WHEN TO SWITCH FROM LUCENTIS TO EYLEA

1. CHALLENGING AMD: HOW LONG AMD
NEED TREATMENT
AJAY DUDANI
MUMBAI RETINA CENTRE

2. HOW LONG
 n AMD CHRONIC DISEASE
 CAN STABILIZE AND CONTROL
 BUT IT DOESN’T HAVE AN END
 VISION IS LOST DUE TO INSUFFICIENT LONG TERM
TREATMENT
 MOST ARE TREATED FOR 3 YRS
 SOME 10 YRS
 UNDERTREATMENT IS THE FIRST ENEMY
 GEOGRAPHIC ATROPHY IS LUXURY
 BECAUSE YOU HAVE AVOIDED SCARRING

3. TREAT AND EXTEND REGIMEN
 VISION MAINTENANCE WITH LONGER TREATMENT INTERVALS
 FLEXIBLE DOSING
 PERSONALISED TREATMENT
 TRIALS WITH 1200 PATIENTS
 REDUCE CLINIC VISITS
 TREAT PROACTIVELY
 PREVENT RELAPSES
 NO RISK 0F VISION LOSS
 3- 4 MONTHLY INJECTIONS

4. RAP LESIONS
 WONDERFUL LESIONS
 DRAMATIC RESPONSE- MORPHOLOGICAL
 TREAT EARLY AND AGRESSIVELY
 PREDICTABLE TIME OF RELASE
 VERY OFTEN BILATERAL

5. TREX
 SPAIDE AND FREUND-10 YRS AGO
 INJECTION AT EACH VISITR
 INTERVAL IS EXTENDED WHEN NO ACTIVITY
 2 WEEKS AT A TIME – 4 IN DME
 6 WEEKS TO 8 TO 10 TO12 WEEKS
 RECURRING ACTIVITY –INTERVAL REDUCED BY 2 WEEKS
 LUCAS STUDY
 ATLAS- EYLEA
 TREX
 TREND
 CANTREAT
 RIVAL STUDY

6. META-ANALYSIS 26 000 PATIENTS
 TREAT AND EXTEND-
 8.8 LETTER GAIN –FIRST YEAR-7.3 INJ
 6.7 LETTERS IN –SECOND YEAR-4.9 INJ
 5.4 LETTERS – THIRD YR- 4 INJ
 PRN-
 3.5 LETTER GAIN – YEAR1---5.4 INJ
 1.3 GAIN IN –YEAR 2—3.7 INJ
 1.9 LETTER LOSS IN –YR 3 ---2.8 INJ

7. REAL WORLD EVIDENCE
 5 YRS FOLLW UP60 MONTHS
 VISION IMPROVED AT 6 MONTHS
 REMAINED FOR 6 YR
 40% PATIENTS INTERVAL OF 12 WEEKS – 1 YR
 REDUCTION IN NO OF INJECTIONS

8. Patients may be switched to EYLEA as a result of:
 Suboptimal response to other anti-VEGF treatments
 Scarring or other negative anatomical changes
 To reduce treatment burden
 Despite the encouraging results of multiple trials, many Lucentis and
Avastin patients have recurrent fluid despite continued monthly injections1
 Patients may have an initial suboptimal response or may develop
resistance to anti-VEGF treatment over time1
 Poor response to anti-VEGF treatment may lead to scarring and other
negative anatomical changes2 – such damage can compromise the
effectiveness of subsequent treatment
Why Switch treatments?
Yonekawa Y, Andreoli C, Miller J et al. Conversion to aflibercept for chronic refractory or recurrent neovascular age-related macular degeneratio
n. Am J Ophthalmol 2013; 156 (1): 29–35. Daniel E, Toth CA, Grunwald JE et al. Risk of scar in the comparison of age-related macular degenera
tion treatments trials. Ophthalmology 2014; 121 (3): 656-666.

9.  Fully human fusion protein of key
domains from human VEGF receptors 1
and 2 with human IgGFc
 Blocks all VEGF-A isoforms and
placental growth factor (PlGF)
 High affinity - binds VEGF-A and PlGF
more tightly than native receptors
 Aflibercept is specially purified and
formulated for intravitreal injection
 Strict 1:1 stoichiometric binding
 Aflibercept maintains significant
intravitreal VEGF-binding activity for
10–12 weeks after a single injection
Aflibercept for intravitreal injection
IgG=immunoglobulin G
VEGFR1 VEGFR2
Fc Portion of IgG VEGF Trap Eye
2
3

10. Aflibercept 15 pM 16 pM 2890 pM 15 pM 26 pM
Bevacizumab 854pM 1476 pM NB 706 pM 1323 pM
Ranibizumab 675 pM 1140 pM NB 686 pM 845 pM
VEGFR1 cell line VEGFR2 cell line
NB: no detectable blocking under the assay conditions used
Data on file, Regeneron Pharmaceuticals, Inc.
IC50 at 20pM
VEGF-A165
IC50 at 20pM
VEGF-A121
IC50 at 20pM
VEGF-A165
IC50 at 20pM
VEGF-A121
IC50 at 40pM
hPlGF2
Aflibercept Potently Blocks VEGF-A and Uniquely Binds
PlGF

11. Unique Binding Mechanism of Aflibercept
VEGF
VEGF
VEGF
VEGF
VEGF
VEGF
VEGF
VEGF
VEGF
VEGF
VEGF
VEGF
VEGF
VEGF
VEGF
VEGF
VEGF
VEGF
VEGF
VEGF
VEGF
VEGF
Aflibercept Bevacizumab Ranibizumab
1:1
stoichiometric
binding
Affinity
maturation
Bevacizumab can daisy-chain” or
“paper-doll” with VEGF leading to
large, multimeric conglomerates
Two ranibizumab
molecules can bind
each VEGF dimer
VEGF
VEGF
VEGF
VEGF
VEGF
VEGF

12. Aflibercept suppresses intraocular VEGF for a mean of 71
days in wet AMD
VEGF suppression in individual wet AMD patients*
27
26
25
24
23
22
21
20
19
18
17
16
15
14
13
12
11
10
9
8
7
6
5
4
3
2
1
Individual
patient
Days after aflibercept injection
0 20 40 60 80 100 120 140 160 180 200
Definite VEGF suppression
Uncertain suppression status
Definite end of suppression
Uncertain end of suppression
Recommended 8-week injection interval
Fauser S et al. Am J Ophthalmol. 2014;158(3):532–536.
*Duration of complete suppression, as well as the end of suppression whenever definable.

13.  Aflibercept binds strongly to both VEGF-A and PlGF1
 Aflibercept suppresses VEGF-A in patients with
wet AMD for almost twice as long as ranibizumab
— VEGF-A was suppressed for a mean of 71 days with aflibercept versus
36 days with ranibizumab2,3
 It is believed that the longer durability of effect for aflibercept will result
in a greater possibility for extension of the treatment interval
Implications for retinal disease
management
1. Papadopoulos N, et al. Angiogenesis. 2012;15 (2):171–185. 2. Fauser S, et al. Am J Ophthalmol. 2014;158(3):532–536. 3. Muether
PS, et al. Am J Ophthalmol. 2013;156(5):989–993.e2.

14.  Monthly dosing has been shown to be highly effective in improving VA1,2
Anti-VEGF agents in retinal disease: Substantial gains in
VA can be achieved
1. Brown DM, et al; ANCHOR Study Group. N Engl J Med. 2006;355(14):1432–1444; 2. Rosenfeld PJ, et al; MARINA Study Group. N Engl J Med. 2006;355(14):1419–1431; 3. Mitchell P. Macular
Degeneration Foundation. 2011. Available at: http://www.mdfoundation.com.au/LatestNews/MDFoundationDeloitteAccessEconomicsReport%202011ExecSummary.pdf. Accessed February 2016; 4.
Reginno CD, et al. Am J Ophthalmol. 2008;145:239–248; 5. CATT Research Group. N Engl J Med. 2011;364(20):1897–1908; 6. Chakravarthy U et al; The IVAN Study Investigators. Ophthalmology.
2012;119(7):1399–1411.
PRN = pro re nata; T&E = treat-and-extend; VA = visual acuity.
PIER4
Standard of care
Fixed
quarterly
Inadequate
treatment,
efficacy
compromised4
Proactive
treatment
CATT5
IVAN6
PRN
Wet AMD
Overwhelming
management
burden3
Monthly
management
burden remains5,6
Next-generation
anti-angiogenic therapy
ANCHOR1
MARINA2
Fixed monthly

15. In practice, patients are often monitored and treated less frequently than regimens used
in clinical trials,1 and this can lead to inferior outcomes
Reduced dosing frequency has been shown
to lead to sub-optimal outcomes in wet AMD
1. Holz FG, et al. Br J Ophthalmol. 2015;99:220–226; 2. Lanzetta P, et al. Br J Ophthalmol. 2013;97:1497–1507.
Mean
change
in
visual
acuity
(ETDRS
letters)
Number of injections from baseline to month 12/week 52
0
SAILOR
MONT
BLANC
SUSTAIN
CATT
EXCITE
VIEW
PIER
HARBOR
HARBOR
CATT
VIEW
ANCHOR
1
2
3
4
5
6
7
8
9
10
11
12
13
0 4 5 6 7 8 9 10 11 12
VA results at:
3 months 12 months
AFL 2 mg (every 8 weeksa)
RBZ 0.5 mg (PRN/quarterlya)
RBZ 0.5 mg (monthly)
aAfter three monthly doses. AFL = aflibercept; RBZ = ranibizumab.
Mean change in VA from baseline to month 12/week 52 by injection frequency2

16. Maximizing benefit, reducing burden
Frequency of dosing
with anti-VEGF agents
is important
If dosing is too high:
OVER-TREATMENT
If dosing is too low:
UNDER-TREATMENT
• Unnecessary burden on patients3
• Could compromise patient
compliance → under-treatment
• Extra burden on healthcare systems
• Potential higher frequency of
treatment-related adverse events
• Sub-optimal efficacy outcomes1
− Vision loss/poor vision
maintained
− Underlying disease pathology
• Burden of poor vision2
− Financial impact
− Wide-ranging effects on QoL
− Burden on family and caregivers
QoL = quality of life.
1. Regillo CD. Retina Today. 2014; 2. Lotery A, et al. Br J Ophthalmol. 2007;91:1303–1307; 3. Monés J. Ophthalmologica. 2011;225:112–119.

17. Aflibercept 15 pM 16 pM 2890 pM 15 pM 26 pM
Bevacizumab 854pM 1476 pM NB 706 pM 1323 pM
Ranibizumab 675 pM 1140 pM NB 686 pM 845 pM
VEGFR1 cell line VEGFR2 cell line
NB: no detectable blocking under the assay conditions used
IC50 at 20pM
VEGF-A165
IC50
VEGF-A121
IC50 at 20pM
VEGF-A165
IC50 at 20pM
VEGF-A121
IC50 at 40pM
hPlGF2
Reason for improved outcomes with aflibercept in SWITCH patients:
Binding to VEGF and PlGF, Tighter binding and Durable VEGF
suppression
Heier JS, et al. Retinal Physician. 2009. Available at: http://www.retinalphysician.com/articleviewer.aspx?articleid=102898. Access
Binds VEGF-A and PlGF with higher affinity than their native receptors
Forms a stable, inert 1:1 complex with VEGF-A, binding both sides of the dimer and preventing interaction
with other molecules
Aflibercept suppresses intraocular VEGF for a mean of 71 days
IgG = immunoglobulin G.

18. What is the evidence for switching patients to EYLEA
therapy?
Meta-analysis
 significant visual and anatomical improvements in eyes diagnosed with AMD for a median of 40-65
months
 Treatment regimens of 3 initial monthly doses followed by either PRN or 2q8 injections.
 The loading phase is of particular importance in maximizing fluid resolution.
Seguin-Greenstein S, et al. J Ophthalmol. 2016

19. Evidence from prospective studies:
TURF Trial
 Aflibercept 2mg maintained mean VA improvements previously achieved with high-dose 2mg
ranibizumab and led to significant anatomic improvement and was required monthly in most
patients.
Wykoff CC et al. BJO. 2014 Feb 11. [Epub ahead of print]
TURF = aflibercepT for subjects with exudative AMD who were incomplete responders to mUltiple Ranibizumab anti-VEGF injections;

20. 50% of patients had a reduction in subretinal fluid; 84% showed increase in VA, gain of
5.9 letters, CST improved 304.1 to 265.5 micrometers at 6 months.
Singh et al. Br J Ophthalmol. 2014
Evidence from prospective studies:
ASSESS Study

21. Chang AA et al. Ophthalmology. 2014;121(1):188-92.
 33% had reduction in CRT of greater than 100 micrometers
 45% of patients were fluid-free after three monthly aflibercept injections
Evidence from prospective studies:
Chang et al. 2014

22. What dosing regimen works in switch
patients?
— Switch to IVT-AFL allowed in both regimens a stabilization of morphological and
functional parameters
— Fixed regimen determines a greater reduction of CRT, fluid and PED height
associated with a slight improvement in the BCVA
— PRN RAN to T&E IVT-AFL switch resulted in a significant reduction in CRT and
stabilization of VA with the same number of treatments given but with a mean of 1.5
less visits per patient
— Both the 2q8 and PRN IVT-AFL regimens were effective in maintaining vision and
anatomical outcomes in treatment-resistant nAMD patients.
— The 2q8 regimen produced better visual outcomes with fewer injections than
the PRN over 48 weeks
— The loading phase is of particular importance in maximizing fluid resolution.
22
Seguin-Greenstein S, et al. J Ophthalmol. 2016
ARVO 2015 abstracts: Comparison of PRN and Fixed Regimen in the Switch of Aflibercept in Neovascular AMD (Daniele De Geronimo), Efficacy Outcomes and Treatmen
t Burden of ‘As Required’ Ranibizumab to ‘Treat and Extend’ Aflibercept for Neovascular Age-Related Macular Degeneration: 12 Month Pre and Post Switch Analysis in Cli
nical Practice (Archana Airody), Comparison of Aflibercept Treatment Regimes for Treatment-Resistant Neovascular Age-Related Macular Degeneration: 8-Weekly vs an ‘
As-Needed’ Regime (Wijeyanthy Wijeyakumar)

23. Summary
 Switching between anti-VEGF treatments showed positive results in patients with
refractory or recurrent wAMD.
 Aflibercept is unique due to its longer half-life in the eye and higher binding affinity to
VEGF compared to other anti-VEGF agents, such as bevacizumab and ranibizumab
— Similar to ranibizumab and bevacizumab, aflibercept binds to multiple isoforms of VEGF-A;
however, aflibercept has been specifically designed to also bind PlGF
— VEGF-A is bound more tightly by aflibercept than by bevacizumab, ranibizumab, or native
VEGF receptors
— Binding of VEGF-A to aflibercept is 45–92x tighter than to bevacizumab and ranibizumab
 Majority of studies support switching to aflibercept based on improved anatomical
outcomes, reductions in intraretinal and subretinal fluid, and extended injection
intervals
Papadopoulos N, Martin J, Ruan Q et al. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by
VEGF Trap, ranibizumab and bevacizumab. Angiogenesis 2012; 15: 171–185.

24. SEVEN –UP STUDY
 SEVEN YR OUTCOMES IN RANIBIZUMAB ARM OF
ANCHOR,MARINA AND HORIZON
 ROFAGA ET AL OPHTHALMOLOGY NOV 2013
 LONGTERM OUTCOMES AT 7-8 YRS
 RANIBIZUMAB FOR CNVM DUE TO AMD
 PRIMARY END POINT BCVA OF 20/70 OR BETTER

25. SEVEN UP-RESULTS
 AT 7.3 YEARS (6.3-8.5)
 37% EYES HAD 20/70 OR BETTER VISION
 23% EYES BCVA 20/40 OR BETTER
 37% EYES BCVA 20/200 OR WORSE
 43% EYES HAD STABLE OR IMPROVED VISION
 34% EYES HAD DECLINED VISION 8.6 LETTERS
 MEAN OF 6.8 LUCENTIS IN 3.4 YRS

26. SEVEN UP -RESULTS
 SD OCT SHOWED LEAKAGE IN 68% EYES
 46% WERE RECEIVING ONGOING LUCENTIS
 MACULAR ATROPHY WAS SEEN IN 98% EYES ON FAF
 MEAN AREA 9.4 MM
 SIGNIFICANT CORRELATION TO POOR VISION(P<0.0001)

27. SEVEN UP CONCLUSIONS
 AFTER 7 TO 8 YEARS OF LUCENTIS
 ONE THIRD OF PATIENTS SHOWED GOOD VISUAL OUTCOMES
 ANOTHER THIRD HAD POOR OUTCOMES
 ALMOST HALF THE EYES WERE STABLE
 ONE THIRD DECLINED BY 15 LETTERS OR MORE
 Lucentis prevents scarring and keeps vessels reopenable by altering
the natural course wet AMD(40% EYES HAD NO FIBROTIC
LESIONS)

28. CASE 1-MYOPIC CNVM
 65 YR LADY ONE EYED
 VISION 6/6 N8
 HIGH MYOPE LATTICE LASERED
 PSEUDOPHAKIC
 MYOPIC CNVM 2009
 15 PRN AVASTINS
 LAMELLAR MACULAR HOLE
 VISION TODAY 6/9P N10
 SWITCH TO ACCENTRIX
 9 MONTHLY INJECTIONS

29. MYOPIC CNVM 2010

34. CASE 2-PED OCCULT CNVM
 75 YR EYE SURGEON
 VISION 6/24 N36 IN OS -2009
 LARGE GIANT PED OS
 OTHER EYE SOFT CONFLUENT DRUSENS
 22 PRN LUCENTIS
 FED UP AND DROPPED OFF TREATMENT
 PED SPONTANEOUS COLLAPSE 6/60
 GOT HIS OTHER EYE CATARACT SURGERY
 REFUSED EYLEA SWITCH

35. OCCULT CNVM

39. CASE 3 -BILATERAL WET AMD -60 INJ -9
YRS FOLLOW UP
 69 YR LADY
 LE CNVM IN 2009 REFUSED TREATMENT 6/60
 RE CNVM 2010 6/9 N8
 55 PRN LUCENTIS TILL DATE LAST -15/7/2015
 RE RECURRENCES
 LE HEALED 6 INJ LUCENTIS PRN
 RE VISION 6/18 N 24
 LE 6/24 N36
 EYLEA SWITCH DONE
 LESION HEALING
 2 EYLEAS AT 2 MONTHLY PRN
 LAST EYLEA 9 MONTHS AGO
 NOW SWITCH BACK TO ACCENTRIX

40. BILATERAL WET AMD
2010

44. 3/14
6/14

45. LESION MORPHOLOGY
 THICK CHOROID-PACHYCHOROID EXUDATIVE MACULOPATHY
 POINTED CONICAL PED-IPCV
 RESPONSE TO ANXIOTYTICS –CSCR
 ADV- OCTA

46. Case 4-Occult CNVM 15 YR STUDY –RAP
 82 year old male
 Strong family history of AMD
 LE – Diagnosed with AMD 14 years ago(2001), Underwent 2 TTT’s, 3
PDT’s with IVTA, now has macular scar with Vn of HM
 RE – Has had 1 PDT (Nov 2005) for extra foveal RAP lesion and 36
injections of Lucentis in the past 11 year
 OCT MONTHLY
 EXTENT AND TREAT
 LUCENTIS TACHYPHYLAXIS?
 RE AFTER SWITCH TO EYLEA -6 INJ OVER 5 YRS
 Repeat eylea after 4 months ON PRN BASIS
 LAST EYLEA 2WEEKS AGO AFTER 12 MONTHS
 VISION 6/9 N6
 GEOGRAPHIC ATROPHY

47. COMPARE PRE AND POST VEGF -RAP
 PRE VEGF EYE—PL
 POST VEGF 6/9 N12
 DOES THE LEAK EVER STOP
 STARTS AS FLOOD
 THEN A DRIZZLE
 ENDS AS A MINOR TRICKLE
 VEGF IS THE DRIVER
 ANTIVEGF IS THE GLUE
 WATERPROOFING THE RETINA
 DR FIXIT

48. Fundus Photos
R eye
L eye

49. Serial angiography-RE
Sep 20
05 (FF
A)
May 2006
(ICG)
Oct 20
08
(FFA)
RAP LESION

50. Serial OCTs - PEDs with fluid
Sep 05 – PDT d
one
May 06 – post lucentis
– 3 injections at 2 mon
thly intervals
May 06 – fluid 6 mo
nths later – Lucenti
s started

51. Serial OCTs
May 07 – Fluid 8 months a
fter last injection – needed
injection every 3 months si
nce..
Jan 09 – eg of OCT post in
jection
March 09 – fluid in
3 months – Thicke
ning of same paraf
oveal area every 3
months

52. Serial OCT’s – Last injection
July13
July 2013 – pre- injection
Feb’13 - extra foveal site

53. Serial SLO photos
Nov 2010
Mar 2009
Sep 2008
July 2013

57. ANTI VEGF SIDE -EFFECTS
 DID IT LEAD TO CHORIODAL ATROPHY
 GEOGRAPHIC ATROPHY
 GLAUCOMA
 HEART ATTACK
 HYPERTENSION
 CENTRAL SCOTOMAS
 SLOW READING SPEED
 LOSS OF CONTRAST SENSITIVITY
 EXTENT AND TREAT