1) The document discusses resistance to anti-VEGF injections for wet age-related macular degeneration (wAMD), including treatment regimens, therapy failure, and treatment switching. 2) It finds that resistance can occur through tachyphylaxis or tolerance, and that switching therapy from ranibizumab to aflibercept or bevacizumab can be effective for patients who do not respond to or lose response to ranibizumab over time. 3) A trial switching patients to aflibercept who were incomplete responders to multiple ranibizumab injections found mean central subfield thickness decreased by 27.3 μm and 15.6% of eyes had a decrease in thickness of

1. Resistance to Anti-VEGF
Injections
Francesco Bandello, MD, FEBO Giovanni Fogliato, MD
Università Vita-Salute
Istituto Scientifico San Raffaele
Milano

2. Financial DisclosureFinancial Disclosure
• Advisory Board Member for:
• Alcon
• Alimera
• Allergan
• Bausch and Lomb
• Bayer
• Genentech
• Novagali
• Novartis
• Pfizer
• Hoffmann-La Roche
• Sanofi-Aventis
• Farmila-Théa
• Thrombogenics

3. Outline
• Overview of anti-VEGF in wAMD
• Treatment regimens
• Therapy failure
• Treatment switching

4. Outline
• Overview of anti-VEGF in wAMD
• Treatment regimens
• Therapy failure
• Treatment switching

5. Anti-VEGF in wAMD

6. Anti-VEGF in wAMD
CATT study
Stalmans et al. Retina (2013)

7. Anti-VEGF in wAMD
CATT study
Stalmans et al. Retina (2013)

8. Anti-VEGF in wAMD
VIEW study

9. Outline
• Overview of anti-VEGF in wAMD
• Treatment regimens
• Therapy failure
• Treatment switching

10. Treatment Regimens
• Fixed regimen
• Loading-phase + PRN
• Quarterly injection
• Bimonthly injection
• PRN
• Fusion regimen
• Treat & extend
• Best results with fixed regimen
• Resistance as effect of less frequent treatment ???

11. Outline
• Overview of anti-VEGF in wAMD
• Treatment regimens
• Therapy failure
• Treatment switching

12. Long-Term Retreatments
• Recalcitrant fluid on OCT after standard mono-therapy
– CATT 2y (51.5% in ranibizumab & 67.4% in bevacizumab) 1
– VIEW1 and VIEW2 (27.6% and 32.3% in aflibercept) 2
• SAVE (Super-dose Anti-VEGF) trial 3
– 2.0 mg ranibizumab for recalcitrant wAMD
– Retinal fluid on OCT in 45/64 (70%) pts after 2 years
1. Martin DF et al. Ophthalmology 2012
2. Heier JS et al. Ophthalmology 2012
3. Wykoff CC et al. Ophthalmology 2013

13. Therapy Failure
• Tachyphylaxis:
– Phenomena causing reduced drug efficacy by repeated
admininstration 1
– 2% of eyes after ranibizumab injections for AMD 2
– 2 strategies:
• Discontinuation (risk of irreversible retinal damage)
• Switching therapy (drug with different mechanism of action)
• Tolerance:
– Slow loss of efficacy over time 1
– Effect restored by increasing dosage or shortening time intervals
1
– Effect not restored by discontinuation 1
1. Binder S. Br J Ophthalmol 2012
2. Eghoj MS et al. Br J Ophthalmol 2012

14. Therapy Failure
• Refractory group: persistent sub/intraretinal fluid
despite monthly IVR injections 1,2,3
• Recurrency group: well response but frequent IVR
injections to maintain a dry macula 1,2,3
• Increased intra/subretinal fluid after 2 or more IVR 3,4
• Persistent retinal fluid or visual deterioration 5
1. Yonekawa Y et al. Am J Ophthalmol 2013
2. Bakall B et al. Am J Ophthalmol 2013
3. Ho VY et al. Am J Ophthalmol 2013
4. Miura M et al. Clinical Ophthalmology 2013
5. Heussen FM et al. Graefes Arch Clin Exp Ophthalmol 2014

15. Outline
• Overview of anti-VEGF in wAMD
• Treatment regimens
• Therapy failure
• Treatment switching

16. Treatment Switching
1. Ranibizumab to bevacizumab 1
2. Ranibizumab to aflibercept 2,3,4,5
– In patients resistant to ranibizumab, overall mean VA passed from
0.47 to 0.25 logMAR and CST from 338 to 272 µm, after mean 2.73
(1-4) aflibercept injections 2
– 33% of cases non-responder to ranibizumab gained VA after
aflibercept treatment 2
3. TURF (aflibercepT for subjects with exudative AMD
who were incomplete responders to mUltiple
Ranibizumab anti-VEGF injections) trial 6
1. Gasperini JL et al. Br J Ophthalmol 2012
2. Heussen FM et al. Graefes Arch Clin Exp Ophthalmol 2014
3. Yonekawa Y et al. Am J Ophthalmol 2013
4. Bakall B et al. Am J Ophthalmol 2013
5. Ho VY et al. Am J Ophthalmol 2013
6. Wykoff CC et al. Br J Ophthalmol 2013

17. Treatment Switching
3. TURF (aflibercepT for subjects with exudative AMD
who were incomplete responders to mUltiple
Ranibizumab anti-VEGF injections) trial 1
– Inclusion criteria:
• Patients who completed SAVE trial (2 years)
• No prior aflibercept
– Exclusion criteria:
• Significant subretinal fibrosis or foveal geographic atrophy
– Procedures (Aflibercept 2.0 mg injections):
• Mandatory at baseline, 1M, 2M and 4M
• As needed, 3M and 5M (if intraretinal/subretinal fluid on OCT or
BCVA decreased >5 letters from previous exam)
1. Wykoff CC et al. Br J Ophthalmol 2013

18. Treatment Switching
3. TURF (aflibercepT for subjects with exudative AMD
who were incomplete responders to mUltiple
Ranibizumab anti-VEGF injections) trial 1
– Results:
1. Wykoff CC et al. Br J Ophthalmol 2013

19. Treatment Switching
3. TURF (aflibercepT for subjects with exudative AMD
who were incomplete responders to mUltiple
Ranibizumab anti-VEGF injections) trial 1
– Results (6M):
1. Wykoff CC et al. Br J Ophthalmol 2013
P=0.71 P=0.018

20. Treatment Switching
3. TURF (aflibercepT for subjects with exudative AMD
who were incomplete responders to mUltiple
Ranibizumab anti-VEGF injections) trial 1
– Results (6M):
• Mean CST (central subfield thickness) decreased of -27.3 µm
• In 7/45 (15.6%) eyes CST decreased >10% [mean -149 µm (-31%)],
with 94% of CST decrease within 2M.
• At 3M and 6M 17(37%) and 10(22%) pts had no fluid, respectively
1. Wykoff CC et al. Br J Ophthalmol 2013

21. Treatment Switching
RPE detachments in wAMD (PED)
• Intravitreal aflibercept may be an effective treatment option for
serous PED in neovascular AMD patients after bevacizumab and
ranibizumab have previously failed (case series, 3 eyes) 1
Polypoidal choroidal vasculopathy (PCV)
• Efficacy of aflibercept on large PED associated to PCV refractory
to ranibizumab (case series, 3 eyes) 2
• Efficacy of aflibercept on PCV with tachyphylaxis to ranibizumab
(increase in intra/subretinal fluid or PED despite 2 or more IVR) 3
1. Patel KH et al. Eye 2013
2. Yamashita M et al. Clinical ophthalmology 2014
3. Miura M et al. Clinical Ophthalmology 2013

22. Conclusions
• Different therapies on the current scenario
• New strategies in selected cases (tachyphylaxis)
• Efficacy of Aflibercept in PED or PCV with PED in wAMD