ΑΝΤΙΠΑΡΑΘΕΣΕΙΣ στην ΟΦΘΑΛΜΟΛΟΓΙΑ

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1 ΑΝΤΙΠΑΡΑΘΕΣΕΙΣ στην ΟΦΘΑΛΜΟΛΟΓΙΑ Wet AMD TREAT and EXTEND ΑΠΟΣΤΟΛΟΣ ΜΑΝΙΑΤΕΑΣ ΧΕΙΡΟΥΡΓΟΣ ΟΦΘΑΛΜΙΑΤΡΟΣ

2 Τι έχουμε μάθει από τα κλινικά δεδομένα μέχρι σήμερα; Marina/ Anchor PrONTO CATT 2009 Harbor Κλινική Πρακτική INJECT Apostolos Maniateas EyeDiagnosis

3 Τι έχουμε μάθει από τα κλινικά δεδομένα μέχρι σήμερα; PRN PrONTO Marina/ Anchor CATT 2009 Harbor Κλινική Πρακτική MONTHLY Apostolos Maniateas EyeDiagnosis

4 ΔΕΝ ΑΝΤΑΠΟΚΡΙΝΟΝΤΑΙ ΟΛΟΙ ΤΟ ΙΔΙΟ... ΕΓΚΑΙΡΗ ΔΙΑΓΝΩΣΗ ΜΟΡΦΟΛΟΓΙΚΟΙ ΠΑΡΑΓΟΝΤΕΣ ΥΑΛΟΕΙΔΟΑΜΦ/ΚΗ ΕΛΞΗ PED - ΠΑΧΟΣ ΧΟΡΙΟΕΙΔΟΥΣ ΤΑΧΥΤΗΤΑ ΣΧΗΜΑΤΙΣΜΟΥ ΝΕΟΑΓΓΕΙΩΝ ΦΑΡΜΑΚΟΚΙΝΗΤΙΚΗ ΤΑΣΗ ΥΠΟΤΡΟΠΗΣ Apostolos Maniateas EyeDiagnosis

5 FOLLOW-UP PRN UNDERTREAT OVERTREAT MONTHLY Apostolos Maniateas EyeDiagnosis

6 AURA collected real- world data on clinical management paterns and resource uxlizaxon from 2,227 neovascular AMD paxents treated with ranibizumab Mean VA difference to baseline by country (LOCF) Year Germany (n=420) France (n=398) United Kingdom (n=410) Italy (n=365) Netherlands (n=350) Total* (N=2,227) Days Number of injecxons Total Good outcomes were achieved in some countries where strict monitoring and retreatment criteria were followed; however, in many countries clinical trial results were not replicated in real life, parxcularly where PRN regimens are typically used in the clinic 5.2 Apostolos Maniateas EyeDiagnosis

7 IDEAL DOSING maximise visual benefit (at least as good as that observed in ANCHOR and MARINA) with the fewest number of injecaons and therefore the fewest risks. Apostolos Maniateas EyeDiagnosis

8 ΑΝΤΙ-VEGF + AMD ΑΞΙΟΛΟΓΗΣΗ ΘΕΡΑΠΕΥΤΙΚΟΥ ΑΠΟΤΕΛΕΣΜΑΤΟΣ Snellen OCT FA ICG ΟΠΤΙΚΗ ΟΞΥΤΗΤΑ ΕΞΙΔΡΩΜΑΤΙΚΑ ΣΤΟΙΧΕΙΑ ΝΕΟΑΓΓΕΙΑΚΗ ΜΕΜΒΡΑΝΗ

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10 Πως επιδρούν οι αντι- VEGF... VEGF VEGF VEGF VEGF VEGF VEGF Apostolos Maniateas EyeDiagnosis

11 Απαραίτητη η εξατομίκευση AMD, age- related macular degeneraxon; VEGF, vascular endothelial growth factor. Fauser S et al. Am J Ophthalmol 2014; 158 (3): Apostolos Maniateas EyeDiagnosis

12 Απαραίτητη η εξατομίκευση ΑΣΘΕΝΕΙΣ: Διαφορετικές ανάγκες για θεραπεία ΑΡΑ Διαφορετικές ανάγκες για follow- up Διατήρηση της Οπτικής οξύτητας σε πολλούς ασθενείς επιτυγχάνεται με ενέσεις ανά διαστήματα μεγαλύτερα του 1 μήνα αντίστοιχα και η επανεξέταση μπορεί να ρυθμίζεται αντίστοιχα Apostolos Maniateas EyeDiagnosis

13 Φάσεις θεραπείας Φάση καταστολής VEGF υποστροφή νεοαγγείωσης Φάση νέας αύξησης VEGF επανασχηματισμός νεοαγγείωσης χωρίς εξιδρωματικά στοιχεία στο ΟCT Φάση επανεμφάνισης εξιδρωματικών στοιχείων TREAT & EXTEND Φάση επιδείνωσης νόσου/κίνδυνος αιμορραγίας PRN Apostolos Maniateas EyeDiagnosis

14 REACTIVATION EARLY DIAGNOSIS Ažer 3 Ranibizumab: VA 9/10 DRUG- FREE for 2 months reacxvaxon at month 3 ažer the 3 rd Ranibizumab

15 OCT-Angio & WET AMD Αξιολόγηση θεραπευτικού αποτελέσματος: ΕΞΙΔΡΩΜΑΤΙΚΑ ΣΤΟΙΧΕΙΑ OCT) ΝΕΟΑΓΓΕΙΑΚΟ ΣΤΟΙΧΕΙΟ (NV OCT- Angio) ΝΕΑ ΠΡΩΤΟΚΟΛΛΑ ΘΕΡΑΠΕΙΑΣ; ΝΕΟΑΓΓΕΙΩΣΗ ΕΜΦΑΝΗΣ ΑΚΟΜΑ ΚΑΙ ΑΝ: - ΜΗ ΕΜΦΑΝΗΣ ΣΤΗ ΦΛΟΥΟΡΟ ΛΟΓΩ ΑΠΟΚΡΥΨΗΣ - ΕΛΛΕΙΨΗΣ ΔΙΑΡΡΟΗΣ - ΜΗ ΕΜΦΑΝΗΣ ΣΤΟ OCT ΛΟΓΩ ΑΠΟΥΣΙΑΣ ΕΞΙΔΡΩΜΑΤΙΚΩΝ ΣΤΟΙΧΕΙΩΝ

16 Treat & Extend regimen (EU ranibizumab label) Disease acavity at visit, reduce extension/re- iniaate monthly Tx 1M 1M 1M+E* 1M+E* 1M+E* VA stable, extend treatment/visit interval (E*) E*: Once maximum VA is achieved and/or there are no signs of disease acxvity, the treatment intervals can be extended stepwise unxl signs of disease acxvity or visual impairment recur. The treatment interval should be extended by no more than two weeks at a xme for wet AMD and may be extended by up to one month at a xme for DME. For RVO, treatment intervals may also be gradually extended, however there are insufficient data to conclude on the length of these intervals. If disease acxvity recurs, the treatment interval should be shortened accordingly. Monthly treatment max VA/no signs of disease acxvity T&E visit: Mandatory treatment including a decision point to extend/reduce the visit interval

17 T&E xps ΑΠΑΡΑΙΤΗΤΟ ΝΑ ΦΤΑΣΕΙ ΣΤΗ ΜΕΓΙΣΤΗ ΔΥΝΑΤΗ Ο.Ο (προσοχή επί αιμορραγιών) Σταθεροποίηση ύψους PED, υπαμφ/κου υγρού κα Επιμηκύνουμε το διάστημα κατά 2 εβδομάδες εως τις 12 εβδομάδες (max) Επί επανεμφάνισης εξιδρωματικών στοιχείων μειώνουμε κατά 2 εβδομάδες Επί μεγάλης υποτροπής εκ νέου μηνιαία χορήγηση Apostolos Maniateas EyeDiagnosis

18 Summary: Treat & Extend studies in namd with 1- year data Reference Treatment regimen Treatment Data availability (months) Paxent number VA gain (mean leters unless otherwise stated) CRT reducxon (mean unless otherwise stated) Number of injecxons/visits Injecxon interval TREX* Wykoff CC, et al. ARVO 2015, May 03 07, 2015, Denver, Colorado. Abstract number A0220 Treat and extend Ranibizumab Prospecave study 12 T&E: 40 Monthly: 20 T&E: 12.2 Monthly: 8.3 Floaang: 8.4 Clinical: 7.0 Hard: 5.9 T&E: Monthly: T&E: 10.1 Monthly: 13.0 Mean maximum extension interval (weeks): 8.4 Oubraham H, et al. Rexna 2011;31:26-30 Treat and extend 2 12 versus PRN Ranibizumab Retrospecave study 12 T&E: 38 PRN: 52 T&E: PRN: +2.3 Injecaons T&E: 7.8 PRN: 5.2 Visits T&E: 8.5 PRN: 8.8 Toalster N, et al. Rexna 2013;33: Treat and extend Ranibizumab Prospecave study Approximately +7 Yr 1: - 65 Injecaons: 8.0 Examinaaon Visits 7.0 Mean treatment interval (weeks): 9.1 *At month 12, for the monthly and T&E arms, VA improved from a baseline of 60.3 and 59.9 leters to a mean of 68.6 and 72.1 leters, respecxvely and CRT decreased from a baseline of 533 and 489 μm to 271 and 290 μm, respecxvely. While for the floaxng, clinical, and hard endpoints, VA improved from a baseline of 59.9 leters each to 68.3, 66.9, and 65.8 leters respecxvely. Monthly endpoints were defined as measurements collected monthly from the monthly arm. Floaxng endpoints were defined as measurements taken between weeks 24-28, and and were measured 4 weeks following the last injecxon. Clinical endpoints were defined as the visit 4 weeks prior to the floaxng endpoint. Hard endpoint was defined at week 52. No injecxons were administered at floaxng or hard endpoints. Legend Three monthly loading doses Extension and shortening of treatment interval (weeks) Maximum extension (weeks) 18

19 Summary: Treat & Extend studies in namd with 2 and 3 years data Reference LUCAS Berg K, et al. Ophthalmology 2015; 122: Berg K, et al. Presented at AAO 2014; Chicago, USA Abedi F, et al. Rexna 2014;34: Treatment regimen Treat and extend 2 12 Treat and extend 2 12 Treatment Ranibizumab Unlicensed bevacizumab Ranibizumab* Data availability (months) Prospecave RCT 24 Prospecave study 24 Paxent number VA gain (mean leters unless otherwise stated) Yr 1: Yr 2: Yr 1: +9.5 Yr 2: +8.0 CRT reducxon (mean unless otherwise stated) Yr 1: Yr 2: Number of injecxons/visits Yr 1: 8.0 Yr 2: 6.9 Yr 1: 8.9 Yr 2: 8.2 Yr 1: 8.6 Yr 2: 5.6 Injecxon interval Proporaon of paaents with 12- week injecaon interval at Yr 1: 37.1% 25.1% Meillon C, et al. Acta Ophthalmol 2014;92 [presented at EVER 2014] Treat and extend Ranibizumab Retrospecave study Up to Median Yr 1: +9 Yr 2: +10 Median Yr 1: - 80 Yr 2: Yr 1: 9 Yr 2: 10 Gupta OP, et al. Ophthalmology 2010; 117: Arnold JJ, et al. Ophthalmology 2015;122(6): Calvo P, et al. J Clin Exp Ophthalmol 2014;5:324 Rayess N, et al. Am J Ophthalmol 2014;159:3-8. Legend Three monthly loading doses 19 Treat and extend 2 12 Treat and extend 1-2 Treat and extend** 2 # 8 Treat and extend 2 Ranibizumab Ana- VEGF treatment (Bevacizumab, ranibizumab, or aflibercept) Ranibizumab Unlicensed bevacizumab (data pooled) Retrospecave study Up to 24 3 Ranibizumab 36 versus PRN (T&O) Extension and shortening of treatment interval (weeks) 92 Approximately Yr 1: +10 (Improvement to 20/77 from 20/135 at baseline) Yr 2: +10 (Improvement to 20/83 from 20/135 at baseline) 212 Yr 1: Yr 2: Yr 3: Yr 1: - 65 Yr 1: - 66 Yr 2: - 76 Yr 3: - 75 Yr 1: 8.36 Yr 2: 7.45 Observaaonal study Injecaons Yr 1: Month 6: +6.4 Yr 2: 5.5 Visits (1198 eyes ) Yr 2: +5.3 Yr 1: 7.9 Yr 2: 6.7 Retrospecave study Approximately Yr 1- T&E: 9.27 Prospecave study Up to 36 Maximum extension (weeks) T&E: 30 T&O: 30 T&E: T&O: T&E: - 74 T&O: - 94 Yr 1- T&O: 7.07 Total at Yr 3- T&E: Total at Yr 3- T&O: Yr 1: 7.6 Yr 2: 5.7 Yr 3: 5.8 Mean longest extension: 79.9 days (~11 weeks) No recurrence: 45.7% One recurrence: 30.4% two recurrences: 23.9% Proporaon of eyes treated & mean treatment interval (weeks): 0-3 months: 72% at 4 weeks 4-6 months: 59% extended to 5-8 weeks >6 months: 21% 29% at 9-15 weeks Mean longest period of extension (weeks): Yr 1: 11.4 Yr 2: 13.7 Yr 3: 13.9 * 27.5% of paxents received bevacizumab as their first injecxon (due to a delay in the ranibizumab approval process) with ranibizumab used for all subsequent treatments; Study reported VA outcomes in Snellen fracxons or logmar units, which were converted to a leter VA score using the table available from: htp://precision- vision.com/introducxon- to- Visual- Acuity- Measurement/a- visualacuity.html [accessed 07 January 2015]; **The study involves T&E and T&O regimens; # If disease acxvity was observed, treatment cycle was restarted (loading dose of 3 monthly injecxons); Of the 1198 eyes, 588 eyes (49%) received ranibizumab; 25 eyes (2%) received bevacizumab, none of the eyes received aflibercept, and 585 eyes (49%) received a combinaxon of 2 agents (9.2% received bevacizumab, 7.9% received aflibercept, and 82.9% received ranibizumab). CRT, central rexnal thickness; PRN, pro re nata; RCT, randomized control trial; T&E, treat and extend; T&O, treat and observe; VA, visual acuity; Yr, years

20 T&E vs MONTHLY (1y) Wykoff CC, et al (TREX). T&E regimen: 1,2 Three iniaal doses of ranibizumab 0.5 mg injecaon at monthly intervals Retreatment criteria: Any fluid on SD- OCT New or persistent hemorrhage Inacxve CNV Acxve CNV Treatment given. Follow- up extended by 2 weeks (maximum 12 weeks) Treatment given. Follow- up reduced by 2 weeks Mean change in VA (ETDRS leters) Ranibizumab 0.5 mg T&E (n = 40 paxents) Ranibizumab 0.5 mg monthly (n = 20 paxents) Months Post loading dose, maximum extension interval was a mean of 8.4 weeks Endpoints # No. of injecaons, mean* Change in VA at Month 12, mean (ETDRS le ers) T&E Monthly *p = 1.18X No injecxons were administered at floaxng or hard endpoints. # Descripxon of endpoints are given in the notes secxon. 1. Wykoff CC, et al. ARVO 2015, May 03 07, 2015, Denver, Colorado. Abstract number A htps://clinicaltrials.gov/ct2/show/nct (Accessed on 08 July, 2015)

21 Oubraham H et al. Re7na 2011; 31 (1): T&E vs PRN Oubraham et al. (2011) retrospecxvely examined the efficacy of ranibizumab in neovascular AMD paxents, administered via a PRN or T&E regimen, over the course of 1 year PRN (n=52) T&E (n=38) P-value Mean number of visits 8.8 ± ± 1.1 P<0.20 Mean number of injections 5.2 ± ± 1.3 P<0.001 Mean gain in VA, ETDRS letters Percentage risk of loss of vision* 2.3 ± ± 8.8 P= P=0.002

22 Ranibizumab T&E regimen provided sustained VA improvements over 2 years T&E Berg K, et al (LUCAS). T&E regimen: 1,2 Three iniaal doses of ranibizumab 0.5 mg injecaon at monthly intervals Retreatment criteria: Any fluid on OCT New or persistent hemorrhage Increased lesion size Inacxve CNV Acxve CNV Treatment given. Follow- up extended by 2 weeks (maximum 12 weeks) Treatment given. Follow- up reduced by 2 weeks Mean change in VA (ETDRS leters) n = 172 Ranibizumab 0.5 mg Months No. of injecxons and clinic visits, mean Change in VA, mean (ETDRS leters) LUCAS is the first large study confirming the validity of individualized monitoring in namd At year 1, 37.1% of paaents received ranibizumab injecaons every 12 weeks and 10% 20% of paaents required 3 injecaons 6.6 Year 1 Year Note: LUCAS was a head to head trial comparing bevacizumab and ranibizumab treatments. Here, results are shown for ranibizumab treatment arm only Berg K et al. Ophthalmology 2014 [Epub ahead of print]. 2. Berg K. Data presented at American Academy of Ophthalmology (AAO) 2014, Nov 2014, Chicago, IL.

23 Ranibizumab T&E regimen provided sustained VA improvements over 2 years T&E Abedi F, et al. T&E regimen: 1 Three iniaal doses of ranibizumab 0.5 mg injecaon at monthly intervals Retreatment criteria: VA drop of >5 leters compared with previous visit New or persistent hemorrhage Subrexnal or intrarexnal fluid on OCT Inacxve CNV Acxve CNV Follow- up and treatment at 6 weeks then follow- up extended by 2 weeks (maximum 12 weeks) Treatment given. Follow- up reduced by 2 weeks Mean change in VA (ETDRS leters) 14 Ranibizumab 0.5 mg n = 120 Months No. of injecxons and clinic visits, mean Change in VA, mean (ETDRS leters) Year 1 Year * 27.5% of paxents received bevacizumab as their first injecxon (due to a delay in the ranibizumab approval process) with ranibizumab used for all subsequent treatments; Abedi F et al. Rexna 2014;34(8):

24 OCT-Angio & WET AMD Αξιολόγηση θεραπευτικού αποτελέσματος: ΕΞΙΔΡΩΜΑΤΙΚΑ ΣΤΟΙΧΕΙΑ OCT) ΝΕΟΑΓΓΕΙΑΚΟ ΣΤΟΙΧΕΙΟ (NV OCT- Angio) ΝΕΑ ΠΡΩΤΟΚΟΛΛΑ ΘΕΡΑΠΕΙΑΣ; ΝΕΟΑΓΓΕΙΩΣΗ ΕΜΦΑΝΗΣ ΑΚΟΜΑ ΚΑΙ ΑΝ: - ΜΗ ΕΜΦΑΝΗΣ ΣΤΗ ΦΛΟΥΟΡΟ ΛΟΓΩ ΑΠΟΚΡΥΨΗΣ - ΕΛΛΕΙΨΗΣ ΔΙΑΡΡΟΗΣ - ΜΗ ΕΜΦΑΝΗΣ ΣΤΟ OCT ΛΟΓΩ ΑΠΟΥΣΙΑΣ ΕΞΙΔΡΩΜΑΤΙΚΩΝ ΣΤΟΙΧΕΙΩΝ

25 Freund KB et al. Re7na 2015; 35 (8): Global consensus on the working definixon of treat- and- extend Standard maximum extension recommended at 12 weeks Also consider the nature of the disease being treated and the agent being used to treat, e.g. shorter for: Neovascular AMD vs. DME or ME secondary to RVO Monocular patients Eyes at high risk for hemorrhage (e.g. patients taking anticoagulants or those with very large lesions) Eyes treated with shorteracting anti-vegf agents Continue monthly treatment until maximum response Maximum response achieved Stable disease Extend treatment interval by up to 2 weeks at a time Primary criteria for extension Absence of any fluid on OCT or stabilization of fluid on OCT (for at least 2 consecutive injections) No new hemorrhage Supporting criteria for extension No further flattening of serous or vascularized PEDs No further visual improvement Does the patient meet criteria for treatment suspension? Maximum response 1. Complete resolution of SRF and IRF without new retinal haemorrhage, or 2. No further reduction of SRF or IRF for at least 2 consecutive visits on OCT in the absence of new retinal hemorrhage Deterioration Minor change (e.g. recurrence or increase in IRF or SRF on OCT, or small extrafoveal hemorrhage) Shorten interval by 1 2 weeks Major change e.g. large recurrence or increase in IRF or SRF on OCT associated with visual loss >6 letters, subfoveal or large extrafoveal hemorrhage) Revert back to monthly treatment Does the patient meet criteria for treatment suspension? Further treatment judged by the physician to be unnecessary or of no potential for continued benefit (e.g. eyes with extended periods of disease quiescence or eyes with advanced fibrovascular scarring and/or geographic atrophy)

26 T&E vs Monthly/PRN Fixed Reacave PRN Proacave treat- and- extend Potenaal benefits: Reduced visit frequency Minimize over dosing Avoids under dosing û û ü û ü ü û û ü Proacave: Maintains dry rexna to prevent fluid accumulaxon and long- term irreversible damage Predictable injecxon requirements ü ü û û ü ü Flexible: Uses VA and anatomic outcomes to determine treatment intensity based on clinical judgment û û ü ü Apostolos Maniateas EyeDiagnosis

27 Μεγαλύτερο κέρδος γραμμάτων από PRN T&E ADVANTAGES Λιγότερες ενέσεις απο μηνιαία σχήματα Δεν κυνηγάμε τη νόσο - Λιγότερες μέρες με εξιδρωματικά στοιχεία Προβλέψιμος ο χρόνος θεραπειών Δεν αποφασίζουμε για τη θεραπεία αλλά για το διάστημα παρακολούθησης

28 ΣΑΣ ΕΥΧΑΡΙΣΤΩ ΓΙΑ ΤΗΝ ΠΡΟΣΟΧΗ ΣΑΣ