P. Stavrakas MD PhD. Consultant Ophthalmologist and vitreoretinal surgeon 2 nd Department of Ophthalmology University of Athens

Transcription

1 P. Stavrakas MD PhD Consultant Ophthalmologist and vitreoretinal surgeon 2 nd Department of Ophthalmology University of Athens

2 Primary diagnose of exudative AMD Anti-VEGF monotherapy treatment Loss of 2 lines from baseline at 1 year With/without persistence or recurrence of fluid

3 MARINA Study: - 3,4% 0.3 mg group - 2,5% 0.5 mg group ANCHOR Study: Severe vision loss (>30 letters) at 24 months At 12 months

4 SEVEN UP STUDY

5 1 Manoj S, Unnikrishnan R, Ramachandran KG. Why does anti-vegf treatment fail in age related macular degeneration. AIOS

6 Diminished therapeutic response to a drug following repeated administration over time Good initial response to anti-vegf: resolution of fluid Recurrence of fluid in spite of additional anti-vegf therapy

7 Ehgoj MS (2012): 2% for lucentis Schaal S (2008): median number IVI avastin 2.9 ForooghianF (2009): median number IVI avastin: 8 (range: 5-10) Keane P (2008)

8 unclear Neutralizing antibodies against bevacizumab/ranibizumab 1 Macrophage mediated upregulation of VEGF production as a response to VEGF blockade 2 Tissue resistance to hypoxia: less dependent on angiogenesis thus less responsive to antiangiogenic therapy 3 1 Forooghian F, Chew E, Meyerle C, Cukras C, Wong W. Investigation of the role of neutralizing antibodies against bevacizumab as mediators of tachyphylaxis. ActaOphthalmologica Forooghian F, Chew E, Meyerle C, Cukras C, Wong W. Tachyphylaxis following intravitrealbevacizumab for exudative age-related macular degeneration. Retina Manoj S, Unnikrishnan R, Ramachandran KG. Why does anti-vegf treatment fail in age related macular degeneration. AIOS 2012

9 ranibizumab bevacizumab 80% demonstrated at least some response after switching therapies 1 1 Gasperini JL, Fawzi AA, KhondkaryanA et al. Bevacizumab and ranibizumabtachyphylaxis in the treatment of choroidal neovascularization. Br J Ophthalmol 2012.

10 Anti-VEGF IVTA, PDT Not much available data Transient results Mostly structural restoration

11 Increasing the dose HARBOR trial: 2.0mg vs 0.5 mg ranibizumab monthly for 12 months: neither noninferior nor superior LAST trial: 2.0mg vs 0.5 mg ranibizumab x 3 loading doses followed by inject and extend for 12 months: superiority in BCVA, CFT, SRF, max PED height but small recruitment (9pts)

12 Increasing the frequency Biweekly regimen of bevacizumab: improved results in some patients 1 BUT Significant cost implications Poor compliance 1 Stewart MW, Rosenfeld PJ, Penha FM et al. Pharmacokinetic rationale for dosing every 2weeks versus 4 weeks with intravitrealranibizumab, bevacizumab and aflibercept. Retina 2010

13 Combination therapy: PDT+anti-VEGF SUMMIT : DENALI+MONT BLANC study DENALI Study: superiority or noninferiority NOT established MONT BLANC Study: noninferiority established No available data on tachyphylaxis

14 Higher VEGF-binding affinity: Aflibercept VIEW 1: 10.9 letters (eylea) vs 8.1 letters (lucentis) VIEW 2: 7.6 letters vs 9.4 letters Switch: Persistent IRF/SRF: BCVA, CFT, PED height and diameter, SRF statistically improved 1 1 Kumar N, Marsiglia M, Mrejen S et al. Visual and anatomical outcomes of intravitrealaflibercept in eyes with persistent subfoveal fluid despite previous treatments with ranibizumab in patients with neovascular age-related macular degeneration. Retina 2013.

15 PCV RAP Tumors Adult vitelliform dystrophy Trauma Other CNV causes

16 FFA findings mimic occult CNV ICGA for diagnosis Anti-VEGF monotherapy: resolution of IRF/SRF BUT persistence of choroidal vascular changes 1,2 1 Kokame GT, Yeung L, Lai JC. Continuous anti-vegf treatment with ranibizumab for polypoidalchoroidalvasculopathy. Br J Ophthalmol 2008;91: Cho HJ, Kim JW, Lee DW et al. Intravitrealbevacizumab and ranibizumab injections for patients with polypoidalchoroidalvasculopathy. Eye (lond) 2012;26:

17 PDT monotherapy Favorable short to mid-term results: 80-95% regression of polyps 1 3 years f/u: 77% recurrence 2 Reduced-fluence PDT: promising results 3 1 Silva RM, Figueira J, Cachulo MLet al. Polypoidalchoroidalvasculopathy and photodynamic therapy with verteporfin. Graefes Arch ClinExpOphthalmol 2005;243: Akaza E, Yuzawa M, Mori R. Three-year follow-up results of photodynamic therapy for polypoidalchoroidalvasculopathy. Jpn J Ophthalmol 2011;55: Yamashita A, Shiraga F, Shiragami C et al. Two-years results of reduced-fluence photodynamic therapy for polypoidalchoroidalvasculopathy. Am J Ophthalmol 2013;155:

18 Combined PDT and anti- VEGF therapy EVEREST study: ranibizumab monotherapy vs PDT+ranimizumab vs PDT monotherapy 28.6% vs 77.8% vs 71.4% Complete regression of polyps at 6 months

19 3 months after PDT+3 monthly ranibizumabintravitreal injections

20 Other RF-PDT+anti-VEGF PDT+anti-VEGF+IVTA PDT+IVTA Direct thermal laser photocoagulation for extrafoveal lesions Pneumatic displacement for massive submacularhaemorrhage

21 Anti-VEGF monotherapy Significant short term functional benefit 1 Long term results suggest that anti-vegf alone may not be sufficient to maintain anatomic and functional improvement 1 1Tarek H, Pearse K, Laurie D. Longterm visual and anatomic outcomes following anti-vegf. Br J Ophthalmol 2010; 94(6):701-5.

22 Anti-VEGF monotherapy 27 months after treatment with absence of IRF, ICS, SRF and PED

23 PDT+anti-VEGF 1 Other PDT+IVB>PDT+IVTA 2 PDT+IVTA>PDT+Ranibizumab / Ranibizumab monotherapy 3 1 Saito M, Lida T, Kano M. Combined intravitrealranibizumab and photodynamic therapy for retinal angiomatous proliferation. Am J Ophthalmol 2012;153(3): Saito M, Shoragami C, Shiraga F. Comparison of intravitreal triamcinolone acetonide with photodynamic therapy and intravitrealbevacizumab with photodynamic therapy for retinal angiomatous proliferation. Am J Ophthalmol 2010; 149(3): Rouvas AA, Papakostas TD, Vavvas D et al. Intravitrealranibizumab, intravitrealranibizumab with PDT and intravitreal triamcinolone with PDT for the treatment of retinal angiomatous proliferation: a prospective study. Retina 2009; 29(4):

24 No resolution of fluid at any point of time during follow up Genetics VMTS

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26 CFH gene: less improvement in VA while receiving ranibizumab therapy 1 C3 gene: reduced thickening and improved retinal architecture 1 VEGFA, FLT1, CFH genes: requiring fewer ranibizumab injections over 12 months 1 1 Francis P. The influence of genetics on response to treatment with ranibizumab (lucentis) for age-related macular degeneration: the lucentis genotype study. Trans Am OphthalmolSoc /109/2011/115.

27 Significantly higher incidence of incomplete PVD in ex AMD 1 Higher incidence of VMTS in ex AMD 1 Concentric configuration of the two processes suggesting a causal relationship 1 Borderline significance of VA improvement after surgery (long-standing cases) 1 1 Mojana F, Cheng L, Bartsch D et al. The role of abnormal vitreomacular adhesion in age related macular degeneration: spectral optical coherence tomography and surgical results. Am J Ophthalmol 2008.

28 Concentric configuration of the two processes

29 Initial response to anti-vegf Yes Taxyphylaxis PCV No RAP Eylea Lucentis Avastin PDT+anti- VEGF Other Combination therapy Other

30 Initial response to anti-vegf Genetics VMTS PCV No RAP Lucentis Avastin PPV PDT+anti -VEGF Other Combined therapy Other

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