Age-related Macular Degeneration (AMD) Update. Michael W. Stewart, MD Professor and Chairman Department of Ophthalmology Mayo Clinic Florida

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1 Age-related Macular Degeneration (AMD) Update Michael W. Stewart, MD Professor and Chairman Department of Ophthalmology Mayo Clinic Florida

2 Disclosure Alkahest Consultant Allergan Research Support Bayer Consultant Regeneron Research Support The audience is advised that this continuing education activity may contain references to unlabeled uses of FDA-approved products (bevacizumab) or to products not approved by the FDA for use in the United States.

3 Major Take-home Points Risk factors HTN, smoking, obesity should be addressed early. Multi-vitamins (AREDS formula) help a small minority of people with intermediate AMD. New visual symptoms central vision loss, metamorphopsia should prompt an eye exam. Repeated anti-vegf injections have cut the risk of blindness by half.

4 Age-related Macular Degeneration Generally regarded as the leading cause of blindness in industrialized nations. But recent introduction of anti-vegf injections has cut rate of blindness in half (Denmark). Does not occur in people under the age of 40 years --- look for another diagnosis. Usual misdiagnosis is Stargardt s disease

5 Prevalence of AMD Worldwide Singh et al. J Asia-Pacific Academy Ophthalmol 2017 Variations due to genetic differences, access to healthcare, definitions of AMD, ages of cohorts

6 Age-Related Macular Degeneration: Genetics and Biology. Kumaramanickavel, Govindasamy Asia-Pacific Journal of Ophthalmology. 5(4): , July/August DOI: /APO

7 AMD Anatomy and Pathophysiology Fritsche et al. Ann Rev Genomics Hum Genet 2014

8 Risk Factors for AMD Non-modifiable Age Genetics Modifiable Systemic Arterial Hypertension Obesity Smoking

These loci modulate: Complement Lipid metabolism ECM

9 Genetics and AMD Mutations at dozens of genetic loci have been associated with increased risk of AMD. These loci modulate: Complement Lipid metabolism ECM remodeling Angiogenesis Cell survival Fritsche et al. Ann Rev Genomics Hum Genet 2014

10 Debate over utility of genetic testing. Genetic Testing?? NEITHER the American Academy of ophthalmology NOR any of the major vitreoretinal societies recommends testing. Why? No proven early intervention. Controlling risk factors is good medical sense for everyone.

11 Treatment of AMD Timeline of Major Milestones Thermal Laser Photocoagulation Discovery of VEGF Ocular Photodynamic Therapy AREDS AREDS Pegaptanib Ranibizumab Bevacizumab Aflibercept Anti-VEGFs

12 What is the role of Vitamin Supplementation? There are hundreds of studies regarding vitamin supplementation for AMD. Dozens of vitamin formulations are being pushed.

13 Age-Related Eye Disease Study (AREDS) Large, prospective, multi-center, randomized, trial. Vit A 500 mg, Vit C 400 IU Beta-carotene 15 mg Zinc 80 mg Copper 2 mg

14 Age-Related Eye Disease Study (AREDS) Some patients with intermediate AMD benefited Those with NO AMD or ADVANCED AMD did not How to interpret results: 1. Risk reduction of 25% 2. No more than 8% of people benefited 3. Standard MVI were also given to most subjects

15 AREDS 2 Large, prospective, multi-center, randomized, trial comparing: Placebo vs. AREDS 2 formulation 500 milligrams (mg) of vitamin C 400 international units of vitamin E 15 mg beta-carotene 25 mg zinc as zinc oxide 2 mg copper as cupric oxide 10 mg lutein and 2 mg zeaxanthin 1000 mg of omega-3 fatty acids (350 mg DHA and 650 mg EPA) Standard MVI were allowed in both arms.

16 AREDS 2

17 Age Related Macular Degeneration 90% of advanced AMD is dry But 90% of vision loss due to wet

18 Symptoms of AMD-related vision loss Central scotoma Metamorphopsia Amsler Grid New symptoms should prompt referral for a dilated eye exam.

19 Drusen major sign of early AMD

20 The Oil Spill in Bruch s Membrane Blood lipids Photoreceptors Bruch s membrane Drusen Pro-inflammatory Angiogenic Choroidal neovacularization Curcio et al. Br J Ophthalmol 2011;95:

21 Age-Related Macular Degeneration International Classification System (1995) Drusen Age-related maculopathy Macular degeneration mild moderate Severe AMD: 1. Geographic atrophy of RPE (dry) 2. Choroidal neovascularization (wet) severe

22 Geographic Atrophy of RPE (Dry) Loss of RPE cells (do not generate) Causes loss of overlying photoreceptors

23 Imaging of Geographic Atrophy Optical Coherence Tomography

24 Treatment of Geography Atrophy? Experimental treatments - Lampalizumab (CFH inhibitor) - failed phase II trials. - No promising treatment for GA on the horizon

25 Wet Macular Degeneration Edema Hemorrhage

26 Fluorescein Angiography

28 Performed without dye The only things moving within the retina are RBCs OCT Angiography

29 Treatment of AMD Timeline of Major Milestones Thermal Laser Photocoagulation Discovery of VEGF Ocular Photodynamic Therapy AREDS AREDS Pegaptanib Ranibizumab Bevacizumab Aflibercept Anti-VEGFs

30 Discovery of Vascular Endothelial Growth Factor (VEGF) 1983: Discovery of vasopermeability factor 1989: Two groups independents discovered vascular endothelial growth factor

31 What We Are Treating in 2018? Chorioretinal Vascular Conditions Stewart M. Mayo Clin Proc. 2012;87:77-88.

32 What Are the Underlying Pathophysiologic Processes? Two major processes contribute to angiogenesis and blood retinal barrier breakdown: 1. Inflammation 2. Ischemia Both upregulate VEGF Stewart M. Mayo Clin Proc. 2012;87:77-88.

33 VEGF and Receptors Christopoulos A, et al. Head Neck. 2011;33:

34 Angiogenesis [VEGF] Exudation Stewart M. Mayo Clin Proc. 2012;87:77-88.

35 Bevacizumab (Avastin ) Monoclonal, murine (humanized) antibody MW: 149 kda Has 2 binding sites Current indications: - Colorectal Ca. - Kidney Ca. - Non-small cell lung Ca. - Ovarian Ca. - Glioblastoma - Breast Ca. (non-us) Intravitreal use is off-label and unlikely to change. Fc fragment

Ranibizumab (Lucentis ) Cleavage of IgG Molecular Substitutions MW: 149 kda MW: 48 kda Ferrara N, et al. Retina. 2006;26:859-870.

36 Ranibizumab (Lucentis ) Cleavage of IgG Molecular Substitutions MW: 149 kda MW: 48 kda Ferrara N, et al. Retina. 2006;26: Affinity Enhancement compared to bevacizumab: 5x - 20x 6x 11x Ferrara N, et al. Retina. 2006;26: Klettner A, et al. IOVS. 2008;49: Yu L, et al. Biochem Biophys Res Comm. 2011;408:

37 Aflibercept (Eylea ) Development Incorporation of binding domain of VEGFR1 increases affinity for VEGF-A and binds VEGF-B and PlGF Simultaneously attaches to both binding sites of VEGF dimer 2-fisted grasp MW: 115 kda Stewart MW. Inflamm Allergy Drug Targets. 2011;10:

38 Current ocular anti-vegf drugs bind diffusible VEGF, thereby preventing receptor binding and activation Ramucirumab (Cyramza ) VEGFR2 blocker Stomach cancer Stewart MW. Exp Rev Clin Pharm. 2014;7:

39 Each of these drugs is administered in the same way Injected Intravitreally to treat choroidal neovascularization (wet AMD)

Mean change in VA from baseline 15 Ranibizumab Was the First Anti-VEGF Therapy to Improve or Maintain Vision for up to 2 Years MARINA 1 ANCHOR 2 Sham (n=238) Ranibizumab0.

40 Mean change in VA from baseline 15 Ranibizumab Was the First Anti-VEGF Therapy to Improve or Maintain Vision for up to 2 Years MARINA 1 ANCHOR 2 Sham (n=238) Ranibizumab0.5 mg (n=240) PDT b (n=143) Ranibizumab 0.5 mg (n=139) 15 (ETDRS letters) a letter difference, P< letter difference, P< Month 14.9 In MARINA and ANCHOR, the primary end point was the proportion of patients losing <15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters at 52 weeks MARINA included patients with minimally classic or occult lesions with a best corrected visual acuity (BCVA) of 20/40 to 20/320 ANCHOR included patients with predominantly classic lesions -15 Month a Prespecified secondary endpoint. Note: Vertical bars are ±1 standard error of the mean. b PDT = verteporfin photodynamic therapy. 1. Rosenfeld P, et al. N Engl J Med. 2006;355: Brown D, et al. Ophthalmology. 2009;116:257.

41 ETDRS letters VIEW : Aflibercept vs. Ranibizumab 2 Years: Mean Change in Visual Acuity In the aflibercept groups was comparable to ranibizumab 9.3 2q4 8.7 Rq q q4 7.9 Rq q q q4 Week * Heier JS, et al. Ophthalmology 2012;119:

42 CATT: Ranibizumab vs. Bevacizumab 2 Year Outcomes Mean no. Rx: R-M: 22 B-M: 23 R-PRN: 12.6 B-PRN: Two main conclusions: 1. Ranibizumab = Bevacizumab 2. Monthly treatment better than PRN * The CATT Research Group. Ophthalmology. 2012;119:

43 Major Points for the Treatment of Wet AMD Each of the drugs aflibercept, bevacizumab, ranibizumab works equally well for most patients. More treatments (monthly injections) is better, but most physicians try to balance results with cost by treating PRN (regular visits, treated when needed) or Treat-and-extend (treat at each visit but lengthen intervals)

44 9/29/2005 Vision 20/2000

46 1 month after bevacizumab 10/31/2005 Vision 20/40

47 2 months after bevacizumab 11/30/2005 Vision 20/30

48 4 months after bevacizumab reactivation 1/11/2006 Vision 20/100

49 What Options are Available to AMD Patients with Poor Vision? For patients with poor vision due to: 1. Geography atrophy 2. Bilateral end-stage scarring 3. Disruption of macular anatomy despite injections Consider offering: 1. Low Vision Exam 2. Intraocular Telescope

50 Low Vision Exam These are usually 1 hour exams performed by specially trained optometrists Focus is on identifying devices that optimize vision. Usually reading vision can be improved more successfully than distance vision.

51 Intraocular Telescope Implantable lens; surgery performed like cataract surgery. Magnifies images by 2.2x but constricts peripheral vision. FDA approved for use in one eye.

52 What About the Future? Developers are working on New anti-vegf drugs New delivery systems Drugs against new biological targets Soon there will be some successes with subsequent FDA approvals. But there have been spectacular failures And safety continues to be an issue.

53 Abicipar pegol (DARPin MP0112) Genetically engineered antibody mimetic proteins. Small, single domain proteins with repeat motifs (24 kda). High affinity VEGF binder t 1/2 ~ 13.5 days Low High Bevacizumab: 58-1,100 pm Ranibizumab: pm Abicipar 2 pm Aflibercept: 0.5 pm Phase 3 AMD trial underway investigating q3month dosing

Small, single chain Ab fragment may allow: - better tissue penetration - higher administered dose Brolucizumab In phase III AMD trials (HAWK and HARRIER)

54 Small, single chain Ab fragment may allow: - better tissue penetration - higher administered dose Brolucizumab In phase III AMD trials (HAWK and HARRIER) brolucizumab vs. aflibercept: Non-inferior BCVA gains at 48 weeks 52% and 57% were controlled with q12wk dosing Similar safety profiles FDA approval will be sought in 2018

55 Conbercept Developed by Chengdu Kanghong Biotech in China - Fusion trap with K d of 0.77 pm - Phase II: improvement in VA at 2 months (0.5 mg and 2 mg) were 9 and 10.4 letters - Approved in China Dec. 18, 2013 for exudative AMD - Phase III AMD trials now in development in US Wang Q, Li T, Wu Z, Wu Q, et al. (2013) Novel VEGF Decoy Receptor Fusion Protein Conbercept Targeting Multiple VEGF Isoforms Provide Remarkable Anti-Angiogenesis Effect In Vivo. PLoS ONE 8(8): e doi: /journal.pone

56 Refillable Drug Delivery Implant Surgically implanted through pars plana no sutures Initially with ranibizumab (250 µg) Manufactured by Genentech with ForSight Vision4 Phase 1 study of 20 treatment naïve patients 1 year study (Latvia) 77 adverse events - 4 significant (endophthalmitis, vitreous hemorrhage (2), cataract) Results comparable to monthly Ranibizumab Phase II LADDER trial now underway United States Patent Application

Encapsulated Cell Technology Dry AMD Phase 2 study for dry AMD Release of ciliary neurotrophic factor (CNTF) Sampling showed half-life of 51 months; statistically stabile levels between 6 and 24

57 Encapsulated Cell Technology Dry AMD Phase 2 study for dry AMD Release of ciliary neurotrophic factor (CNTF) Sampling showed half-life of 51 months; statistically stabile levels between 6 and 24 months Kauper K, et al. Invest Ophthalmol Vis Sci. 2012;53(12): Wet AMD NT-503 series releases high affinity VEGF binding protein (VEGFR2) for namd Phase II trial terminated early due to lack of efficacy Cells engineered to over-synthesize desired protein

58 Adenovirus Delivered Anti- VEGF Gene Therapy Avalanche and Genzyme Anti-VEGF promoter gene in an adenovirus vector. Tyrosine kinase inhibitor highly specific for VEGFR1 and VEGFR2 Safe and promising in phase 1 trials Injections were given: Subretinally (Avalanche) Intravitreally (Genzyme) Avalanche phase II trial showed poor VA change, requiring frequent rescue injections.

Angiopoietin (Ang)-2/ Tie2 Inhibition Ang2 is upregulated by ischemia; independently or with VEGF promotes neovascularization and hyper-permeability.

59 Angiopoietin (Ang)-2/ Tie2 Inhibition Ang2 is upregulated by ischemia; independently or with VEGF promotes neovascularization and hyper-permeability. Ang2 inhibition together with anti-vegf investigated for the treatment of namd and DME. Clinical trials: 1. Co-formulation with aflibercept failed to outperform aflibercept monotherapy for AMD - further development halted 2. Bispecific antibody (with anti-vegf) continues in phase II trials for AMD and DME.

Platelet Derived Growth Factor (PDGF) PDGF serves as a growth and survival factor for pericytes and stromal fibroblasts. Phase II trial with anti-pdgf aptamer produced superior VA improvements vs.

60 Platelet Derived Growth Factor (PDGF) PDGF serves as a growth and survival factor for pericytes and stromal fibroblasts. Phase II trial with anti-pdgf aptamer produced superior VA improvements vs. ranibizumab at 6 months (10.5 vs. 6.1 letters). - Phase III trial failed to outperform ranibizumab. - Phase II trial with a anti-pdgf Ab failed to outperform aflibercept. All anti-pdgf trials have been halted.

61 Safety

62 Compounded Bevacizumab AJO 2012;153:

63 Systemic Safety Concerns Systemic bevacizumab doubles stroke risk Stewart M, Mayo Clin Proc. 2012;87:77-88.

64 Systemic Risks of Anti-VEGF Therapy Curtis et al (Arch Oph 2010): - 146,942 Medicare beneficiaries with AMD ( ) - Mortality: ranibizumab < PDT (0.85), pegaptanib (0.84) bevacizumab = other groups - MI: ranibizumab < PDT (0.73) bevacizumab = other groups - Stroke: similar among all groups Campbell et al: - 116,288 Ontario residents with AMD ( ) - No change in stroke hospitalizations with introduction of ranibizumab bevacizumab. Campbell et al, Ophthalmology 2012

65 Stem Cells With great promise comes great peril vs Status as of 2018 beware of the scam artists

66 The Good Success was defined as a few surviving cells. Function was not addressed in this manuscript.

67 The Bad Three S. FL pts. blinded by the injection of fat-derived stem cells Severe fibroblast proliferation with retinal detachments Kuraiyan et al. N Engl J Med 2017;376;

68 Conclusions Modifiable risk factors HTN, smoking, obesity should be addressed early. Multi-vitamins (AREDS formula) help a small minority of people with intermediate AMD. New visual symptoms central vision loss, metamorphopsia should prompt an eye exam. Long-term anti-vegf injections have cut the risk of blindness by half.

2/1/2017. Agenda. David F. Williams, MD, MBA. History of Current Treatment. Current Treatment/Wet AMD Anti-VEGF Drugs. History of Current Treatment

2/1/2017. Agenda. David F. Williams, MD, MBA. History of Current Treatment. Current Treatment/Wet AMD Anti-VEGF Drugs. History of Current Treatment UPDATE ON CLINICAL TRIALS FOR AMD David F. Williams, MD, MBA Agenda Brief History of Current Rx Recently Completed/New CTs: Wet AMD Recently Completed/New CTs: Dry AMD Current Treatment/Wet AMD Anti-VEGF