Age-related Macular Degeneration (AMD)

From the Posterior Segment Conference 2009, presented by the Ocular Immunology and Uveitis Foundation

Jeffrey S. Heier, MD, Assistant Professor, Tufts University School of Medicine, Clinical Instructor, Harvard Medical School, and Vitreoretinal Specialist, Ophthalmic Consultants of Boston, MA

Educational Objectives

The goal of this program is to improve the management of age-related macular degeneration (AMD). After hearing and as­similating this program, the clinician will be better able to:

1.   Describe the anatomic and visual outcome measurements used in clinical trials of AMD therapies.

2.   Compare and contrast the different methods of measuring geographic atrophy.

3.   Evaluate the results of clinical studies using anti-VEGF agents to treat exudative AMD.

4. Assess the benefits and drawbacks of new therapeutic agents under development for wet and dry AMD.

5.   Summarize the roles of extended delivery technologies in the treatment of AMD.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, Dr. Heier reported receiving research grants from or serving as an investigator for Alcon, Allergan, Alimera Sciences, Genentech, Genzyme, Jerini, NeoVista, Neuro­tech, Novagali, Regeneron, and Schering-Plough; he has also received honoraria from or served as a consultant for Acucela, Alcon, Allergan, Fovea, Genentech, iScience Interventional, ISTA, NeoVista, Neurotech, Novagali, Oraya, Pfizer, Potentia, Regeneron, Sightpath, Schering-Plough, and SARCode. The planning committee reported nothing to disclose. In his lec­ture, Dr. Heier discusses the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Lectures by Dr. Heier were recorded at Fourth Annual Ocular Immunology and Uveitis Foundation Physician Education Conference: “New Paradigms in the Treatment of Posterior Segment Disease”, held November 14, 2009, in Cambridge, MA, and sponsored by the Ocular Immunology and Uveitis Foundation and the Massachusetts Eye Research and Surgery Institution. The Audio-Digest Foundation thanks Dr. Heier and the sponsors for their cooperation in the production of this program.

Assessment, Monitoring, and End Points in AMD

Advances in treatment: previously, loss of £14 letters or 3 lines of vision over 2 yr considered treatment success; Treatment of Age-related macular degeneration with Photodynamic therapy (TAP) study found only 15% overall change between treatment and placebo arms; since recent introduction of anti-vascular endothelial growth factor (anti-VEGF), eg, ranibizumab (Lucentis), patients have true gains of vision at 12 and 24 mo of therapy; study showed patients in control arm lost 15 letters over 2 yr, but patients in treatment arm gained vision (4-line differ­ence between treatment and control arms)

End Points

Phase I studies: patients have more advanced disease, often have not responded to previous treatment, and likelihood of visual response low; studies focus on anatomic outcomes and safety

Phase II studies: outcomes include efficacy, but not necessarily visual improvement; study of VEGF-Trap measured changes on optical coherence tomography (OCT) as indicator of decrease in retinal thickness (primary anatomic outcome)

Pivotal trials (phase III): usually rely on visual acuity (VA) as primary outcome, with anatomic change, reading speed, contrast sensitivity, or patient-reported quality of life used as proof of benefit

End points accepted by United States Food and Drug Administration (FDA): VA most important; visual field, contrast sensitivity, and color vision possibly acceptable if clinical benefit demonstrated; 3-line change in VA con­sidered clinically significant; previous studies of diabetes and vein occlusion accepted 2-line changes, but 3-line gain now considered minimum; previous primary outcomes (eg, prevention of moderate vision loss) now achieved at rates >90% by anti-VEGF therapy; intravitreal injections well tolerated and safe; reducing number of injections not acceptable outcome (rate of poor outcomes from injections estimated at 1 in 2000 to 1 in 3000)

Combination studies: must demonstrate benefit; reduced frequency of treatment must lessen adverse consequences; decreased time to retreatment (thus lowering costs) important to Centers for Medicare and Medicaid Services (CMS), but not to FDA

Nonexudative Disease

Retrospective review: 40% of patients in phase II and III trials started on ranibizumab in 2001 or 2002 (2-6 yr of fol­low-up) developed fibrosis; 50% developed atrophy alone, and 7% atrophy plus fibrosis; largely due to progression of underlying disease (fellow eye also develops atrophy over time)

Geographic atrophy (GA): FDA accepts decreased rate of enlargement of GA as approved outcome

Dry AMD end points: prevention of progression to wet AMD, VA (not always applicable), GA itself, contrast sensi­tivity, reading speed, and visual field; microperimetry under evaluation; several serve as supportive but not primary outcomes; FDA and National Eye Institute considering change in rate or extent of anatomic progression of GA as acceptable outcome, but only if clinical significance documented; patient with progressing GA may have VA of 20/20 but impaired reading speed and contrast sensitivity

Laser treatment of drusen: studies tested application of light grid pattern of laser; study showed removing drusen had no significant effect on vision; with inappropriate application of laser, risk for neovascularization increased

Measurements of GA: fundus photography, autofluorescence, or spectral domain OCT (SD-OCT); areas of GA cor­relate with visual function and areas of dense scotoma; reading rates fall as GA increases; rates of growth (reach­ing 1.5-2 mm/yr for many lesion types) consistent among patients; color photography  —may overestimate GA by 30%; autofluorescence  —reproducible and yields predictive information from different patterns; normally, retinal pigment epithelium (RPE) breaks down metabolic byproducts with little buildup of lipofuscin granules; aging, trauma, and insults increase buildup, which correlates with GA; black areas represent dead cells; white ar­eas of autofluorescence around outside demonstrate progression; different patterns characteristic of different rates of progression (eg, areas of GA with no autofluorescence or focal areas of autofluorescence do not progress, but areas with trickling pattern show progression of >3 mm/yr); symmetric pattern often seen in fellow eye; such measurements may reduce duration of trials needed to show efficacy; SD-OCT  —  high correlation with autofluo­rescence; evaluates photoreceptor junctions and RPE layers; measuring drusen  —  evaluate changes in soft or small drusen

Selecting patients for trials: evaluating genotypes (eg, complement factor H polymorphisms) may predict patients at high risk for progression; fellow eyes have 20% risk for progression in 1 yr; such patients could shorten length of trials needed to demonstrate benefit

Anti-VEGF therapies  ranibizumab and bevacizumab (Avastin): goals for treatment include stabilization or re­covery, safety (ocular and systemic), and treatment burden; 4 large phase III trials of ranibizumab therapy showed good early response in all patients; however, Genentech phase III open-label extension study of participants from earlier trials showed that, after switching to prn dosing regimen, initial gain of 10 letters over 2 yr of continuous treatment dropped to 2 letters; possibly, but not necessarily, due to undertreatment (may be due to natural progres­sion of disease); optimal dosing regimen  —  practical regimens under evaluation include “treat and follow” (patients receive injections, then retreated when disease recurs), or “treat and extend” (time between injections gradually in­creased); speaker considers more frequent treatments in patients with certain characteristics (monocular, bilateral, lesions that threaten but do not involve macula, or frequent recurrences) and less frequent treatments for patients with good vision in fellow eye or lesions far from center

Future Horizons in the Treatment of AMD

Wet AMD

Vascular endothelial growth factor: stimulates growth of new vessels; multiple forms (A, B, C, and D) discovered; many other growth factors may play role in retinal disease and angiogenesis; success of blocking VEGF shows im­portance of approach, but other factors possibly important

VEGF Trap-Eye: fusion protein of VEGF receptors 1 and 2 that binds to VEGF with higher affinity than ranibi­zumab or bevacizumab (may increase efficacy and duration of action); also binds placental growth factor (PIGF); studies showed corneal angiogenesis (new vessels and permeability) in normal mice, but not in knockout mice lack­ing gene for PIGF; in phase II study, improvement in VA gained during 3 mo of VEGF Trap-Eye treatment per­sisted (92% stability) during prn phase; 71% of patients had no loss or gain of VA at 2 yr; 30% to 40% had significant gain; group of patients who received quarterly doses lost some gains; gains not recovered after switch­ing to prn dosing; shows importance of loading dose; in prn phase, mean of <5 injections required over 21 mo, and patients had good durability of VA; time to first injection in prn phase, 5 to 6 mo; >2400 patients enrolled in 2 on­going phase III studies, with 600 taking ranibizumab at 0.5 mg; studies in diabetes and retinal vein occlusion (RVO) also in progress

Radiation therapy (RT) for exudative AMD: has antiangiogenic, anti-inflammatory, and antifibrotic actions, but has numerous side effects; works well in combination with anti-VEGF therapy (eg, RT plus bevacizumab for co­lon cancer); previously, not administered selectively enough to prevent side effects; cellular response to radiation (death vs repair; early vs late) depends on cell type and phase of cycle; cells in AMD not often in G₂ and mitotic phases (ie, have limited radiosensitivity)

NeoVista: device uses b-emitter (strontium 90) with good depth of penetration for AMD (2-4 mm), but effect di­minishes by 10% every 0.1 mm of distance from point source (90% lost at »1 cm); requires 4 to 5 min of expo­sure; administered surgically under local anesthesia; can perform core vitrectomy with 20-, 23-, or 25-gauge, but device requires 20-gauge port; radiation delivered directly to treatment area; vitrectomy may also have therapeu­tic effect by increasing oxygenation and decreasing blood flow; one dose delivers 24 Gy to center of lesion, 2.4 Gy to optic nerve, and 0.6 mGy to lens (does not cause radiation retinopathy); creates minimal exposure for pa­tient and clinicians; phase II study combined NeoVista RT with 2 injections of bevacizumab (1 mo apart); showed initial gain, with stability to 18 mo and good prevention of moderate loss of VA; numerous patients with gain of 3 lines of VA and/or decreased central retinal thickness observed; at 18 mo, »75% of patients had re­ceived no additional injections, and 8 patients received additional injection; patients probably undertreated

Oraya Iray System: uses noninvasive x-ray beam with robotic control of cornea; no surgery required, and possibly suitable for office setting; after stabilization of eye under topical anesthesia, 3 beams delivered through sclera, bypassing lens and cornea; reproducible delivery shown in animal studies; procedure well-tolerated; effect from radiation alone observed; some patients have improved vision, despite persistence of fluid; suggests potential benefit of irradiation beyond drying of fluid and shutting down vessels

Designed ankyrin repeat proteins (DARPins): small stable nonimmunoglobulin proteins; inexpensive to produce; 50- to 100-fold greater affinity than VEGF-Trap; stable at room temperature, with long half-life in eye; animal studies suggest administration by drops possible

Platelet derived growth factor (PDGF): regulates associations between pericytes in mature new vessels and endo­thelial cells; blocking PDGF may complement effect of anti-VEGF therapy by keeping vessels immature; animal data show absence of pericytes after treatment; under development by Ophthotech; patients receiving combination of anti-PDGF and anti-VEGF agents had gain in vision and absence of fibrosis

Vascular disrupting agents: designed to reduce blood flow to tumors; combretastatin A-4-phosphate (CA4P) binds tubulin in microtubules and causes breakdown of vessels; however, toxic side effects seen in trials of systemic and intravitreal administration; currently evaluating topical use; shows breakdown of vessels in animal models

Sirolimus (rapamycin): immunosuppressive agent for prevention of organ rejection and coronary restenosis, and treatment of cancer; targets mammalian target of rapamycin (mTOR), which affects cell maturation and regulation; may help with inflammation and fibrosis; formulated for intraocular or subconjunctival administration; self-form­ing drug depot provides sustained tissue levels with full absorption; neovascular AMD studies  —  safety and bio­logic activity demonstrated by best corrected vision and OCT; showed rapid gain in VA but delayed anatomic response; current studies include monotherapy and combination therapy with ranibizumab; other studies  —  efficacy in diabetic macular edema (DME) and RVO; case example of patient receiving subconjunctival rapamycin showed good response at 2 mo, return of some fluid at 4 mo, but continued response with ongoing treatment; may evaluate in patients in Age-Related Eye Disease Study (AREDS)

Dry AMD

Prevalence: GA present in 3.5% of patients >75 yr of age, 20% to 25% of patients >90 yr of age

Treatment goal: halt atrophy of RPE cells and loss of photoreceptor cells to prevent progression

Agents: glatiramer acetate (Copaxone)  —  treatment for multiple sclerosis; modifies modulation of microglia; study showed reduction of high-risk drusen over 12 wk (but prognosis unknown); brimonidine (Alphagan)  shows neuro­protective (and possibly neuroenhancement) effects in retinal ganglion, bipolar, and photoreceptor cells after sev­eral insults; in blue light-induced photoreceptor degeneration model, exposure of rats to blue light for 8 hr leads to cell death, but brimonidine preserves cell layer; currently in phase I study in patients with GA and high-risk drusen (delivered via biodegradable ocular implant [Posurdex])

Complement inhibition: complement system has 30 enzymes and regulatory proteins that defend against infection and modulate immunity and inflammatory responses; analyses of complement factors in drusen from donor eyes show unexpected composition and origins; Bruch’s membrane and RPE sequester factors; all present in drusen; ev­idence points to defect in alternative pathway, but how defects lead to different diseases unknown; studies in mice show that genetically ablating complement receptors limits laser-induced choroidal neovascularization; disorders associated with complement deficiency lead to dense-deposit disease or membranoproliferative glomerulonephritis type II and early-onset soft drusen (as in AMD); moderating this disease associated with disappearance of drusen; point mutations in complement factor H cause highly penetrant AMD in large families; protective types of comple­ment factor H also exist (ie, cannot look only at blocking complement factor); patients with variations in comple­ment factor H have higher risk of developing AMD earlier and more rapidly; possibly less susceptible to anti-VEGF; presence of many of these factors raises risk of developing AMD »300-fold; Genentech evaluating inhibi­tion of complement factor D

Extended delivery: encapsulated cell technology under evaluation for treating exudative disease; cell lines in implant still functioning after 12 yr; creates “implantable protein factory” that may provide longer duration of therapy; long-lasting injections include emulsions, oils, and microspheres; removable implants under development; fluocin­olone implant may last 12 to 36 mo; more posterior implantation may minimize side effects

Suggested Reading

Allikmets R et al: The SERPING1 gene and age-related macular degeneration. Lancet 374:875, 2009; Anderson DH et al: The piv­otal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited. Prog Retin Eye Res Dec 1, 2009 [Epub ahead of print]; Bearelly S et al: Spectral domain optical coherence tomography imaging of geographic atrophy margins. Ophthalmology 116:1762, 2009; Bressler NM: Antiangiogenic approaches to age-related macular degeneration today. Ophthalmol­ogy 116:S15, 2009; Bressler SB: Introduction: Understanding the role of angiogenesis and antiangiogenic agents in age-related mac­ular degeneration. Ophthalmology 116:S1, 2009; Do DV: Antiangiogenic approaches to age-related macular degeneration in the future. Ophthalmology 116:S24, 2009; Freeman SR et al: Optical coherence tomography-raster scanning and manual segmentation in determining drusen volume in age-related macular degeneration. Retina Dec 1, 2009 [Epub ahead of print]; Joussen AM et al: Is significant relevant? Validity and patient benefit of randomized controlled clinical trials on age-related macular degeneration. Surv Ophthalmol 52:266, 2007; Klettner A, Roider J: Treating age-related macular degeneration – interaction of VEGF-antagonists with their target. Mini Rev Med Chem 9:1127, 2009; Ni Z Hui P: Emerging pharmacologic therapies for wet age-related macular degener­ation. Ophthalmologica 223:401, 2009; Nguyen QD et al: A phase I study of intravitreal vascular endothelial growth factor trap-eye in patients with neovascular age-related macular degeneration. Ophthalmology 116:2141, 2009; Pai AS et al: Complement factor H and the bilaterality of age-related macular degeneration. Arch Ophthalmol 127:1339, 2009; Parodi MB et al: Laser treatment of dru­sen to prevent progression to advanced age-related macular degeneration. Cochrane Database Syst Rev Jul 8(3):CD006537, 2009; Schmitz-Valckenberg S et al: Fundus autofluorescence and progression of age-related macular degeneration. Surv Ophthalmol 96:117, 2009 Squirrell DM et al: Visual outcome after intravitreal ranibizumab for wet age-related macular degeneration: a compar­ison between best-corrected visual acuity and microperimetry. Retina Dec 4, 2009 [Epub ahead of print]; Wagner E, Frank MM: Therapeutic potential of complement modulation. Nat Rev Drug Discov Dec 4, 2009 [Epub ahead of print]; Wittes J, Downs M: Outcome measures to assess efficacy of treatments for age-related macular degeneration. Ophthalmology 116:S8, 2009; Zipfel PF, Serka C: Complement regulators and inhibitory proteins. Nat Rev Immunol 9:729, 2009.