1. MYOPIC MACULAR DEGENERATION
CLINICAL ASPECTS and THERAPY
ALFREDO PECE

2. RACIAL AND ETHNIC VARIATIONS
68%
ESKIMO
75%
TAIWAN

3. PREVALENCE OF MYOPIA Age In Taiwan (1995) In western countries
7 years old: 12%
12 years old: 56%
15 years old: 76%
18 years old: 84%
In western countries
20 years old: 20%

4. 27-33% of the myopic eyes DEGENERATIVE MYOPIA
% of the population
27-33% of the myopic eyes

5. THE PREVALENCE OF MYOPIA INCREASES AS THE LEVEL OF EDUCATION RISES
SOCIOECONOMIC AND ENVIROMENTAL FACTORS
THE PREVALENCE OF MYOPIA INCREASES AS THE
LEVEL OF EDUCATION RISES
GOLDSCHMIDT 1968
STUDENTS 32% FARMWORK,FISHERMEN 2.5%
SCHOOLCHILDREN AGED SINGAPORE 37%
XIAMEN-CHINA 18.5%

6. P< .0.5
P< .01

7. B. Freund, A. Ciardella, L. Yannuzzi, A. Pece
B.Freund, A.Ciardella, L.Yannuzzi, A.Pece. PERIPAPILLARY DETACHMENT IN PATHOLOGIC MYOPIA.
Arch of Ophthalmol, 2003;121:

8. Patologie causa di CNV Oltre 50 anni: AMD Meno di 50 anni miopia 62%
POHS 12%
strie angioidi 5%
altre 4%
idiopatica 17%

9. STAPHYLOMA
POSTERIOR POLE
MACULAR
PERIPAPILLARY
NASAL
INFERIOR

10. POSTERIOR POLE STAPHYLOMA
44%

11. MACULAR STAFYLOMA 3%

12. 13%

13. 20%
20%

14. Peripapillary crescent

15. By Centervue

16. CNV FROM THE CRESCENT

17. By OPTOS

18. CHORIORETINAL AREAS OF ATROPHY

19. CHORIORETINAL AREAS OF ATROPHY

21. lacquer cracks

22. Retinography
Blu
Red-free
FAG
Red

23. “COIN” LESION

24. 1 mo. later
natural evolution
2 y later
2 mo.later

25. IN 56% LACQUER CRACKS PROGRESS LACQUER CRACKS & CNV
K.OHNO-MATSUI ET COLL RETINA 16:29-37, 1996.
LACQUER CRACKS PROGRESS
IN 56%
LACQUER CRACKS & CNV

27. CNV
CNV AFFECT 5-10% OF THE MYOPIC POPULATION

28. 58-74% OF CNV DIRECTLY INVOLVE THE FOVEA ON
INITIAL EXAMINATION
CNV

29. Leakage evidente o scarso
CNV a margini
ben delimitati
CNV a margini
mal delimitati

30. Ruolo dell’
ICG

33. Ruolo dell’
ICG= limitato

34. CNV in myopic macular degeneration

35. P.Milani et Al: Importance of SDOCT in Myopic CNV
Courtesy P.Milani B IR AF
Initial FA
Middle FA
Late FA
P.Milani et Al: Importance of SDOCT in Myopic CNV

36. OCT IS HELPFUL for the DIAGNOSIS
Myopic CNV often small, mild leakage
Myopic Fundus.
Staphiloma
Multiple areas of chorioretinal atrophy
Tassellation-distrophy of the RPE
There may be angiographic diagnostic difficulties even when using the SLO which gives more contrast and better definition

37. VISION DISTURBANCES SINCE 2 WEEKS, UNCERTAIN LEAKAGE
CNV PRESENCE ?
VISION DISTURBANCES SINCE 2 WEEKS, UNCERTAIN LEAKAGE
P. Milani

38. CNV nella PM: diagnosi differenziale

39. CNV nella PM: diagnosi differenziale

40. Storia naturale della CNV nella PM
Perdita visiva
1/2 degli occhi dopo 2 anni
2/3 degli occhi dopo 5-10 anni
Involuzione spontanea con buon esito funzionale RARA

41. NATURAL EVOLUTION

42. 15 years later

43. New Therapies in MYOPIC-CNV

44. 1°
DIAGNOSI CORRETTA

45. Myopic CNV

46. 2°
QUALE TERAPIA?

47. Laser photocoagulation of non-subfoveal myopic CNV
Randomized studies (1,2): effective but VA decreases during the time. No benefit at 5 years
Retrospective studies (3): VA decrease 42% (5 years) up to 63% (10 years) in treated vs 68% in untreated
NO MORE LASER
1) Soubrane 1986, 2)Fardeau 1992, 3) Secretan 1997

49. 4 mo after laser
2 y after laser
4 y after laser

50. VIP Trial: Patients with Pathologic Myopia Primary Visual Acuity Outcome
pdt
Eyes with <1.5-line loss (%) 80
P=0.003
Verteporfin-treated patients were more likely to have stabilized vision (defined as losing <1.5 lines) at month 12 60 40 20
Verteporfin
(n = 81)
Placebo
(n = 39)

51. VIP Trial: Patients with Pathologic Myopia
VIP Trial: Patients with Pathologic Myopia. Primary VA Outcome at 2 years
Eyes (%) with stable (<1.5 line)
and improved (more than 1 line) vision
The VIP trial have shown the beneficial effect of PDT in terms of preservation of visual acuity.
In fact at 2 years verteporfin-treated patients were more likely to have preserved vision
and an higher median visual acuity of 20/64 when compared to 20/100 of untreated group
Verteporfin
(n = 81)
Placebo
(n = 39)

53. Background
PDT with Verteporfin is currently the only approved treatment for subfoveal CNV that has shown stabilization of vision compared with placebo
At 1 year 72% of treated eyes compared with 44% of placebo eyes lost <8 letters (mean visual improvement 0,2 lines at 1 year)
At 2 years this treatment benefit was no longer detected (36% vs 51% lost 8 letters)
More than 50% persistent leakage at 1 year, 13% visual loss of 3 linee or more at 1 year
VIP Trial, Ophthalmol 2001 and 2003

54. EYLEA ® and LUCENTIS ® MACUGEN ® and AVASTIN®
AFLIBERCEPT
VEGF
RANIBIZUMAB
INJECTION AS
THE FIRST THERAPY
(rhu Fab v1) Fc
Avastin (generically known as bevacizumab) and LUCENTIS are both anti-VEGF-A biologics; however, the 2 molecules were developed along parallel yet separate tracks.
Although both are derived from a common precursor molecule, an anti-VEGF mouse monoclonal antibody, the rationale and strategies of development of these biologics were independent of one another.
In the case of LUCENTIS, the anti-VEGF-A sequences from the precursor mouse monoclonal antibody were introduced into a human Fab framework, generating rhu Fab v1.
Using rhu Fab v1 as a starting point, a series of Fabs were created in order to generate optimal VEGF-A binding though an affinity maturation process.
The maturation process generated a Fab with a 140-fold higher affinity for VEGF-A than rhu Fab v1 and that is produced in an E. coli expression system. This Fab is now known as LUCENTIS.
In contrast, the Avastin group at Genentech inserted the anti-VEGF-A sequences from the precursor mouse monoclonal antibody into a structurally distinct human Fab framework, generating Fab-12. This Fab was later used to create the full-length human IgG now known as Avastin.
Avastin did not undergo affinity maturation.
Avastin is produced in Chinese hamster ovary (CHO) cells, a different expression system from that used for LUCENTIS. This mammalian expression system is necessary to produce Avastin for 2 main reasons, the first being its large size. E. coli produces large proteins poorly, while CHO cells are fully capable of producing large proteins. The second reason is that mammalian cells can properly glycosylate IgGs like Avastin. Glycosylation is an important factor in conferring stability to full-length IgGs. LUCENTIS is not glycosylated.
Thus, LUCENTIS and Avastin were developed for 2 different purposes (neovascular AMD and cancer, respectively) using 2 different development strategies and expression systems.
Characterization of the LUCENTIS molecule will be discussed in the next few slides.
BEVACIZUMAB
PEGAPTANIB

55. RADIANCE (CRFB002F2301) 12 Months Study Results

56. Mean change in BCVA from baseline overtime up to Month 12
Ranibizumab treatment showed a continuous improvement in BCVA in Group I (+13.8 letters) and Group II (+14.4 letters) from baseline to Month 12
In the vPDT group, the BCVA gain was less up to Month 3 and showed a steady increase after switching to ranibizumab treatment
Months
Mean change (±SE) in BCVA from baseline (ETDRS letters)
13.8
14.4
9.3 D8
12.1
12.5
1.4
Ranibizumab 0.5 mg/vPDT as of Month 3 as per investigators’ discretion ;
BCVA: best-corrected visual acuity; D8: Day 8; ETDRS: early treatment diabetic retinopathy study; SE: standard error; VA: visual acuity; vPDT: verteporfin photodynamic therapy

58. W H I C D R U G S H O U L D B E D?

59. Intravitreal bevacizumab in myopic CNV
Prospective interventional case series
Mean follow up 12 months - 29 eye (16 pdt,13 naive)
Loading phase with 3 monthly IV injections - 3 additional monthly in eyes with recurrent
Significant improvement of BCVA (mean of +2.4 lines)
- greater improvement in naive eyes (3.7 lines vs 2.0 lines)
Significant reduction of central foveal thickness (mean 43 µm, p<0.011)
Mean num of i.v. 3.6 (range 3-12)
86% pz required only the loading phase
Chan WM, Lay TYY BJO 2009

60. Intravitreal Ranibizumab in myopic CNV
Retrospective interventional case series
Maximum follow up 12 months , 16 eyes naive
Loading phase with 3 monthly IV injections-3 additional monthly in eyes with recurrent
Significant improvement of BCVA (mean 3.0 lines, 75% >2 lines) (Vip study 0,2 lines and 13% visual loss of 3 linee or more at 1 year!!!)
Significant reduction of central foveal thickness (from 292 to 233 µm at 6 months)- FAG 93.8% eyes no leakage at 3 months (Vip study leakage in 93.1% at 3 months !!!- More than 50% persistent leakage at 1 year !!! )
Mean num of i.v. 3.8 (range 3-9)
81,3% required only loading phase
Lai TY L ,Chan WM, Retina 2009

61. Vadalà M, Pece A, BJO 2011 May;95(5):657-61
Myopic choroidal neovascularization treated with intravitreal Ranibizumab
Prospective interventional case series
40 eyes of 39 patients
Mean age 53±13 years, mean RE -13.5D
Mean follow up 13 months
Is ranibizumab effective in stopping the loss of vision for choroidal neovascularisation in pathologic myopia? A long-term follow-up study.
Vadalà M, Pece A, BJO 2011 May;95(5):657-61

62. Mean num “on demand” intravitreal injection: 2.8
Results
Mean baseline VA was 0.67 LogMAR
After a follow up of 13 months mean VA improved to 0.27 LOgMAR
82% patients improved VA, 58%>2 lines
Mean OCT CRT was reduced from ± 70m at baseline to 175 ± 46 m
Mean num “on demand” intravitreal injection: 2.8

63. Intravitreal bevacizumab in myopic CNV
Long-term results of
Intravitreal bevacizumab in myopic CNV
Prospective interventional case series
Follow up 24 months (three montly IVB). 32 eyes and
36 mo for 27 pt
Significant improvement of BCVA (from 30 lett to 45 letters )
Mean number of injection was 4.1,1.1,0.5,at one, 2 and 3 years. 47% of pt received only the loading phase
Gharbiya M et al, BJO 2012

64. Bevacizumab vs Ranibizumab
25 eyes IVB vs 23 eyes IVR with subfoveal CNV over 18 mos of f-up
PRN re-treatment based on detection of fluid on OCT and/or leakage on FA every month
Similar results
Mean # inj 4.7 with IVB vs 2.5 with IVR over 18 mos f-up
Mean VA and CFT Over the Follow-up
Iacono P, Parodi MB, Papayannis A, Bandello F. Retina 2012

65. ranibizumab vs bevacizumab in myopic CNV A randomized study Milano
Intravitreal
ranibizumab vs bevacizumab
in myopic CNV
A randomized study
Milano
Palermo
Roma
Napoli
Messina
Pece, M.Vadalà, G.Fasolino, P.Milani,
J.Trombetta, G.De Crecchio
Graefe’s Arch 2014,

66. multicenter, randomized, prospective case series
Beva vs Ranibizumab
multicenter, randomized, prospective case series
78 eyes of 78 patients
Mean age 59±13 years, mean RE -13.5D
follow up 19 months
Mean # inj 2.7 with IVB vs 2.3 with IVR
BCVA 54let pre e 54 let post IVB
BCVA 45let pre e 58 let post IVR

67. odds ratio 2.96, 95% confidence interval 1.11-7.90, p 0.03

68. 4°Messaggio
NOVITA’

69. AFLIBERCEPT Fusion protein of key domains from human VEGF
VEGFR1
VEGFR2 1 2 3 4 5 6 7 2
Contains “all human” amino acid sequences
Penetrates all layers of the retina (MW ~110,000 Daltons)
VEGF Trap-Eye is specially iso-osmotic purified solution formulated for intravitreal injection 3
Fc IgG
Fusion protein of key domains from human VEGF
receptors 1 and 2 with human IgG Fc 4

70. AFLIBERCEPT: alta affinità di legame con i membri della famiglia VEGF1
Agisce come falso recettore solubile2 1
Blocca e cattura tutte le isoforme del dimero VEGF-A3 2
Blocca l’azione degli altri fattori di accrescimento: PIGF* e VEGF-B3
Lega VEGF-A e PlGF con affinità superiore a quella dei loro recettori naturali2
*PlGF = Fattore di crescita placentare
1. Browning DJ et al. Aflibercept for Age-Related Macular Degeneration: A Game-Changer or Quiet Addition 2. Eylea®, Riassunto delle Caratteristiche di Prodotto. 3. Stewart MW. Clinical and differential utility of VEGF inhibitors in wet age-related macular degeneration: focus on aflibercept. Clin Ophthalmol. 2012;6:

71. Intravitreal
AFLIBERCEPT
in myopic CNV
A prospective study
Pece in press

72. Caratteristiche Demografiche
Campione Totale
Numero pazienti 32
Femmine, n (%)
28 (88%)
Età (media ± SD)
56 ± 13

73. Valori espressi in /10 come media ± SD
Andamento BCVA
Refrazione
Basale
12 mesi
Delta
P-value
>-15
0.23 ± 0.18
0.41 ± 0.26
0.18 ± 0.13
0.035
Da -15 a -11
0.36 ± 0.32
0.55 ± 0.35
0.18 ± 0.24
0.014
Da -10 a -6
0.40 ± 0.31
0.56 ± 0.30
0.15 ± 0.20
Overall
0.36 ± 0.30
0.53 ± 0.31
0.17 ± 0.21
<0.0001
Valori espressi in /10 come media ± SD

74. Terapia con Aflibercept
Campione Totale
Numero iniezioni (media ± SD)
range
2.1 ± 1.1
1-4
Durata follow-up
12 mesi

75. Conclusions
Intravitreal anti-VEGF drugs appear to be safe and efficacy in eyes with CNV secondary to pathologic myopia.
Intravitreal AntiVEGF injections show a significant improvement of functional parameters
NO Loading phase
How to follow the pt? OCT? FA? VA?
Long term controlled clinical trials are warranted to validate these promising results

77. grazie