Impact of a nationwide screening program for Diabetic retinopathy

Treatment options in CI-CSME in DME

Somdutt Prasad MS FRCSEd FRCOphth FACSConsultant Ophthalmologist

AMRI Medical Centre & Fortis Medical CentreKolkata, Indiawww.somduttprasad.com

sprasad@rcsed.ac.uk +91 7044 06 7754

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Diabetes1550 BC - Ebers Papyrus of ancient Egypt171 million worldwideIndia 2000 - 31.7 million366 million in 2030Maximum increase in India79.4 million India42.3 million China

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DME patient population is younger than nAMD patients, and has many associated co-morbid conditions1. Petrella RJ, et al. J Ophthalmol 2012;1591672. Bandello F. Presented at COPHy 2014, Lisbon, PortugalAverage age at diagnosisDME patients are of working age and require long-term management80 years2AMD50-60 years1,2DME

Disease driven byAgeDiabetes2DME patients often present with co-morbidities

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OCT possibleTreat Macula to stabilityPhaco + IOL (Hydrophobic Acrylic)Use topical NSAIDs pre and post opMonitor Retina

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American Journal of Ophthalmology2014 157, 505-513.e8DOI: (10.1016/j.ajo.2013.11.012)

9Diabetic macular edema (DME) treatment flow diagram. Treatment should be given according to the Early Treatment for Diabetic Retinopathy Study (ETDRS) guidelines in patients without center involvement, and in patients with center involvement but with vision better than 20/30. Antivascular endothelial growth factor (anti-VEGF) treatment is recommended in patients with center involvement and vision 20/30 or worse. OCT= optical coherence tomography; VA= visual acuity.

Avastin

Ziv Aflibercept or Zaltrap

Aflibercept or EyeLea

RanibizumabLucentis / AccentrixBiosimilar Razumab - IndiaConbercet - China

Intravitreal Anti-VEGFs in DME

First-line treatment of DME preferentially involves anti-VEGF therapy1,2

Laser photocoagulationRanibizumabCorticosteroidsDME, diabetic macular edema; VEGF, vascular endothelial growth factor1. Messenger WB, et al. Drug Des Devel Ther 2013;7:425-34; 2. Ford JA, et al. BMJ Open 2013;3:e002269; 3. www.intechopen.com/download/pdf/29195Early-onset disease3

Chronic disease3

Corticosteroids may be considered for chronic disease that is refractory to ranibizumab and / or laser photocoagulation

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Ozurdex (Allergan, Irvine, CA, USA): dexamethasone (DEX) posterior segment drug delivery systemInjectable, biodegradable intravitreal implant with needle applicator4Designed to provide sustained delivery of DEX4Approved in Europe and the US for the treatment of macular edema following BRVO or CRVO and for the treatment of non-infectious posterior segment uveitis5,6Approved in the US (since June 2014) and EU (since August 2014) for DME5,6Intravitreal corticosteroid implants in DME Iluvien (Alimera, Alpharetta, GA, USA): fluocinolone acetonide (FAc) intravitreal implantInjectable, non-erodible intravitreal implant with needle applicator1 Designed to deliver a low dose of FAc over an extended period1Approved as second-line therapy in several European countries for treatment of vision impairment associated with chronic DME insufficiently responsive to available therapies1,2Not approved by the US FDA due to concerns regarding benefit-to-risk and safety profiles3BRVO, branch retinal vein occlusion; CRVO, central retinal vein occlusion; FDA, Food and Drug Administration; DME, diabetic macular edema; DEX, dexamethasone1. Iluvien. UK Summary of Product Characteristics, 2014; 2. Sanford M. Drugs 2013;73:187-93; 3. investor.alimerasciences.com/releasedetail.cfm?ReleaseID=798338;4. London NJS, et al. Adv Ther 2011;28:351-66; 5. Ozurdex. US Prescribing Information, 2014; 6. Ozurdex. EU Summary of Product Characteristics, Aug 26, 2014

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Core studyExtension study (Ranibizumab 0.5 mg PRN)

+8.0+6.7+6.0RESTORE EXTENSION STUDY:Mean change in BCVA from baselineSafety set (last observation carried forward)BCVA: best-corrected visual acuity; ETDRS: early treatment diabetic retinopathy study; PRN: pro re nata; SE: standard errorIn patients treated with ranibizumab in the core phase, mean BCVA gain at Month 12 was maintained from Month 12 to Month 36 In patients treated with laser alone in the core phase, mean BCVA progressively improved from Month 12 to Month 36 with ranibizumab treatmentMitchell P et al. AAO Nov 2012 PO532Novartis data on file

Source:CSR (CRFB002D2301E1), and PTT 14.2-1.2 page 270 and 400-435

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Mean change in CRT from baseline over timeSafety set (last observation carried forward)CRT: central retinal thickness; PRN: pro re nata; SE: standard errorCore studyExtension study (Ranibizumab 0.5 mg PRN)In patients treated with ranibizumab in the core phase, mean CRT decrease at Month 12 was maintained from Month 12 to Month 36In patients treated with laser alone in core phase, mean CRT observed at Month 12 decreased from Month 12 to Month 36 with ranibizumab treatment in the extension phase-127.8-139.7-63.3-142.1-145.9-142.7-140.6-129.1-126.6

Mitchell P et al. AAO Nov 2012 PO532Novartis data on file

Source:CSR (CRFB002D2301E1), PTT 14.2-4.2 page 2915-2934

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RETAIN Study:T&E regimen is a feasible treatment option for DME patients who require long-term Rx & follow-upCMH test (row mean scores statistic) with the observed values as scores; Full analysis set (MV/LOCF, mean value interpolation/last observation carried forward)8.36.58.1MonthsMean change (SE) in BCVA from baseline (ETDRS letters)RETAIN: first study to demonstrate non-inferiority of a T&E regimen to PRN dosing in DME

BCVA, best-corrected visual acuity; ETDRS, early treatment diabetic retinopathy study; MV/LOCF, mean value interpolation/last observation carried forward; PRN pro re nata; RBZ, ranibizumab; T&E, treat and extend

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Protocol T: 2Yr Results

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Similar VA gains in overall population between aflibercept and ranibizumab at 2 yearsMean change from baseline in visual acuity letter score

252025105004812162024283236404448526884104

AfliberceptBevacizumabRanibizumabWeek+12.8+12.3+10.0At Year 1, the improvement was greater, but not clinically meaningful, with aflibercept than with the other two drugs.1 At Year 2, the difference in VA gain between aflibercept and ranibizumab was no longer significant (p = 0.47), indicating that a dose of ranibizumab that is 60% of the 0.5 mg ex-U.S. approved dose produced equivalent VA gains over 2 years to the full aflibercept 2.0 mg dose.21. Wells JA, et al. NEJM 2015;372:1193-203; 2. Wells JA, et al. . Ophthalmology 2016;XX:1-9 http://dx.doi.org/10.1016/j.ophtha.2016.02.022

+13.5+11.5+10.0

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No significant difference in the proportion of patients with 10- or 15-letter gains between aflibercept and ranibizumab at 2 yearsp = 0.22p = 0.50p = 0.51p = 0.49p = 0.15p = 0.39p = 0.70p = 0.70p = 0.70p = 0.84p = 0.84p = 0.84There were no significant differences in the proportion of patients that had a 10 or 15-letter improvementor worseningProportion of patients with 10- or 15-letter gain or lossWells JA, et al. . Ophthalmology 2016;XX:1-9 http://dx.doi.org/10.1016/j.ophtha.2016.02.022

The 2-year analyses mimicked the 1-year analyses. The primary analysis consisted of three pairwise comparisons of mean visual acuity change from baseline in the 3 treatment groups using an analysis of covariance model, adjusted for baseline visual acuity, with the Hochberg method used to control overall type I error. The primary analysis followed the intention-to-treat principle and included all randomized eyes. Multiple imputation was used to impute missing 2-year visual acuity data. Outlying values were truncated to 3 standard deviations from the mean.

Treatment group comparisons are from ANCOVA models adjusted for continuous baseline visual acuity or from binomial regression models adjusted for categorical baseline visual acuity. Reported P-values have been adjusted for multiple treatment group comparisons to account for an overall Type 1 error rate of 0.049 (see Hochberg for computation of the Hochberg-adjusted P-values2) and corresponding (1-/i)*100% confidence intervals were reported, where i is the rank (1, 2, or 3) of the Hochberg-adjusted P-value from among the descending ordered raw pairwise P-values. This could result in identical P-values for all three pairwise comparisons.

Tests for treatment group interaction with baseline visual acuity from ANCOVA model for mean change in visual acuity adjusted for baseline visual acuity (using the multiple imputation datasets and computing the P-value associated with the average of the F statistics from each imputed dataset):P-value for interaction, treating baseline visual acuity as continuous = 0.02P-value for interaction, treating baseline visual acuity as categorical (69) = 0.11

Visual acuity change truncated using 1 year mean +/- 3SD (-22 and +44) to minimize the effects of outliers for 6 eyes in the aflibercept group (3 on the positive end, 3 on the negative end) , 5 eyes in the bevacizumab group (1 on the positive end , 4 on the negative end), and 4 eyes in the ranibizumab group (1 on the positive end , 3 on the negative end). 2-year visit data unavailable for 23 eyes in the aflibercept group, 33 eyes in the bevacizumab group, and 27 eyes (including one eye which had a 2 year visit but was missing visual acuity at the visit) in the ranibizumab group. Descriptive statistics were based on observed data; Markov chain Monte Carlo multiple imputation3 (100 imputations) was used to estimate the missing 2 year change in visual acuity for the treatment group comparisons (including tests for interaction).19

No difference in injection frequency over 2 yearsacross the three treatment armsAfliberceptBevacizumabRanibizumabp valueafliberceptranibizumabTotal no. of injections in Year 11*(maximum = 13)N = 208N = 206N = 206Mean (standard deviation)9.2 (2.0)9.7 (2.3)9.4 (2.1)Median (25th, 75th percentile)9 (8, 11)10 (8, 12)10 (8, 11)0.19Total no. of injections in Year 22N = 201N = 185N = 192**Mean (standard deviation)5.0 (3.4)5.5 (3.9)5.4 (3.8)Median (25th, 75th percentile)5 (2, 7)6 (2, 9)6 (2, 9)0.32Total no. of injections over 2 years2N = 201N = 185N = 192**Mean (standard deviation)14.2 (4.6)15.3 (5.3)14.8 (5.0)Median (25th, 75th percentile)15 (11, 17)16 (12, 20)15 (11, 19)0.08

See notes for table key and footnotes1. Wells JA, et al. NEJM 2015;372:1193-203; 2. Wells JA, et al. . Ophthalmology 2016;XX:1-9 http://dx.doi.org/10.1016/j.ophtha.2016.02.022

*Only includes participants that completed the 1 year visit.Seven ranibizumab eyes received 1 injection and 2 ranibizumab eyes received 2 injections of 0.5 mg of ranibizumab prior to the FDA approving a 0.3mg dosage of ranibizumab for DME treatment.Global (overall 3 group comparison) P-value from Kruskal-Wallis Test: P=0.045. Pairwise comparisons from Wilcoxon Rank Sum Test (adjusted for multiple comparisons by taking the maximum of the global and pairwise comparison P-values): aflibercept-bevacizumab: P=0.045, aflibercept-ranibizumab: P=0.19, bevacizumab-ranibizumab: P=0.22**1 ranibizumab eye had 3 injections of commercial ranibizumab (not through the study). These injections are not counted in the injection counts, and 2 of these are counted as injections required but not given via the protocol system. Global (overall 3 group comparison) P-value from Kruskal-Wallis Test for number of injections in the given time interval.Seven ranibizumab eyes received 1 injection and 2 ranibizumab eyes received 2 injections of 0.5 mg of ranibizumab prior to the FDA approving a 0.3mg dosage of ranibizumab for DME treatment.20

Percentage of laser treatments over 2 yearsAfliberceptBevacizumabRanibizumabp value afliberceptranibizumabN = 208N = 206N = 206At least one focal/grid photocoagulation laser treatment between 24 weeks and 1 year1*, %37%56%46%0.058N = 201N = 185N = 192At least one focal/grid photocoagulation laser treatment in Year 22, %20%31%27%0.12At least one focal/grid photocoagulation laser treatment over 2 years2, %41%64%52%0.04

See notes for table key and footnotes1. Wells JA, et al. NEJM 2015;372:1193-203; 2. Wells JA, et al. . Ophthalmology 2016;XX:1-9 http://dx.doi.org/10.1016/j.ophtha.2016.02.022

*Only includes participants that completed the 1 year visit.Seven study eyes received 1 injection and 2 eyes received 2 injections of 0.5 mg of ranibizumab prior to the FDA approving a 0.3mg dosage of ranibizumab for DME treatment.Global (overall 3 group comparison) P-value from Fishers Exact Test for proportion with no laser versus any laser prior to 1 year: P