. DOSAGE AND ADMINISTRATION Administered in a 0.3 mg dose once every six weeks by  intravitreal  injection  Marketed as a pre-filled syringe Following a 3 mg monocular dose, plasma t ½ is about 10 days Usage stopped as doesn’t inhibit VEGF completely, thus lower efficacy

13. BEVACIZUMAB Widely used but still not FDA approved Recombinant humanized monoclonal antibody that blocks angiogenesis by inhibiting  VEGF-A (all isoforms) It received its first approval in 2004, for combination use with standard chemotherapy for metastatic colon cancer  It has since been approved for use in Certain lung cancers, Renal cancers, Ovarian cancers Glioblastoma multiforme  of the brain

14. DOSAGE AND ADMINISTRATION In ophthalmology, Bevacizumab is typically given by transconjunctival intravitreal injections into the posterior segment   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. Estimated half-life is approximately 20 days

15. RANIBIZUMAB ( LUCENTIS ) NON BINDING FRAGMENT Makes it Humanized Therefore Less antigenic Fab FRAGMENT Mouse Derived Active against all Isoforms of VEGF High affinity binding site

16. DOSAGE AND ADMINISTRATION Available as intravitreal injection 10 mg/mL or 0.5 mg (0.05 mL)  Binds to and inhibits the biologic activity of VEGF-A Vitreous elimination half-life is approximately 9 days.

17. BEVACIZUMAB (AVASTIN) Full Sized Antibody. 148 kilodaltons . Half Life 20 days. Clearance is slow . Long action & less dosage. Cost’s less. RANIBIZUMAB (LUCENTIS) Antibody Fragment. 48 kilodaltons . Half Life of 3 days. Clearance 100 folds faster. 140 times higher affinity. Costly.

18. AFLIBERCEPT 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

19. Intravitreal Aflibercept Injection Binds a Single VEGF Dimer “Like a Trap” 1. Dixon JA et al. Expert Opin Investig Drugs. 2009;18(10):1573-1580. 2. Stewart MW. CML – Ophthalmology. 2012;22(4):105-113. 3. Zhang A et al. Pharm Res. 2012;29(1):236-250. Bevacizumab 1,2 Ranibizumab 1,2 Aflibercept 1,2 Affinity maturation 2 ranibizumab molecules can bind each VEGF dimer Bevacizumab can “daisy-chain” or “paper-doll” with VEGF leading to large, multimeric conglomerates 2,3 1:1 Stoichiometric binding 19

20. DOSAGE AND ADMINISTRATION Dosage is 2 mg (0.05 mL) administered by intravitreal injection every 4 weeks (monthly) for the first 3 months, followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks (2 months). t1/2 of free aflibercept in plasma is 5 to 6 days.

21. DRUG INTERACTIONS Irinotecan/5–fluorouracil/leucovorin: The incidence of epistaxis and GI hemorrhage, minor gum bleeding, vaginal hemorrhage) . Live vaccines: Coadministration of live vaccines may result in a reduced immune response. Paclitaxel: Decreased paclitaxel exposure when given in combination with bevacizumab. Sunitinib: Coadministration of Bevacizumab and sunitinib has been reported to cause unexpected severe toxicity (eg, microangiopathic hemolytic anemia). Coadministration of Sunitinib and Bevacizumab is not recommended.

22. CONTRAINDICATIONS TO AntiVEGF Major Systemic Events in past 3 months: Stroke Cardiac arrest Uncontrolled hypertension Anticoagulants

23. ADVERSE OCULAR EVENTS  Infectious endophthalmitis remains one of the most devastating complications of intravitreal injections. In multicenter clinical trials with anti-VEGF therapy the incidence of endophthalmitis per patient has been reported to range from 0.019 to 1.6 % Intraocular inflammation 1.4–2.9 %. Rhegmatogenous retinal detachment (RRD) is low (0 to 0.67 %). Subconjunctival hemorrhage has been reported to occur in nearly 10% of injections, with higher frequency in patients who were receiving aspirin . Increase in IOP

24. ADVERSE SYSTEMIC EVENTS  Intraocular injection of ranibizumab was linked to a significant increase in nonocular hemorrhagic events, including ecchymosis, gastrointestinal hemorrhages, hematoma, vaginal hemorrhages, and subdural hematomas. The rates of any cause of deaths, myocardial infarctions, and cerebrovascular events were not significantly increased . In a retrospective study of 1173 patients receiving bevacizumab injections, the reported systemic events included acute blood pressure elevations (0.59%), cerebrovascular accidents (0.5%), myocardial infarctions (0.4%), iliac artery aneurysms (0.17%), and five deaths.

25. Safety profile of R anibizumab Serious ocular adverse events in 2 year MARINA study for ranibizumab 0.5 mg: Endophthalmitis – 1.3% Uveitis – 1.3% . Retinal tear – 0.4% Lens damage – 0.4% 25

26. Safety profile of R anibizumab Serious ocular adverse events in 1 year ANCHOR study for ranibizumab 0.5 mg : Endophthalmitis – 1.4 % Uveitis – 0.7% There was no increase in systemic adverse effects such as HTN, arterial thromboembolism in either study 26

27. Anti VEGF Agents: Uses Posterior Segment ARMD Diabetic Retinopathy Vascular Occlusion Retinopathy of Prematurity Neovascular Glaucoma IPCV, Coats Disease etc. Anterior Segment Pterygium Post Keratoplasty Corneal Vascularization Chemical Burns Herpetic Stromal Keratitis Steven Johnson Syndrome As adjuncts with surgical p rocedures Phacoemulsfication in CSME PPV in PDR and non clearing VH Glaucoma surgery

28. AMD

29. Ranibizumab better than PDT and Sham

30. Ranizumab Monthly/PRN better than quarterly doses.

31. Ranibizumab Monthly better than PRN. Ranibizumab and Bevacizumab equivocal. Similar side effect profile.

32. VEGF Trap monthly/2monthly dose similar to monthly Ranizumab in subfoveal CNVM

33. Ranizumab alone and with PDT improves vision and Reduced Fluence no additional benefits in sub foveal CNV Ranibizumab with PDT better than Ranibizumab alone

34. CNVM

35. Choroidal neovascularisation (CNV) is one of the complications of pathological myopia and occurs in 5.2–11.3% of patients with high myopia. Visual prognosis in myopic CNV is varied. Poor prognostic indicators include lower baseline visual acuity, age above 40 years, extensive chorioretinal atrophy, subfoveal location of the CNV, and lesion size above 400  μ m. Based on the REPAIR and RADIANCE trials, Wong et al. have presented an anti-VEGF treatment algorithm for myopic CNV.

36. DME

37. Ranibizumab is better than Laser alone in DME Less complications and better VA

38. Bevacizumab can be used in CSME without macular ischemia VEGF Trap better than Macular Laser in DME

39. Anti VEGF decreases Post Operative Vitreous Cavity Hemorrhage

40. Vascular Occlusion + Macular Edema Pre Treatment Post Treatment

41. BVOS AND CVOS Laser decreases ME but no gain in VA 1 monthly FU visits to look for NVI PRP doesn’t prevent INV Wait for 3months to laser in BRVO

42. Ranibizumab can be used in BRVO and CRVO with low rates of ocular and systemic side effects

43. VEGF Trap can be used in BRVO and CRVO with low rates of ocular and systemic side effects

44. ROP

45. Bevacizumab causes longer-term reduction in systemic VEGF levels in adults compared to ranibizumab and, therefore, may be more damaging to the preterm infant. However, in preterms , ranibizumab also reduced serum VEGF. Ranibizumab penetrates more deeply into the eye, and there is concern this might affect the choroidal circulation, which provides oxygen to the developing retina and is believed important in the pathophysiology of ROP. Bevacizumab is contemplated in cases in which corneal, lenticular, or vitreous opacities preclude treatment with laser, it should only be used for stage 3+ ROP in zone I and not for zone II ROP. Follow up must be performed for a longer period of time than after conventional laser treatment, because recurrent stage 3 ROP has been reported at later time points than after conventional laser (16 +/− 4.6 weeks vs. 6.2 +/− 5.7 weeks). To Use or Not to Use?

46. Neovascular Glaucoma Cochrane review, 2013 states that currently available evidence is insufficient to evaluate the effectiveness of anti-VEGF treatments, such as intravitreal ranibizumab or bevacizumab , as an adjunct to conventional treatment in lowering IOP in NVG. Anti VEGF RETINAL HYPOXIA VEGF Conc . > 890 pg /ml of Aqueous Iris and Angle Neovascularization Intravitreal injection of Anti VEGF VEGF Conc . < 550 pg /ml of Aqueous NEOVASCULARIZATION REGRESSES

47. This prospective, interventional study establishes a therapy strategy for NVG as follows. First , the core purpose of all treatments is to lower IOP and preserve the patient’s visual function. Second , anti-VEGF treatment can regress neovascularization at the iris and anterior chamber angle, which allows optimal conditions for intraocular surgery. Third , using anti-glaucoma surgery with or without phacoemulsification or vitrectomy contributes to creating the conditions necessary for the completion of PRP. Last but not least, a change in the current view is needed because the nature of NVG changes after PRP is completed, when NVG changes into general glaucoma. Then treat residual glaucoma in a general way.

48. Evidence from Literature: NVG Effective way to give Anti VEGF in NVG is intracameral Anti VEGF+ Trab better than AGV alone in NVG AGV+anti VEGF better than AGV alone in NVG

49. Pterygium

50. SUBCONJUNCTIVAL Anti VEGF IN PTERYGIUM PRIMARY PTERYGIUM : Subconjunctival Bevacizumab (Avastin) 1.25mg/0.05ml causes regression of vascularity, symptoms (irritation, redness) up to 7 wks. post injection only. Teng CC, et al. Cornea. 2009 May; 28(4):468-70 3 weeks

51. TOPICAL Anti VEGF IN PTERYGIUM RECURRENT PTERYGIUM : Topical Bevacizumab (Avastin) 25mg/ml QID dosing for 3 weeks, in a case of recurrent impending pterygium prevented recurrence up 6 mths follow up. Wu PC, et al. Cornea.2009 Jan;28(1):103-4 14 Days

52. Equivocal 97% success rate in 5FU and Avastin adjuncts to conjunctival autografts

53. Post keratoplasty corneal neovascularization

54. Avastin has been used as a combination therapy to prevent corneal neovascularization along with PDT and Argon Laser therapy. Avastin has also been tried for corneal stromal vascularization in DALK.

55. Chemical Burns Anti VEGF role in preventing neovascularization and accelerating repair has been demonstrated in animal models.

56. Anti VEGF used as topical drops have been shown to be of aid in chemical burns.

57. Herpetic Stromal Keratitis

58. Steven-Johnson Syndrome Anti VEGF used as topical drops and injections have been shown to be of aid in SJS. Studies show that effect of injection on one eye may have therapeutic effect on untreated eye as well.

59. Repeated Anti VEGF injections lead to hemostasis in the choriocapillaries of the RPE complex Leads to atrophy of the RPE Photoceptor Complex May lead to Geographical Atrophy in Humans

60. The CATT is a randomized clinical trial that showed that out of 1185 participants who were treated with ranibizumab or bevacizumab (both are anti-VEGF drugs), 156 patients developed GA at the end of the second year .(13%)  The study found that even after taking into account several baseline risk factors for GA, patients treated with ranibizumab still had both higher GA area enlargement from the initial lesion and GA incidence than those treated with bevacizumab . The study also found that patients treated with monthly anti-VEGF treatment had higher GA progression rate than as needed treatment.

61. Anti VEGF Therapy: Resistance