AMD EYLEA PAGENAX ACCENTRIX BIOSIMILARS

1. My preferred molecule for the management of
nAMD
Ranibizumab
And why do I choose it over Biosimilars??

2. AMD is a major cause of world blindness
Neovascular
AMD
~10% of all patients with AMD have the Neovascular form (~2.5 million
people worldwide); however, AMD is responsible for 90% of severe
visual loss due to AMD
Potentially as
debilitating as
arthritis, COPD,
and AIDS
AMD
AMD affects 20-25 million people worldwide,
and 2.3% of people
≥65 years of age in Europe3
Aging
population
In 2013, there were an estimated
841 million people worldwide ≥60 years of age, which is expected to rise
to
2 billion by 2050
1. Ferris FL, et al. Arch Ophthalmol 1984;102:1640-2; 2. Chopdar A, et al. Br Med J 2003;326:485-8; 3. Augood CA, et al. Arch Ophthalmol 2006;124:529-35; 4. Vision Problems in the US: Prevalence of
Adult Vision Impairment and Age-Related Eye Disease in America. http://www.preventblindness.net/site/DocServer/VPUS_2008_update.pdf [Accessed May 2014]; 5. Williams RA, et al. Arch
Ophthalmol 1998;116:514-20; 6. Ivers RQ, et al. J Am Geriatr Soc 1998;46:58-64;
2. http://www.un.org/en/development/desa/population/publications/pdf/ageing/WorldPopulationAgeing2013.pdf [Accessed May 2014]

3. Pathogenesis of AMD
1. Augustin AJ, Kirchhoff J. Expert Opin Ther Targets 2009;13:641-51; 2. Kijlstra A, et al. Age-Related Macular Degeneration:
Immunological Factors in the Pathogenesis and Therapeutic Consequences. In: Pleyer U, Foster JV, Uveitis and Immunological Disorders.
Heidelberg: Springer, 2009. p. 73-85

4. Treatment advances in AMD
Pre-1980
No
treatment
Early 1980’s
Thermal
Laser
Early 2000s
Photodynamic
Therapy
2006 onwards
Anti-VEGF
Therapy
2018 and
beyond
Vision Loss Halt disease progression Stabilize and optimize vision
1.Kent C. Rev Ophthalmol 2009.
2. DM et al. N Eng Journal Medicine. 2006;355:1432-44

5. 1. www.ema.europa.eu/docs/en_GB/document _library/EPAR_-_Scientific_Discussion/human/000715/WC500043550.pdf;
2. Ranibizumab prescribing information, www.ema.europe.eu; 3. Aflibercept® prescribing information, www.fda.gov;
4. Dixon JA et al. Expert Opin Investig Drugs 2009;18:1573-80; 5. Tew WP et al. Clin Cancer Res 2010;16:358-66;
6. Bevacizumab® prescribing information, www.ema.europe.eu; 7. Zhu Q et al. Ophthalmology 2008;115:1750-5
Note :* Bevacizumab is an unapproved drug for the ocular usage
*
Considering Anti-VEGFs there are 3 molecules that are available

6. Chronologically multiple studies prove the efficacy and safety of
Ranibizumab
Numerous
clinical trials1-15
Including: ANCHOR, CABERNET, CATT, EXCITE, GEFAL, HARBOR, HORIZON, IVAN,
MARINA, PIER, SAILOR, SEVEN UP, SUSTAIN, VIEW 1, VIEW 2
Trials of fixed and individualized
dosing regimens1,3,4,6-15
Fixed: monthly or quarterly (ranibizumab 0.3 mg and 0.5 mg)
Individualized: PRN or treat/wait and extend
Tolerability14
Up to 7 years after treatment initiation, ranibizumab
has been well tolerated, with low incidence of serious
ocular and non-ocular AEs
Efficacy12,13 Monthly treatment or prompt / earlya PRN treatment resulted
in significant increases in VA, which were maintained
1. http://clinicaltrials.gov/show/NCT00061594 (ANCHOR); 2. http://www.clinicaltrials.gov/ct2/show/NCT00454389 (CABERNET); 3. http://clinicaltrials.gov/ct2/show/NCT00593450 (CATT);
4. http://clinicaltrials.gov/ct2/show/NCT00275821 (EXCITE); 5. http://clinicaltrials.gov/ct2/show/NCT01170767 (GEFAL); 6. http://clinicaltrials.gov/ct2/show/NCT00891735 (HARBOR);
7. http://www.clinicaltrials.gov/ct2/show/NCT00379795 (HORIZON); 8. http://www.controlled-trials.com/ISRCTN92166560 (IVAN); 9. http://clinicaltrials.gov/ct2/show/NCT00056836 (MARINA);
10. http://clinicaltrials.gov/ct2/show/NCT00090623 (PIER); 11. http://clinicaltrials.gov/ct2/show/NCT00251459 (SAILOR); 12. http://clinicaltrials.gov/ct2/show/NCT01256827 (SEVEN UP);
13. http://clinicaltrials.gov/ct2/show/NCT00331864 (SUSTAIN); 14. http://clinicaltrials.gov/ct2/show/NCT00509795 (VIEW1); 15. http://clinicaltrials.gov/ct2/show/NCT00637377

7. In the figure, a number of landmark randomized clinical trials that
have brought a paradigm change in the management of neovascular
age-related macular degeneration, and led to the approval (by United
States Food and Drug Administration) of therapeutic agents such as
ranibizumab and aflibercept, among others, have been chronicled.
There has been an extensive evidence and wealth of data that
supports the safety and efficacy of Ranibizumab
Timeline of major milestones in the
field of pharmacotherapeutics for
age-related macular degeneration

8. Results: The Marina Study
-10.4
-14.9
2 14 16 18 22 24
4 6 8
0
10
5
0
5
-10
-15
-20
ETDRS
letters
Month
Ranibizumab 0.5 mg (n = 240)
Ranibizumab 0.3 mg (n = 238)
+5.4
+6.6
+6.5
+7.2
12
10 20
Sham (n = 238)
Ranibizumab (0.3mg) Ranibizumab
(0.5mg)
Sham Injection
Primary Endpoint (Loss of <
15 letters) 12 (24) months
94.5% 94.6% 62.2%
BCVA letters at 12 (24)
months
+6.5 +7.2 -10.4
Philip J. Rosenfeld et al. N Eng J Med 2006: 355;14-17

9. Results: The Anchor Study
ETDRS
letters
Month
Ranibizumab 0.5 mg (n = 140)
Ranibizumab 0.3 mg (n = 140)
Verteporfin (n = 143)
-9.6
-9.8
2 10 12 14 16 18 20 22 24
6 8
4
0
15
10
5
0
-5
-10
-15
+11.3 +10.7
+8.1
+8.5
Verteporfin PDT +
SHAM inj
SHAM PDT +
RZB (0.3 mg)
SHAM PDT + RZB (0.5
mg)
Mean change in BCVA after 2 years -9.8 8.1 10.7
% of patients with improvement of >
15 letters inVA after 2 years
6.3 34.3 41
David M et al. American Academy of Ophthalmology 2009;116:57-65

10. SUSTAIN: patients who received most frequent
retreatment with ranibizumab had poorest VA
maintenance
BCVA, best-corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study; PRN, pro re nata; SE, standard error; VA, visual acuity
Holz F, et al. Ophthalmology 2011;118:663-71. Figure reprinted from Holz F, et al. Safety and efficacy of a flexible dosing regimen of ranibizumab in neovascular age-related
macular degeneration: the SUSTAIN study. Ophthalmology 2011;118:663-71, Copyright 2011, with permission from Elsevier

11. EXCITE: profile of patients on quarterly treatment
shows that there is a variable response to treatment
BCVA, best-corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study; SE, standard error
Eldem B, et al. Presented at ARVO, May 3-7, 2009, Fort Lauderdale, FL, USA: Poster D1107
0 1 2 3 4 5 6 7 8 9 10 11 12
Gained/not maintained
n = 80
Gained/maintained
n = 99
No initial gain
n = 44
15
Month
Mean
BCVA
change
from
baseline
(ETDRS
letters
±
SE)
10
5
0
-5
-10
-15
Treatment: ranibizumab quarterly (0.3 + 0.5 mg), pooled
Response:
ranibizumab injection

12. HARBORa: individualized ranibizumab dosing results in
clinically meaningful VA gains, which are sustained over
24 months
aNote that the primary efficacy endpoint of HARBOR was not met. Primary endpoint: non-inferiority of 0.5 mg PRN vs 0.5 mg Monthly (4 letter margin)
BCVA, best-corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study; OCT, optical coherence tomography; PRN, pro re nata
Faber D, et al. Presented at ARVO Annual Meeting, May 9, 2013, Seattle, WA, USA: Poster #6308

13. Pooled VIEW 1 & 2: visual gains with monthly
ranibizumab dosing were maintained when switched to
PRN dosing
0
1
2
3
4
5
6
7
8
9
10
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96
Mean
change
from
baseline
(BCVA)
Letters
Week
+8.7
+7.9
PRN: 4.7 injections
Patients switched to
capped PRN regimen
BCVA, best-corrected visual acuity; PRN, pro re nata
Schmidt-Erfurth U, et al. Ophthalmology 2014;121:193-201

14. Long-term follow-up (SEVEN-UP): vision decline remains
a long-term risk of neovascular AMD, requiring further
treatment
ap < 0.005 vs SEVEN-UP Year 7.3; bp < .0001 vs SEVEN-UP Year 7.3; cp < .001 vs SEVEN-UP Year 7.3; AMD, age-related macular degenration; ETDRS, Early Treatment Diabetic
Retinopathy Study; SEM, standard error of the mean
Rofagha S, et al. Ophthalmology 2013;120:2292-9; Image reproduced from Rofagha S, et al. Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and
HORIZON. Ophthalmology 2013;120:2292-2299 (Copyright © 2013 American Academy of Ophthalmology. Reprinted with permission from Elsevier)

15. Biologics:
A wide range of products such as vaccines, blood and blood components and
recombinant therapeutic proteins that prevent, treat or cure a disease
Manufacturing biologics demands stringent conditions for
• Standardization
• Characterization
• Purification
• Maintenance of quality (Efficacy and Safety)
Biosimilar:
A biopharmaceutical drug designed to have active properties
similar to one that has previously been licensed
Manufacturing Biosimilars aims at designing structural
analogues to the innovator molecule
There may be minute differences(Chemical analogues) that go
unnoticed

16. • Biosimilars - the size and complexity of proteins
make it virtually impossible to produce an exact
copy of an originator, hence the name “similar”
• A major concern with biosimilars is that small
(undetectable) differences compared with
originator products might lead to unexpected
immunogenicity in patients
Biosimilars .....only “Similar” not
“Identical”
Bridges Jr SL, White DW, Worthing AB. American College of Rheumatology. The science behind biosimilars: entering a new era of biologic therapy. Arthritis Rheum. 2018;70(3):334-44.
Brinks V. Immunogenicity of biosimilar monoclonal antibodies. Generics and Biosimilars Initiative Journal (GaBI Journal). 2013 Dec 1;2(4):188-93.

17. Manufacturing Biosimilars is not only size but
complexity
https://www.gene.com/stories/building-biologics

18. There is a significant difference in the focus of
Manufacture of Biologics and Biosimilars
Innovator medication focus on
Robust evidence based on
Clinical studies
Biosimilars focus on Analytical
Studies for the chemical
characterization
Kiss S, Fine HF, Krawitz J. Coming of Age: Biosimilars. Ophthalmic Surgery, Lasers and Imaging Retina. 2018 Mar 21;49(3):162-5.

19. Note :* Bevacizumab is an unapproved drug for the ocular usage
Corticosteroids Laser Bevacizumab* Ranibizumab Aflibercept Biosimilars
Wealth of Data      
Damage to the Peripheral
area      
Damage due to prolonged
systemic presence      ?
IOP/Cataract risk      ?
Safely and efficacy evidence      
At a glance we can compare the available treatment modalities for
the management of DME

20. Thus Ranibizumab
• As it is safe for the Eye , and approved for AMD
• It has a long history to prove its safety and efficacy
• It has been proven beneficial , not only in reduction in CST but also gaining BCVA
• It has a wealth of data , been beneficial in all the regimen

21. 78 yr lady one eyed other
lost to AMD/PCV?
75 prn Ranibizumab over
10 yrs
Today 6/18 and needs
injection 2-3 monthly
Feb 2011

22. 78 yr lady one eyed other
lost to AMD/PCV?
75 prn Ranibizumab over
10 yrs
Today 6/18 and needs
injection 2-3 monthly
Feb 2012

23. 78 yr lady one eyed other
lost to AMD/PCV?
75 prn Ranibizumab over
10 yrs
Today 6/18 and needs
injection 2-3 monthly
Jan 2013

24. 78 yr lady one eyed other
lost to AMD/PCV?
75 prn Ranibizumab over
10 yrs
Today 6/18 and needs
injection 2-3 monthly
Mar 2014

25. 78 yr lady one eyed other
lost to AMD/PCV?
75 prn Ranibizumab over
10 yrs
Today 6/18 and needs
injection 2-3 monthly
Jan 2015

26. 78 yr lady one eyed other
lost to AMD/PCV?
75 prn Ranibizumab over
10 yrs
Today 6/18 and needs
injection 2-3 monthly
Feb 2016

27. 78 yr lady one eyed other
lost to AMD/PCV?
75 prn Ranibizumab over
10 yrs
Today 6/18 and needs
injection 2-3 monthly
Apr 2017

28. 78 yr lady one eyed other
lost to AMD/PCV?
75 prn Ranibizumab over
10 yrs
Today 6/18 and needs
injection 2-3 monthly
Jan 2018

29. 78 yr lady one eyed other
lost to AMD/PCV?
75 prn Ranibizumab over
10 yrs
Today 6/18 and needs
injection 2-3 monthly
Jan 2019

30. 78 yr lady one eyed other
lost to AMD/PCV?
75 prn Ranibizumab over
10 yrs
Today 6/18 and needs
injection 2-3 monthly
Jan 2020

31. This is a case which portrays the evolution of
treatment of AMD over a time period of 15 Years
Patient details
88 year old male
Known complaint and Strong family history of AMD
Vision details
Eye Past Present (Jan 2019)
LE Diagnosed with AMD 18 years ago (2001) VA limited to HM
RE Diagnosed CNVM 15 years ago (2004) Current VA= 6/12

32. Left Eye (Since 2002) Right Eye (Since 2005)
• 5 PDTs with IVTA • 1 PDT given Nov 2005 for extrafoveal RAP lesion
• 5 TTTs • Followed by 36 injections of Ranibizumab * for a span of 11 years
• Followed up with monthly OCT
• Treat and extend regime deployed thoroughly
• Therapy switched to Aflibercept 5 years ago
• 6 injections given till date
• Aflibercept injections repeated every 4 months (PRN regime)
• Last injection given in Jan 2019(time interval of 12 months)
• Current Observation
• Current situation shows
Macular scar
• Geographic atrophy
Visual Acuity results
• HM • 6/9
Treatment regime deployed
* Note: This patient was the first patient in India to receive Ranibizumab injection, this was
imported on compassionate basis

33. Fundus Photos
Right eye

34. Fundus Photos
Left eye

35. Milestones of treatment(Fundus Photos)
Sep 2005
FFA

36. Milestones of treatment(Fundus Photos)
May
2006
ICG
RAP LESION

37. Milestones of treatment(OCT Images)
Sept
2005
1St PDT Done

38. Milestones of treatment(OCT Images)
May
2007
Fluid 8 months after last injection – needed
injection every 3 months since..

39. Milestones of treatment(OCT Images)
Mar
2009
Fluid in 3 months – Thickening of same parafoveal
area every 3 months

40. Milestones of treatment(OCT Images)
Feb 2013
Extra foveal site

41. Milestones of treatment(Serial SLO images)
Sept
2008

42. Milestones of treatment(Serial SLO images)
Mar
2009

43. Milestones of treatment(Serial SLO images)
Nov 2010

44. Milestones of treatment(Serial SLO images)
July
2013

45. Milestones of treatment (Consolidated Report)
16 May
2016

46. OCT and Fundus Photo
06/10/2018
OCT and Fundus Photo
09/01/2019
Right Eye

47. OCT and Fundus Photo
06/10/2018
OCT and Fundus Photo
09/01/2019
Right Eye