Update on Age Related Maculopathy

UPDATE ON AGE RELATED MACULAR DEGENERATION

DR KHALED AL KHALED, MD, MRCOPHTH

INTRODUCTION

• AGE-RELATED MACULAR DEGENERATION (AMD) IS THE LEADING CAUSE OF ADULT BLINDNESS AND SEVERE VISUAL IMPAIRMENT IN INDUSTRIALIZED COUNTRIES

1BRESSLER NM. AGE-RELATED MACULAR DEGENERATION IS THE LEADING CAUSE OF BLINDNESS... JAMA 2004; 291:1900.

DRY (ATROPHIC) AMD

ANTIOXIDANT VITAMINS AND ZINC

• AREDS1:• VITAMIN C (500 MG)• VITAMIN E (400 IU)• BETA-CAROTENE (15 MG)• ZINC (ZINC OXIDE 80 MG)• CUPRIC OXIDE 2 MG

1AGE-RELATED EYE DISEASE STUDY RESEARCH GROUP. A RANDOMIZED, PLACEBO-CONTROLLED, CLINICAL TRIAL OF HIGH-DOSE SUPPLEMENTATION WITH VITAMINS C AND E, BETA CAROTENE, AND ZINC FOR AGE-RELATED MACULAR DEGENERATION AND VISION LOSS: AREDS REPORT NO. 8. ARCH OPHTHALMOL 2001; 119:1417.

ANTIOXIDANT VITAMINS AND ZINC• IN A META-ANALYSIS, 88 PERCENT OF PATIENTS WERE IN THE

AREDS COHORT, AND THE REVIEWERS CONCLUDED THAT THE OTHER STUDIES ADDED LITTLE TO THE EVALUATION

1AGE-RELATED EYE DISEASE STUDY RESEARCH GROUP. A RANDOMIZED, PLACEBO-CONTROLLED, CLINICAL TRIAL OF HIGH-DOSE SUPPLEMENTATION WITH VITAMINS C AND E, BETA CAROTENE, AND ZINC FOR AGE-RELATED MACULAR DEGENERATION AND VISION LOSS: AREDS REPORT NO. 8. ARCH OPHTHALMOL 2001; 119:1417.2EVANS JR. ANTIOXIDANT VITAMIN AND MINERAL SUPPLEMENTS FOR SLOWING THE PROGRESSION OF AGE-RELATED MACULAR DEGENERATION. COCHRANE DATABASE SYST REV 2006; :CD000254.


2EVANS JR. ANTIOXIDANT VITAMIN AND MINERAL SUPPLEMENTS FOR SLOWING THE PROGRESSION OF AGE-RELATED MACULAR DEGENERATION. COCHRANE DATABASE SYST REV 2006; :CD000254.

ANTIOXIDANT VITAMINS AND ZINC• AREDS2:

• ORIGINAL DOSE ZINC (80 MG AS ZINC OXIDE)• COPPER OXIDE (2 MG)• VITAMIN E (400 IU)• VITAMIN C (500 MG)• LUTEIN (10 MG) • ZEAXANTHIN (2 MG)• BETA-CAROTENE (15 MG)

1THE AGE-RELATED EYE DISEASE STUDY 2 (AREDS2) RESEARCH GROUP, LUTEIN + ZEAXANTHIN AND OMEGA-3 FATTY ACIDS FOR AGE-RELATED MACULAR DEGENERATION THE AGE-RELATED EYE DISEASE STUDY 2 (AREDS2) RANDOMIZED CLINICAL TRIAL. JAMA. 2013;309(19):2005-2015. DOI:10.1001/JAMA.2013.4997.

LASER THERAPY

1PARODI MB, VIRGILI G, EVANS JR. LASER TREATMENT OF DRUSEN TO PREVENT PROGRESSION TO ADVANCED AGE-RELATED MACULAR DEGENERATION. COCHRANE DATABASE SYST REV 2009; :CD006537. (UPDATED 2015)

LASER THERAPY

STEM CELLS THERAPY

• A PROSPECTIVE STUDY IN NINE PATIENTS WITH ATROPHIC AMD (MEDIAN AGE 77 YEARS) FOUND THAT:• SUBRETINAL TRANSPLANTATION OF HUMAN EMBRYONIC

STEM CELL-DERIVED RETINAL EPITHELIAL CELLS IMPROVED VISUAL ACUITY AT 12 MONTHS IN THE TREATED EYE COMPARED WITH THE UNTREATED EYE

STEM CELLS THERAPY

STEM CELLS THERAPY

• THESE FINDINGS SUPPORT A PROOF-OF-CONCEPT, BUT ARE TOO PRELIMINARY TO SUGGEST A MEANS OF TREATMENT.

WET(NEOVASCULAR OR EXUDATIVE)

RANIBIZUMAB (LUCENTIS)

• IS A RECOMBINANT HUMANIZED MONOCLONAL ANTIBODY WITH SPECIFICITY FOR VEGF. INTRAVITREAL RANIBIZUMAB IS AVAILABLE FOR THE TREATMENT OF WET AMD AT A DOSE OF 0.5 MG BY INTRAVITREAL INJECTION EVERY MONTH

• SEVERAL RANDOMIZED TRIALS OF PATIENTS WITH WET AGE-RELATED MACULAR DEGENERATION (AMD) HAVE SHOWN BENEFIT.

• THE MARINA TRIAL• THE ANCHOR TRIAL.. ETC..

1ROSENFELD PJ, BROWN DM, HEIER JS, ET AL. RANIBIZUMAB FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION. N ENGL J MED 2006; 355:1419.2BROWN DM, KAISER PK, MICHELS M, ET AL. RANIBIZUMAB VERSUS VERTEPORFIN FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION. N ENGL J MED 2006; 355:1432.

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SAFETY PROFILE OF RANIBIZUMAB :

• SAFETY PROFILE OF RANIBIZUMAB 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%

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SAFETY PROFILE OF RANIBIZUMAB :

• SAFETY PROFILE OF RANIBIZUMAB 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

BEVACIZUMAB (AVASTIN)

• TREATMENT WITH INTRAVITREAL BEVACIZUMAB FOR AMD IS FAR LESS EXPENSIVE THAN TREATMENT WITH INTRAVITREAL RANIBIZUMAB.

• RANIBIZUMAB IS ESSENTIALLY AN ANTIBODY FRAGMENT (FAB FRAGMENT) OF BEVACIZUMAB WITH SOME MODIFICATIONS TO THE AMINO ACID SEQUENCE THAT INCREASE ITS BINDING OF VEGF.

• BEVACIZUMAB IS APPROVED IN THE UNITED STATES AS AN INTRAVENOUS INFUSION FOR THE SYSTEMIC THERAPY OF COLORECTAL CANCER.

RANIBIZUMAB VS BEVACIZUMABSYSTEMATIC REVIEWS 1





FOREST PLOT SHOWING ESTIMATED RISK RATIOS (RRS) WITH THEIR 95% CONFIDENCE INTERVALS (CIS) FOR BEVACIZUMAB VERSUS RANIBIZUMAB FOR GAIN OF ≥15 LETTERS FROM BASELINE FOR EACH OF THE 6 INDIVIDUAL TRIALS AND COMBINED. A, ONE-YEAR FINDINGS. B, TWO-YEAR FINDINGS.

AFLIBERCEPT (EYLEA)

• RECOMBINANT FUSION PROTEIN THAT COMPETES FOR BINDING OF VEGF AND THEREFORE HAS AN EFFECT SIMILAR TO VEGF INHIBITORS

• THE MOST RECENT DRUG TO BE APPROVED BY THE FDA FOR TREATING PATIENTS WITH WET AMD1 (2011).

• INSTEAD OF BEING AN ANTIBODY TO THE VEGF MOLECULE, IT IS A FUSION PROTEIN CONSISTING OF PORTIONS OF THE RECEPTORS FOR THE VEGF MOLECULE (VEGFR-1, VEGFR-2), THEREBY BINDING AND BLOCKING VEGF

1WWW.FDA.GOV/NEWSEVENTS/NEWSROOM/PRESSANNOUNCEMENTS/UCM280601.HTM

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AFLIBERCEPT (EYLEA)

• IN TWO RANDOMIZED TRIALS OF 2419 ADULT PATIENTS WITH WET AMD, INTRAVITREAL AFLIBERCEPT (0.5 MG MONTHLY, 2.0 MG MONTHLY, OR 2.0 MG EVERY TWO MONTHS) WAS SIMILARLY EFFECTIVE IN IMPROVING VISUAL ACUITY AT ONE AND TWO YEARS COMPARED WITH INTRAVITREAL RANIBIZUMAB 0.5 MG MONTHLY.

1HEIER JS, BROWN DM, CHONG V, ET AL. INTRAVITREAL AFLIBERCEPT (VEGF TRAP-EYE) IN WET AGE-RELATED MACULAR DEGENERATION. OPHTHALMOLOGY 2012; 119:2537.2SCHMIDT-ERFURTH U, KAISER PK, KOROBELNIK JF, ET AL. INTRAVITREAL AFLIBERCEPT INJECTION FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: NINETY-SIX-WEEK RESULTS OF THE VIEW STUDIES. OPHTHALMOLOGY 2014; 121:193.

AFLIBERCEPT (EYLEA)

AFLIBERCEPT VS RANIBIZUMAB

• FOREST PLOT OF COMPARISON: 1 AFLIBERCEPT VS RANIBIZUMAB, OUTCOME: 1.1 MEAN CHANGE IN BCVA IN ETDRS LETTERS AT 1 YEAR.

• FOREST PLOT OF COMPARISON: 1 AFLIBERCEPT VS RANIBIZUMAB, OUTCOME: 1.2 GAIN OF ≥ 15 LETTERS OF BVCA AT 1 YEAR.





• AFLIBERCEPT IS LESS COSTLY THAN RANIBIZUMAB AND MAY ALLOW FOR LESS FREQUENT DOSING (EVERY TWO MONTHS).

PEGAPTANIB (MACUGEN)

• FIRST VEGF INHIBITOR TO BE APPROVED BY THE FDA (DECEMBER 2004)

• STUDIED IN TWO RANDOMIZED TRIALS WITH A TOTAL OF 1186 PATIENTS AGED ≥50 WITH SUBFOVEAL CHOROIDAL NEOVASCULARIZATION SECONDARY TO AMD.

• IS ADMINISTERED IN A 0.3 MG DOSE ONCE EVERY 6 WEEKS BY INTRAVITREAL INJECTION.

• OTHER INTRAVITREAL ANTI-VEGF MEDICATIONS PROVIDE GREATER BENEFIT WITH LESS TOXICITY AND PEGAPTANIB IS ONLY RARELY USED FOR AMD

1GRAGOUDAS ES, ADAMIS AP, CUNNINGHAM ET JR, ET AL. PEGAPTANIB FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION. N ENGL J MED 2004; 351:2805.2VEGF INHIBITION STUDY IN OCULAR NEOVASCULARIZATION (V.I.S.I.O.N.) CLINICAL TRIAL GROUP, CHAKRAVARTHY U, ADAMIS AP, ET AL. YEAR 2 EFFICACY RESULTS OF 2 RANDOMIZED CONTROLLED CLINICAL TRIALS OF PEGAPTANIB FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION. OPHTHALMOLOGY 2006; 113:1508.E1.

SCHEDULE

• THE OPTIMAL FREQUENCY FOR INJECTIONS OF VEGF INHIBITORS IS NOT KNOWN, ALTHOUGH BOTH THE MARINA AND ANCHOR TRIALS EVALUATED MONTHLY INTRAVITREAL INJECTIONS. CURRENT USUAL SCHEDULES OF RANIBIZUMAB AND BEVACIZUMAB ARE MONTHLY. MONTHLY INJECTIONS POTENTIALLY INCREASE EXPENSE AND MAY BE POORLY ACCEPTED BY PATIENTS. THE SCHEDULE FOR AFLIBERCEPT IS TO ADMINISTER THREE DOSES (2 MG) AT FOUR WEEK INTERVALS, FOLLOWED BY 2 MG EVERY EIGHT WEEKS.

Discussion

ANTI-VEGF (GENOTYPING TO GUIDE THERAPY)

THERMAL LASER PHOTOCOAGULATION

THERMAL LASER PHOTOCOAGULATION

PHOTODYNAMIC THERAPY

• PHOTODYNAMIC THERAPY INVOLVES INTRAVENOUS INJECTION OF THE PHOTOSENSITIZING DYE VERTEPORFIN JUST PRIOR TO TREATMENT WITH A PHOTO-ACTIVATING LASER APPLIED THROUGH THE EYE WITH A SPECIFIC CONTACT LENS




• THE ROLE FOR PHOTODYNAMIC THERAPY HAS DECREASED WITH THE INCREASING USE OF ANTI-VEGF THERAPY. WE SUGGEST PHOTODYNAMIC THERAPY (WITH OR WITHOUT INTRAVITREAL BEVACIZUMAB, AFLIBERCEPT, OR RANIBIZUMAB) FOR PATIENTS WHO FAIL TO RESPOND TO INITIAL ANTI-VEGF THERAPIES.

PHOTODYNAMIC THERAPY AND ANTI-VEGF INJECTION


• THERE WAS NO DIFFERENCE IN CORRECTED VISUAL ACUITY OR LESION AREA BETWEEN GROUPS.1

1SÖDERBERG AC, ALGVERE PV, HENGSTLER JC, ET AL. COMBINATION THERAPY WITH LOW-DOSE TRANSPUPILLARY THERMOTHERAPY AND INTRAVITREAL RANIBIZUMAB FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: A 24-MONTH PROSPECTIVE RANDOMISED CLINICAL STUDY. BR J OPHTHALMOL 2012; 96:714.



• AREDS: REPORT 8: FOUND A STATISTICALLY SIGNIFICANT BENEFIT OF ANTIOXIDANTS PLUS ZINC SUPPLEMENTATION ON PROGRESSION OF EARLY AMD IN ONE EYE IN PATIENTS WITH WET AMD OR VISION LOSS DUE TO AMD IN THE OTHER EYE.

• SUBSEQUENTLY, THE AREDS2 TRIAL FOUND THAT SUBSTITUTION OF LUTEIN AND ZEAXANTHIN FOR BETA-CAROTENE, AND USING A LOWER ZINC DOSE, DID NOT IMPACT THE TREATMENT BENEFIT


• AREDS2:• ORIGINAL DOSE ZINC (80 MG AS ZINC OXIDE)• COPPER OXIDE (2 MG)• VITAMIN E (400 IU)• VITAMIN C (500 MG)• LUTEIN (10 MG) • ZEAXANTHIN (2 MG)• BETA-CAROTENE (15 MG)

1THE AGE-RELATED EYE DISEASE STUDY 2 (AREDS2) RESEARCH GROUP, LUTEIN + ZEAXANTHIN AND OMEGA-3 FATTY ACIDS FOR AGE-RELATED MACULAR DEGENERATION THE AGE-RELATED EYE DISEASE STUDY 2 (AREDS2) RANDOMIZED CLINICAL TRIAL. JAMA. 2013;309(19):2005-2015. DOI:10.1001/JAMA.2013.4997.

ANTIOXIDANT VITAMINS AND ZINC (GENOTYPING TO GUIDE THERAPY)

SURGERY (MACULAR TRANSLOCATION)

• MACULAR TRANSLOCATION SURGERY IS EXPERIMENTAL AND INVOLVES MOVING THE MACULA TO A LESS DISEASED AREA OF THE RETINA IN PATIENTS WITH SUBFOVEAL CHOROIDAL NEOVASCULARIZATION.

• THE ADVENT OF EFFECTIVE PHARMACOLOGIC THERAPY HAS LIMITED THE USE OF THIS SURGICAL MODALITY TO PATIENTS WITH LARGE SUBMACULAR HEMORRHAGES, OR PATIENTS UNRESPONSIVE TO VEGF INHIBITORS.



• COMPARISON 1 MACULAR TRANSLOCATION VERSUS PHOTODYNAMIC THERAPY, OUTCOME 3 MEAN CHANGE OF VISUAL ACUITY AT 12 MONTHS


SURGERY (SUBMACULAR SURGERY)

• SUBMACULAR SURGERY INVOLVES THE REMOVAL OF ABNORMAL SUBRETINAL NEOVASCULARIZATION AND LARGE SUBMACULAR HEMORRHAGES, IF PRESENT. CLINICAL TRIALS HAVE BEEN LARGELY DISAPPOINTING, SHOWING LACK OF BENEFIT AND HIGH RATES OF RETINAL DETACHMENT




RADIATION THERAPY

VISUAL AIDS

THANK YOU

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Update on Age Related Maculopathy