Treatment pathways for Intravitreal therapies in Diabetic Macular Oedema (DMO) Louise Downey Consultant Ophthalmologist MBChB BSc PhD FRCOphth

Transcription

1 Treatment pathways for Intravitreal therapies in Diabetic Macular Oedema (DMO) Louise Downey Consultant Ophthalmologist MBChB BSc PhD FRCOphth

2 Disclosures and acknowledgements Financial disclosures; Alcon, Alimera, Allergan, Bayer, Novartis, Thrombogenics, Oraya Advisory board work, travel grants, speakers fees, research studies. Elements of this slide deck were taken from Bayer published slide deck (UK DMO slide deck v 13) plus Allergan, Alimera and Novartis slide decks

3 Plan for this presentation a long list! What treatment options are available for DMO? (evidence base) What treatment should I start with at baseline? Re-treatment algorithms for intravitreal DMO therapies When should I switch/combine therapies? The bigger picture Other eye The patient as a whole The service -coping with capacity

4 Plan for this presentation a long list! What treatment options are available for DMO? (evidence base) 1.)What treatment should I start with at baseline? 2.)Re-treatment algorithms for intravitreal DMO therapies 3.)When should I switch/combine therapies? 4.)The bigger picture Other eye/peripheral retinopathy The patient as a whole The service -coping with capacity compromises?

5 DMO treatment options 1.)What treatments should I use at baseline?? ETDRS based laser therapies ADJUNCT? Surgery VMT/ERM Pan-retinal photocoagulation?? INTRAVITREAL ANTI-VEGF; Lucentis (Ranibizumab) Eylea (Aflibercept) Avastin (Bevacizumab) STEROIDS; Iluvien (Fluocinolone) Ozurdex (Dexamethasone)

6 6 RCO recommendations for the treatment of CSMO CSMO No centre involvement Centre involvement Photocoagulation > 78 letters (normal/minimally reduced VA) VA letters Photocoagulation Phakic Pseudophakic Anti-VEGF* Anti-VEGF** *Fluocinolone is an option for eyes unresponsive to other treatments but potential side effects must be considered; **Triamcinolone +/- adjunctive laser or fluocinolone may be considered for eyes unresponsive to other treatments. The Royal College of Ophthalmologists. Diabetic Retinopathy Guidelines

7 7 DMO treatment options What treatments should I use at baseline?? ETDRS based laser therapies? = Clinically significant macular oedema (CSMO) The ETDRS defined CSMO as DMO that threatens the centre of the macula (fovea) 1, and forms the basis of current recommendations for the treatment of CSMO 2 CSMO is diagnosed if any of the following parameters are met: µm 1 disc diameter Fovea 500 µm 1 disc diameter 1. Retinal thickening within 500 µm of the centre of the macula ETDRS = Early Treatment Diabetic Retinopathy Study. 1. ETDRS Research Group. Arch Ophthalmol. 1985;103: ; 2. Bandello F, et al. Eye (Lond). 2012;26(4): Hard exudates within 500 µm of the centre of the macula, if associated with thickening of the adjacent retina 3. Retinal thickening of >1 disc area in size, any part of which is located within 1 disc diameter of the centre of the macula Date of Prep Jan 2015 L.GB f

8 8 ETDRS based laser therapies? = Clinically significant macular oedema (CSMO) The ETDRS defined CSMO as DMO that threatens the centre of the macula (fovea) 1, and forms the basis of current recommendations for the treatment of CSMO 2 CSMO is diagnosed if any of the following parameters are met: 1 LASER??? 500 µm 1 disc diameter Fovea 500 µm 1 disc diameter 1. Retinal thickening within 500 µm of the centre of the macula ETDRS = Early Treatment Diabetic Retinopathy Study. 1. ETDRS Research Group. Arch Ophthalmol. 1985;103: ; 2. Bandello F, et al. Eye (Lond). 2012;26(4): Hard exudates within 500 µm of the centre of the macula, if associated with thickening of the adjacent retina 3. Retinal thickening of >1 disc area in size, any part of which is located within 1 disc diameter of the centre of the macula

9 9 RCO recommendations for the treatment of CSMO CSMO No centre involvement Centre involvement Photocoagulation > 78 letters (normal/minimally reduced VA) VA letters Photocoagulation Phakic Pseudophakic Anti-VEGF* Anti-VEGF** ILUVIEN (chronic/unresponsive) OZURXEX (no improvement) The Royal College of Ophthalmologists. Diabetic Retinopathy Guidelines

10 DMO treatment options What treatments should I use at baseline?? ETDRS based laser therapies ADJUNCT? Surgery VMT/ERM Pan-retinal photocoagulation?? INTRAVITREAL ANTI-VEGF; Lucentis (Ranibizumab) Eylea (Aflibercept) Avastin (Bevacizumab) STEROIDS; Iluvien (Fluocinolone) Ozurdex (Dexamethasone)

11 11 DMO treatment options What treatments should I use at baseline based on evidence from RCT data?? Anti-VEGF Laser Steroids ETDRS vs laser BOLT DA VINCI VIVID and VISTA vs sham RESOLVE RISE and RIDE RELIGHT DRCR.net PROTOCOL T READ-2 RESTORE RETAIN REVEAL Anti-VEGF (in combination with laser) DRCR.net (Protocol I) Steroids (in combination with laser) vs laser DRCR.net (Protocol B) vs sham FAME MEAD Bevacizumab Ranibizumab Aflibercept Fluocinolone acetonide Dexamethasone Triamcinolone

12 What therapy do I choose for my patient at baseline? Which treatments can I access?? NICE TA 274 Lucentis for DMO April 2013 NICE TA 346 Eylea for DMO July 2015 OCT >400um 1 st line if OCT suitable NICE TA 301 Iluvien for DMO Nov 2013 NICE TA 349 Ozurdex for DMO July 2015 Chronic DMO PSEUDOPHAKIC Patients insufficiently responsive to existing therapies PSEUDOPHAKIC Not improved with noncorticosteroid or such treatment is not suitable for them

13 What therapy do I choose for my patient at baseline? ANTI-VEGF Superior to ETDRS argon laser in terms of efficacy

14 RESTORE 36 month Lucentis prn extension study Lucentis monotherapy vs Lucentis plus laser vs laser alone Schmidt-Erfuth U et al; Ophthalmology (5) Core study assessment Interim analysis Full analysis/ study completion Mean of the change in ETDRS BCVA Core study Extension study (ranibizumab 0.5 mg PRN) Prior ranibizumab 0.5 mg + sham laser (n=83) Prior ranibizumab 0.5 mg + active laser (n=83) Prior sham injections + active laser (n=74) Months

15 15 RISE and RIDE (Lucentis monthly dosing): Mean change in BCVA over 36 months RISE Mean change in BCVA (ETDRS letters) RISE & RIDE RIDE Mean change in BCVA (ETDRS letters) Ranibizumab 0.3 mg Ranibizumab 0.5 mg Sham/ranibizumab 0.5 mg Brown DM, et al. Ophthalmology. 2013;120(10): Time (months) Date of Prep Dec 2014 L.GB X

16 Eylea =VIVID and VISTA: Mean change in BCVA to week 100 Korobelnik J-F et al. Ophthalmology 2014; 121 (11): Brown DM et al. Ophthalmology 2015; Jul 18 [Epub ahead of print]. Mean change in BCVA letter score VIVID Week 100 VISTA Week q8 * q4 * 1.2 Laser q4 * q8 * 0.2 Laser Week Laser 2q4 2q8 *P< vs. laser. VIVID: Laser: n=132; 2q4: n=136; 2q8: n=135; VISTA: Laser: n=154; 2q4: n=154; 2q8: n=151. Full analysis set. 2q4, 2 mg every 4 weeks; 2q8, 2 mg every 8 weeks; BCVA, best corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study q4 * 9.4 2q8 * 0.7 Laser q4 * q8 * 0.9 Laser

17 What therapy do I choose for my patient at baseline? ANTI-VEGF.if OCT > 400um So. Which one?

18 18 Key trials in DMO Anti-VEGF Laser Steroids ETDRS vs laser BOLT DA VINCI VIVID and VISTA vs sham RESOLVE RISE and RIDE READ-2 RESTORE RETAIN REVEAL Anti-VEGF (in combination with laser) DRCR.net (Protocol I) Steroids (in combination with laser) vs laser DRCR.net (Protocol B) vs sham FAME MEAD DRCR.net PROTOCOL T Bevacizumab Ranibizumab Aflibercept Fluocinolone acetonide Dexamethasone Triamcinolone

19 PROTOCOL T (DRCR.net) Aflibercept, Bevacizumab or Ranibizumab for Diabetic Macular Edema. N Engl J Med Mar 26;372(13): The Diabetic retinopathy Clinical Research Network February 18, USA study NIHR funded n=660 Lucentis 0.3mg not 0.5mg, Eylea 2mg, Avastin 1.25mg Eylea protocol not the licensed regime Avastin unlicensed RETREATMENT protocol First 6 months inject every month 95% of patients UNLESS VA=6/6 AND OCT DRY Then 2 nd six months if no change after 3 visits DEFER otherwise keep injecting monthly Recurs need at least 2 injections ie 3 months of stability. STABILITY = 10% Oct change or VA 5 letter change STABILITY and residual OCT thickness >250um LASER

20 Protocol T 1 year visual acuity outcomes 20 20/50 = 6/15 or worse = < /32-20/40 = 6/9.6 6/12= Mean change in BCVA Visit Week Mean change in BCVA Visit Week Aflibercept Bevacizumab Ranibizumab

21 Protocol T OCT outcomes year Mean change in CST Visit Week Aflibercept Bevacizumab Ranibizumab

22 Conclusions Protocol T year 1 data Eylea was statistically superior in terms of visual acuity to 0.3mg Lucentis and to Avastin FOR PATIENTS WITH VA worse than 69 letters Eylea and Lucentis were statistically superior in terms of OCT CRT reduction to Avastin for all patients regardless of baseline vision. No safety differences between the three drugs

23 SUMMARY What do I choose for my patient at baseline? OCT central retinal thickness (CRT)? Pseudophakic Attempts at prior treatment duration of DMO? < 400um IFR licensed anti-vegf or Avastin +/-ETDRS laser? PSEUDOPHAKIC Iluvien Ozurdex Chronic DMO PSEUDOPHAKIC Patients insufficiently responsive to existing therapies Not improved with non-corticosteroid or such treatment is not suitable for them > 400um = Anti-VEGF Which one??? Depends on baseline vision <6/15? Eylea Fixed dosing attractive (Eylea)?

24 Which steroid Ozurdex or Iluvien? No head to head data Revisit this when we think about switching from ANTI-VEGF to steroid

25 Assuming we have started with an anti-vegf agent what are the re-treatment algorithms in DMO

26 Treatment posologies Ranibizumab 1 Aflibercept 2 Treatment is initiated with one injection per month until maximum VA is achieved and/or there are no signs of disease activity i.e. no change in VA and in other signs and symptoms of the disease under continued treatment. In patients with DMO, initially, three or more consecutive, monthly injections may be needed. Thereafter, monitoring and treatment intervals should be determined by the physician and should be based on disease activity, as assessed by VA and/or anatomical parameters If patients are being treated according to a treat-and-extend regimen, once maximum VA is achieved and/or there are no signs of disease activity, the treatment intervals can be extended stepwise until signs of disease activity or visual impairment recur. The treatment interval may be extended by up to one month at a time for DMO. treatment is initiated with one injection per month for five consecutive doses, followed by one injection every two months. There is no requirement for monitoring between injections After the first 12 months of treatment the treatment interval may be extended based on visual and/or anatomic outcomes. The schedule for monitoring should be determined by the treating physician. DMO, diabetic macular oedema; VA, visual acuity.. 1. Novartis Pharmaceuticals UK Ltd. 30 October Available at: Accessed: 04 September Bayer Pharma AG. February Available at: Accessed: 04 September 2015.

27 Re-treatment algorithms for anti-vegf agents in DMO LOADING PHASE Lucentis label = monthly until stability Eylea label = 5 x 1/12 then every 8 weeks ie fixed regime year 1 DRCR.net protocol T = effectively 6 x1/12 for majority (95%) BUT actually only mandated for first 3 months then prn likely that majority will receive injections monthly for first 6 months INDIVIDUALISED PHASE Once stable based on VA and OCT NB May never get a dry OCT so treat to stability THEN? Treat and extend? prn

28 What does Treat and Extend mean???

29 Pathway overview = Lucentis prn Loading phase = injections every 4 weeks until stable for 3 visits Then observe UNTIL VA decreases or OCT increase = prn Once reactivates need at least 2 injections until stable again over 3 visits Jan Feb Mar AprMay Jun Jul Aug Sep Oct NovDec Jan Feb Mar AprMay Jun Jul Aug Sep Oct NovDec..

30 Pathway overview = Treat and Extend Loading phase = injections every 4 weeks until stable for 3 visits or Eylea year 1 Then keep injecting but extend the interval between injections gradually ie keep treating even if perfect Jan Feb Mar AprMay Jun Jul Aug Sep Oct NovDec If reactivates need at least 2 injections until stable again over 3 visits Jan Feb Mar AprMay Jun Jul Aug Sep Oct NovDec..

31 Pathway overview = Eylea fixed dosing year 1 Eylea = 5 x 1/12 injection then every 8 weeks Jan Feb Mar AprMay Jun Jul Aug Sep Oct NovDec Then individualised UNTIL VA decreases or OCT increase = prn Once reactivates need at least 2 injections until stable again over 3 visits Jan Feb Mar AprMay Jun Jul Aug Sep Oct NovDec.. Average 6 injections yr 2. Beyond that????

32 Pros and cons of Treat and Extend vs Prn T+E PROS Proactive; patient and service get advance warning of injection capacity and demand planning easier One stop Fewer visits than prn Overtreatment advantageous for peripheral retinopathy?? CONS Overtreatment = risk/expense/inconvenience Evidence base scant Bilateral disease tricky PRN Only treated when active ie no overtreatment Aggressive year 1 protocols (DRCRN I few injections needed thereafter DMO tolerant of reactivations (???) Reactive so need enough emergency capacity to inject when disease flares up No advance warning to patient/service that injection needed NEED TO DO IT WELL NHS real life audits prn based regimes not good resultsundertreatment in year 1? Affects long term prognosis and treatment burden

33 Pros and cons of Treat and Extend vs Prn T+E PROS Proactive; patient and service get advance warning of injection capacity and demand planning easier One stop Fewer visits than prn Overtreatment advantageous for peripheral retinopathy?? CONS Overtreatment = risk/expense/inconvenience Evidence base scant Bilateral disease tricky PRN Only treated when active ie no overtreatment Aggressive year 1 protocols (DRCRN I few injections needed thereafter DMO tolerant of reactivations (???) Reactive so need enough emergency capacity to inject when disease flares up No advance warning to patient/service that injection needed NEED TO DO IT WELL NHS real life audits prn based regimes not good resultsundertreatment in year 1? Affects long term prognosis and treatment burden

34 DMO anti-vegf Treat and Extend Retain study the only RCT data Br J Ophthalmol Oct 9. pii: bjophthalmol doi: /bjophthalmol [Epub ahead of print] Ranibizumab 0.5 mg treat-and-extend regimen for diabetic macular oedema: the RETAIN study. Prünte C 1, Fajnkuchen F 2, Mahmood S 3, Ricci F 4, Hatz K 5, Studnička J 6, Bezlyak V 7, Parikh S 7, Stubbings WJ 7, Wenzel A 7, Figueira J 8 ; and the RETAIN Study Group.

35 35 RETAIN: Phase III trial evaluating the efficacy of treat and extend regimen (ARVO 2014) Patients with DMO and visual impairment (n = 372) were randomised 1:1:1 to one of three groups for 24 months: Ranibizumab 0.5 mg monotherapy in T&E regimen Two phases to dosing schedule: Phase A Ranibizumab 0.5 mg in T&E regimen plus laser Ranibizumab 0.5 mg PRN Patients in all groups were initially treated with monthly ranibizumab until BCVA remained stable Phase B Patients in the T&E groups whose vision remained stable had treatment- free intervals that were increased incrementally by 1 month for a maximum of 3 months Patients in the PRN group had ongoing monthly monitoring In all groups, Phase A was resumed if a decrease in BCVA was observed at a visit

36 36 RETAIN: Visual acuity endpoints Mean average change in BCVA (ETDRS letters) Mean average change in BCVA at 12 months (primary endpoint) Ranibizumab T&E Ranibizumab T&E + laser Ranibizumab PRN Mean change in BCVA (ETDRS letters) Ranibizumab T&E Mean change in BCVA at 24 months Ranibizumab T&E + laser Ranibizumab PRN p< for both ranibizumab T&E groups versus PRN for primary endpoint. Prünte C. ARVO 2014 Annual Meeting Abstracts. Abstract 1700.

37 37 RETAIN: Patient visits and monitoring with T&E regimen over 24 months The T&E regimen provided an approximately 40% reduction in the number of treatment visits required compared with the ranibizumab PRN regimen Approximately 70% of patients receiving T&E regimens had monitoring intervals 2 months, compared with ongoing monthly monitoring in the ranibizumab PRN group Informed the license for Lucentis in DMO (extend by 1 month at a time)

38 INTRAVITREAL STEROIDS Which intravitreal steroid is better?? Licensed steroids Ozurdex (Dexamethasone) and Iluvien (Fluocinolone acetonide Which steroid is best in terms of VA outcomes???? WE DON T KNOW FOR SURE no head to head studies for licensed drugs; either between steroids or between anti-vegf and steroids STEROIDS ARE efficacious in DMO MEAD FAME DRCRnet protocol I NICE Ozurdex and Iluvien second-line agents

39 Ozurdex A biodegradable co-polymer implant degrades in time to lactic and glycolic acid releasing Dexamethasone 22gauge injection MEAD study N=1048 Dex 0.7mg vs 0.35mg vs sham No rescue therapy 3 year follow up max 6 monthly dosing ie 7 over 3 years Gan IM et al, Greafes Acrh Clin Exp Ophthalmol 2005

40 Mean Change From Baseline BCVA (Letters) Mean Change from Baseline BCVA (Letters) MEAD study;mean BCVA change from baseline based on baseline lens status Pseudophakic Total Month DEX Implant 0.7 mg (n = 86) Sham (n = 101) DEX 700 (n=351) Sham (n=350) 0.7mg dose is approved as Ozurdex by the FDA and EMA. 0.35mg dose not commercially available Month 1. Boyer DS et al. Ophthalmology 2014, 121, Boyer DS et al. Ophthalmology 2014;121: Results analyzed in the ITT population with LOCF for missing values.

41 ILUVIEN Implant Technology FAc implant Nonbioerodible micro implant (polyimide) containing 190µg of fluocinolone acetonide (FAc) Consistent daily submicrogram delivery of 0.2 µg/d FAc for up to 36 months. Posterior point of release 3.5 mm 0.37 mm non-bioerodable micro implant. 25-gauge injector creates self-sealing wound. No measurable systemic exposure. ILUVIEN SPC.

42 Design of Phase 3 FAME Study (FAME A and B = same protocol) Additional laser therapy allowed after week 6 a Retreatment any time after month 12 (if eligible b ) Study ends Patients with DMO and: At least 1 previous laser tx BCVA 19 and 68 letters TD-OCT FTH 250 μm ILUVIEN 0.2 µg/d FAc (n = 376) 0.5 µg/d FAc (n = 395) Control: sham injection N = 956 (n = 185) Randomisation 2:2:1 Month: Primary readout BCVA = best corrected visual acuity; DMO = diabetic macular oedema; TD-OCT,=time domain optical coherence tomography.; FTH = foveal thickness a At masked investigator s discretion. b If BCVA loss 5 letters or retinal thickening 50 µm from best reading in previous 12 months.

43 15 letter Gain is Greater in Chronic DMO Patients 15-Letter Improvement in BCVA From Baseline, % Full Population 28.7% Δ = 9.8% 18.9% Patients With Chronic DMO 34% Δ = 20.6% 13.4% Months Months

44 Steroid re-treatments Ozurdex Longer half-life than anti-vegf in the eye Redosing regimes not very helpful from RCT data eg MEAD study only 6/12 dosing In reality re-treatment interval may be shorter POSOLOGY Patients treated with OZURDEX who have experienced an initial response and in the physician's opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment. Retreatment may be performed after approximately 6 months if the patient experiences decreased vision and/or an increase in retinal thickness, secondary to recurrent or worsening diabetic macular oedema. Iluvien 70% of patients in FAE only needed 1 injection over 3 years!!! BUT additional rescue treatments allowed POSOLOGY Each ILUVIEN implant releases fluocinolone acetonide for up to 36 months. An additional implant may be administered after 12 months if the patient experiences decreased vision or an increase in retinal thickness secondary to recurrent or worsening diabetic macular oedema

45 MEAD MEAD: TREATMENT PROTOCOL First treatment given at randomisation (day 0) Patients assessed for retreatment eligibility every 3 months from months 6 36 Patients were eligible for retreatment if: 6 months since most recent study treatment AND Retinal thickness in 1 mm central macular subfield by OCT >175 µm* OR Evidence of residual retinal oedema (intraretinal cysts or any regions of increased retinal thickening), as assessed by investigator from OCT* Patients receiving escape medication were exited from MEAD before administration 1 Macular laser rescue treatment allowed in RISE/RIDE (Lucentis ) from 3 months 2 Focal/grid laser allowed in FAME (Iluvien ) from 6 weeks 3 *Amendment in May 2010 revised anatomic criterion for retreatment; before this time the threshold was >225 µm 1.Boyer DS et al. Ophthalmology 2014, 121, Nguyen QD et al. Ophthalmology 2012;119: Campochiaro PA et al. Ophthalmology 2011;118: OCT: optical coherence tomography

46 Treatment burden ILUVIEN Control (n =112) 0.2 µg/d FAc (n =209) Study Treatments(sham injection or ILUVIEN 0.2 µg/day or FAc 0.5µg/day) 1 treatment 66.1% 76.1% 2 treatments 27.7% 18.7% 3 treatments 6.3 % 5.3% Rescue Laser Treatments (at masked physician s discretion after week 6) Patients, 60.7% 40.7% Off-Protocol Treatments (IVTA, bevacizumab, ranibizumab, intravitreal dexamethasone) Patients, 29.5% 11.5% OZURDEX = 2.3injections year 1, 4.1 by year 3 No other Rx

47 Summary of side effects with intravitreal steroids Drug device Evidence base Cataract risk IOP rise (requiring drops) ILUVIEN FAME studies 80% cat surgery (27.3% sham) Ozurdex MEAD 59.2% had cataract surgery (7.2% sham) 38.4% (14% control) 21.5% (end of study) (3.4% sham) Glaucoma surgery 4.8% 0 0.6% 0 endophthalmitis Trivaris+ laser vs Luc+laserx2 vs laser Protocol I Ophthalmology % 42% (ONE OF: >10mmHg rise >30mmHG Start drops) 2/186 0

48 NICE guidance for intravitreal steroids in DMO Iluvien NICE TA 301 Iluvien for DMO Nov 2013.for treating chronic diabetic macular oedema that is insufficiently responsive to available therapies only if: the implant is to be used in an eye with an intraocular (pseudophakic) lens and the manufacturer provides fluocinolone acetonide intravitreal implant with the discount agreed in the patient access scheme.

49 NICE guidance for intravitreal steroids in DMO Ozurdex NICE TA 349 Ozurdex for DMO July 2015 there is an artificial lens in the eye to be treated, and their diabetic macular oedema has not improved with non-corticosteroid treatment, or such treatment is not suitable for them.

50 Steroids = second line therapy When do I switch? Anti-VEGF first line for centre involving DMO NICE TA insufficiently responsive not improved not suitable OTHER TREATMENTS 2 scenarios 1.) Anti-VEGF can t be funded ie OCT<400um, + PSEUDOPHAKIC 2.) Already had a course of treatment with laser/anti-vegf + PSEUDOPHAKIC ie SWITCHING from anti-vegf to steroid Plus chronic DMO 3 years duration in FAME (18months) for ILUVIEN Chronic DMO not essential for Ozurdex

51 FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID Drug response Patient factors Heavy user VA improved but not far enough ie needs to regain driving license Struggles with intra-vitreal technique NO RESPONSE VA no change OCT no change SUBOPTIMAL VA better/same OCT improved but plateau GOOD But frequent recurrences and redosing at 1 month intervals

52 FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID Drug response Patient factors Heavy user VA improved but not far enough ie needs to regain driving license Struggles with intra-vitreal technique NO RESPONSE VA no change OCT no change SUBOPTIMAL VA better/same OCT improved but plateau GOOD But frequent recurrences and redosing at 1 month intervals Protocol T patients may not improve in first 6 months

53 54 Mean change in BCVA (ETDRS letters) RISE and RIDE (Lucentis monthly dosing): Mean change in BCVA over 36 months RISE RIDE VA improvement continues throughout year 1 with monthly dosing Mean change in BCVA (ETDRS letters) Ranibizumab 0.3 mg Ranibizumab 0.5 mg Sham/ranibizumab 0.5 mg Time (months) Brown DM, et al. Ophthalmology. 2013;120(10): Date of Prep Dec 2014 L.GB X

54 FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID Drug response NO RESPONSE VA no change OCT no change SUBOPTIMAL VA better/same OCT improved but plateau GOOD But frequent recurrences and redosing at 1 month intervals Patient factors Heavy user more than protocol I?? VA improved but not far enough ie needs to regain driving license Struggles with intra-vitreal technique DRCRN protocol I 5 year outcomes Injections 8-9 in year 1 Year 2 = 2-3 Year 3= 1-2 Year 4 = 0-1 Year 5 = 0

55 FACTORS AFFECTING DECISION TO SWITCH FROM ANTI-VEGF TO STEROID Drug response Patient factors Heavy user VA improved but not far enough ie needs to regain driving license Struggles with intra-vitreal technique NO RESPONSE VA no change OCT no change SUBOPTIMAL VA better/same OCT improved but plateau GOOD But frequent recurrences and redosing at 1 month intervals Wait for plateau?? = stability in protocol T laser Patient factors again!

56 Judgement of response to anti-vegf timeframe??? Wait 6 months in poor responders Wait 1 year for heavy users Tempting to try steroids earlier than this if No glaucoma not a deal breaker? Ozurdex better short term option? Pseudophakic Clues from the disease? chronic PATIENT FACTORS! Any eyes avoid steroids advanced glaucoma,cscr?? Or prior viral retinitis RARE!!! Any eyes avoid anti-vegf; pregnancy/trying to concieve, recent CVA???

57 BIOMARKERS AT BASELINE WOULD BE USEFUL! RESTORE subgroup analysis of OCT features Andreas Pollreisz EURETINA 2015 OCT biomarkers (RESTORE data) Better effects with anti-vegf if Small rather than large intra-retinal cyst Sub-retinal fluid present Vitreo-macular adhesion at baseline No disruption of ELM and IS/OS junction No disorganisation of inner retinal layers (DRIL)

58 RESTORE subgroup analysis of OCT features Andreas Pollreisz EURETINA? 2015 OCT biomarkers (RESTORE data) Better effects with anti-vegf if Small rather than large intra-retinal cyst Sub-retinal fluid present Vitreo-macular adhesion at baseline No disruption of ELM and IS/OS junction No disorganisation of inner retinal layers (DRIL) Better baseline characterisation/classification ERG Contrast sensitivity OCT Angiography Microperimetry = clues as to who responds best to which drug

59 Plan for this presentation a long list! What treatment options are available for DMO? (evidence base) What treatment should I start with at baseline? Re-treatment algorithms for intravitreal DMO therapies When should I switch/combine therapies? The bigger picture Other eye The patient as a whole The service -coping with capacity compromises?

60 The bigger picture Other eye The patient as a whole The service -coping with capacity compromises? OTHER EYE may create problems!! Treat and extend reduce # of visits plus Eylea license no need for monitoring may not benefit if lots of visits due to PDR other eye. PERIPHERAL RETINA: anti-vegf supresses proliferative disease -? Rebound on stopping Rx?? PATIENT Anti-VEGF heavy user -? Will comply One stop much better than two stop for patient??? Treat and extend SERVICE Capacity and demand planning = fixed/t+e more predictable at least 1 month in advance flexible nurse injectors. Steroids even if well controlled (Iluvien for 3 years) need IOP check Need pan-retinal examination both eyes separate visits?

61 Summary CSMO No centre involvement Centre involvement Photocoagulation > 78 letters (normal/minimally reduced VA) VA letters Photocoagulation Phakic Pseudophakic Anti-VEGF* Anti-VEGF**

62 CSMO No centre involvement Centre involvement LASER > 78 letters (normal/minimally reduced VA) OCT >400um VA letters EYLEA OR LUCENTIS OR AVASTIN???? Funding issues Protocol T poor VA < 65 letters (6/15) LOADING Monthly injections until stability OR 5 x 1/12 (EYLEA) = 6 MONTHS then 8 weeks RETREATMENT1 TREAT AND EXTEND - PRN PRN SWITCH? glaucoma Injection tolerance Medical issues/recent CVA Peripheral disease Bilateral Rx PSEUDOPHAKIC ILUVIEN Chronic disease Prior Rx? RETREATMENT OZURDEX OZURDEX OCT >175um or any residual oedema ILUVIEN after 12 months if risks<benefits

63 ANTI-VEGF INJECTION PATHWAYS Baseline visit MAC001 for wet AMD RV001 for CRVO/BRVO Med ret clinic for DMO LOADING PHASE Eylea/Lucentis #1 within 48hrs of baseline Eylea/Lucentis #2 (and LogMAR VA plus OCT same visit) Eylea/Lucentis #3 (and LogMAR VA plus OCT same visit) Eylea/Lucentis #4 (TEinj)(and Logmar VA plus OCT same visit AFTER INJECTION #4 data goes off to be reviewed immediately as a. TREAT AND EXTEND assessment the next interval will depend on the response to the loading phase NB -DMO patients majority (95%) will need 6 injctions x 1/12 of Lucentis OR Eylea 5 x 1/12 then 8 weekly. ONCE STABLE for 3 x injection in TE phase VIRTUAL CLINIC MONITORING OF MACULOPATHY AND PRN RETREATMENT FACE TO FACE CLINICS RUNNING IN PARALLEL = MAC002 every 6 months (optom or doctor) routine check for cataract/tolerance of injections/glaucoma issues etc =MAC003 (DOCTOR) for problems as needed no fixed interval;discharge/stop treatment/declines treatment/? diagnosis; CSR overlay etc/switch drugs =RV002- (DOCTOR) every 6 months =DM002 (DOCTOR) variable interval determined by last assessing doctor First visit at 6 months from 1 st injection if mild NPDR Otherwise determined by retinopathy generally

64 Pathways too many directions??? Better that than.

65 Thank you