Resistance to Anti-VEGF Injections

Francesco Bandello, MD, FEBO Giovanni Fogliato, MD

Università Vita-Salute

Istituto Scientifico San Raffaele

Milano

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

Outline

• Overview of anti-VEGF in wAMD

• Treatment regimens

• Therapy failure

• Treatment switching

Outline

• Overview of anti-VEGF in wAMD

• Treatment regimens

• Therapy failure

• Treatment switching

Anti-VEGF in wAMD

Anti-VEGF in wAMDCATT study

Stalmans et al. Retina (2013)

Anti-VEGF in wAMDCATT study

Stalmans et al. Retina (2013)

Anti-VEGF in wAMD

VIEW study

Outline

• Overview of anti-VEGF in wAMD

• Treatment regimens

• Therapy failure

• Treatment switching

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 ???

Outline

• Overview of anti-VEGF in wAMD

• Treatment regimens

• Therapy failure

• Treatment switching

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 20122. Heier JS et al. Ophthalmology 2012

3. Wykoff CC et al. Ophthalmology 2013

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 20122. Eghoj MS et al. Br J Ophthalmol 2012

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 20132. Bakall B et al. Am J Ophthalmol 2013

3. Ho VY et al. Am J Ophthalmol 20134. Miura M et al. Clinical Ophthalmology 2013

5. Heussen FM et al. Graefes Arch Clin Exp Ophthalmol 2014

Outline

• Overview of anti-VEGF in wAMD

• Treatment regimens

• Therapy failure

• Treatment switching

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 20122. Heussen FM et al. Graefes Arch Clin Exp Ophthalmol 2014

3. Yonekawa Y et al. Am J Ophthalmol 20134. Bakall B et al. Am J Ophthalmol 2013

5. Ho VY et al. Am J Ophthalmol 20136. Wykoff CC et al. Br J Ophthalmol 2013

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

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

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

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

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 20132. Yamashita M et al. Clinical ophthalmology 2014

3. Miura M et al. Clinical Ophthalmology 2013

Conclusions

• Different therapies on the current scenario

• New strategies in selected cases (tachyphylaxis)

• Efficacy of Aflibercept in PED or PCV with PED in wAMD