Incorporating the
`Latest Findings From
`Clinical Trials Into the
`Management of
`Diabetic Retinopathy
`for the Comprehensive
`Ophthalmologist
`
`Diana Do MD
`Course #235
`Sunday, October 25
`2:00 – 3:00 PM
`West 3018
`
` 2009 American Academy of Ophthalmology. All rights reserved.
`
`Samsung Bioepis Exhibit 1023 - Page 1
`Biocon Exhibit 1023 - Page 1
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`
`Latest Findings From
`Clinical Trials Into the
`Management of
`Diabetic Retinopathy
`for the Comprehensive
`Ophthalmologist
`
`Diana Do MD
`Course #235
`Sunday, October 25
`2:00 – 3:00 PM
`West 3018
`
` 2009 American Academy of Ophthalmology. All rights reserved.
`
`Samsung Bioepis Exhibit 1023 - Page 1
`Biocon Exhibit 1023 - Page 1
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`I.
`
`Course Outline:
`Diagnosis and Management of Non-Proliferative Diabetic
`Retinopathy
`David Telander, MD, PhD
`UC Davis
`
`Update on glycemic control and retinopathy
`a. Epidemiology Reminders:
`i. 18.2 million American have diabetes
`1. 5.2 million don't know they have it.
`ii. Type 2 diabetes accounts for up to 95% of all diabetes
`1. 8% of the population aged 20 and older.
`2. 18.6% of the population 60 years and older
`3. The prevalence of type 2 diabetes has tripled in the last 30
`years, much of it due to an increase in obesity
`4. Only 50% of patients with diabetes receive regular dilated eye
`examinations, and many patients go blind without treatment
`iii. WESRC
`1. Wisconsin Epidemiologic Study of Diabetic Retinopathy
`(WESDR) -- valuable prevalence and risk factors information.
`In the younger-onset group (diagnosis of diabetes < 30 yrs and
`taking insulin -- presumably type 1), retinopathy, either
`proliferative or non-proliferative, was seen in 13% of patients
`with less than a 5-year duration of diabetes and in 90-98% of
`patients with a duration of 10 to 15 years. Type 2 group (older
`onset) was 29% at 5 years and 78% at 15 years.
`
`2.
`
`3.
`b. Glycemic control and retinopathy?
`i. Glycemic fluctuations vs. HgbA1C
`ii. DCCT: Key Facts (Reminders):
`1. Showed 3-year risk of developing retinopathy was reduced by
`75% in the intensive insulin treatment group compared with the
`standard treatment group
`2. With existing retinopathy -- 50% reduction in the rate of
`progression of retinopathy compared with controls
`3. When stratified by hemoglobin A1C (HbA1C) levels, there was a
`35% to 40% reduction in the risk of retinopathy progression for
`every 10% decrease in HbA1C (e.g., from 8% to 7.2%).
`iii. UKPDS – similar data for type 2 DM
`iv. Recommended Goal by the ADA to have HbA1C level below 7%
`
`c. What is the Role of Genetics in determining a patient’s susceptibility to
`nonproliferative diabetic retinopathy?
`1. Epidemiology Studies:
`
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`2. Genetic Poiymorphisms: identifying specific markers will refine
`our screening algorithms and interventions in patients such as
`high risk patients
`
`Promising Genetic Markers Associated with Any Diabetic Retinopathy (i.e. Risk Markers)
`Genetic Marker
`Polymorphism
`Reference
`Awata26
`-634CC
`VEGF genotype
`Demaine35
`(CA)n repeat; Z-2/X where X is any allele other than Z+2
`Aldose Reductase promoter
`Rietveld24
`(CA)n : Heterozygosity for the 192- or 194 base pair alleles
`IGF-1 promoter
`G-888C
`Szaflik, J.P.
`SDH promoter
`haplotypes 112 (Glu298/4b/-786C) and 222 (Asp298/4a/-
`Ezzidi, I
`eNOS promoter
`786C)
`*=at position 634 relative to the transcription start of the VEGF gene, C is present on both alleles
`
`ii. Update on influence of other co-morbidities
`1. Hypertension
`a. UKPDS: Tight blood pressure control resulted in a 37%
`reduction in microvascular diseases, predominantly
`reduced risk of retinal photocoagulation, when compared
`to less tight control
`b. Promise in the renin-angiotension aldosterone system
`inhibitors – inhibitors in this pathway to decrease BP
`effective in limiting retinopathy
`2. Hyperlipidemia
`a. WESDR, a population-based study, and the ETDRS
`found that elevated levels of serum cholesterol were
`associated with increased severity of retinal hard
`exudates
`b. Elevated serum triglyceride levels were also associated
`with a greater risk of developing high-risk PDR in the
`ETDRS patients
`3. Renal Disease: proteinuria and increased BUN is a predictor of
`retinopathy
`4. Pregnancy: q 3 month screening.
`
`iii. Screening Schedules:
`
`Eye examination schedule
`Time of onset of diabetes
`mellitus
`Less than 30 years of age
`Age 30 and older
`Before pregnancy
`
`Recommended time for first
`examination
`5 years after onset
`At time of diagnosis
`Before or soon after conception
`
`Routine minimum follow-
`up
`Annually
`Annually
`At least every 3 months
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`Recommended follow-up schedule
`Status of retinopathy
`No retinopathy or microaneurysms only
`Mild/moderate NPDR without macular edema
`Mild/moderate NPDR with macular edema that is not clinically significant
`Mild/moderate NPDR with clinically significant macular edema
`Severe/very severe NPDR
`
`Follow-up (months)
`12
`6 to 12
`4 to 6
`3 to 4
`3 to 4
`
`1.
`
`In UK, out of 15,080 pt with DM only 479 (3%) were referred to
`ophthalmologist and 80% of these had DR.
`2. Tele-imaging – Many advances and many advantages
`
`II.
`
`III.
`
`Recognizing severe non-proliferative diabetic retinopathy and its importance
`a. Reminders: Classification
`i. Mild nonproliferative diabetic retinopathy
`1. Microaneurysms only
`ii. Moderate nonproliferative diabetic retinopathy
`1. More than just microaneurysms but less than severe
`nonproliferative diabetic retinopathy
`iii. Severe nonproliferative diabetic retinopathy
`1. Any of the following:
`a. More than 20 intraretinal hemorrhages in each of four
`quadrants
`b. Definite venous beading in more than two quadrants
`c. Prominent intraretinal microvascular abnormalities in
`more than one quadrant and no signs of proliferative
`retinopathy
`
`Management of severe non-proliferative diabetic retinopathy
`a. Early PRP laser or observation: Diabetic Retinopathy Study (DRS)
`b. Analyses of ETDRS data have suggested that early scatter treatment is
`particularly effective in reducing severe visual loss in patients with type 2
`diabetes. These data provide an additional reason to recommend early
`scatter photocoagulation in older patients with very severe NPDR.
`
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`QuickTime™ and a
`decompressor
`are needed to see this picture.
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`c.
`
`d. Diabetic Macular Edema: see following sections
`e. Macular Ischemia
`f. Medical Management for severe NPDR
`i. Aspirin
`ii. protein kinase C (PKC) β inhibitor – ruboxistaurin—
`1. Though successful in animal studies and smaller clinical
`studies, the drug showed only marginal success in initial clinical
`trials
`2. More recent data continues to show benefit
`iii. Advanced Glycosylation End Product Inhibitors
`iv. Statins
`v. Antioxidants
`vi. Anti-VEGF
`vii. renin-angiotensin blockade
`1. DIRECT study using oral candesartan 32 mg daily
`
`References:
`Abhary S, Hewitt A, Burdon K, Craig J. A systematic meta-analysis of genetic association studies
`for diabetic retinopathy. Diabetes. 2009 Jul 8. [Epub ahead of print]
`
`Chew EY, Klein ML, Ferris FL III et al. Association of elevated serum lipid levels with retinal hard
`exudate in diabetic retinopathy. Arch Ophthalmol 1996; 114:1079-1084
`
`Ferris F. Early photocoagulation in patients with either type I or type II diabetes. Trans Am
`Ophthalmol Soc 1996; 94:505-537
`
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`Jyothi S, Elahi B, Srivastava A, Poole M, Nagi D, Sivaprasad S. Compliance with the quality
`standards of National Diabetic Retinopathy Screening Committee. Prim Care Diabetes. 2009
`May;3(2):67-72. Epub 2009 Jun 18.
`
`Klein BE. Overview of epidemiologic studies of diabetic retinopathy. Ophthalmic Epidemiol. 2007
`Jul-Aug;14(4):179-83. Review.
`
`Klein BEK, Moss SE, Klein R et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy.
`XIII. Relationship of serum cholesterol to retinopathy and hard exudates. Ophthalmology 1991;
`98:1261-1265.
`
`Klein R, Klein BEK, Moss SE et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy.
`II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years. Arch
`Ophthalmol 1984; 102:520-526.
`
`Centers for Disease Control (www.cdc.gov/diabetes/news/docs/dpp.htm)
`
`McGill JB Improving microvascular outcomes in patients with diabetes through management of
`hypertension.. Postgrad Med. 2009 Mar;121(2):89-101. Review.
`
`Moss S, Klein R, Klein B. Factors associated with having eye examinations in persons with diabetes.
`Arch Fam Med 1995; 4:529-534
`
`Wright AD, Dodson PM. Diabetic retinopathy and blockade of the renin-angiotensin system: new
`data from the DIRECT study programme. Eye. 2009 Jul 24.
`
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`2009 Meeting of the American Academy of Ophthalmology
`
`Anti VEGF Therapies forAnti-VEGF Therapies for
`
`
`Diabetic Macular EdemaDiabetic Macular Edema
`
`Quan Dong Nguyen MD MScQuan Dong Nguyen, MD, MSc
`
`Wilmer Eye Institute
`Johns Hopkins University
`School of Medicine
`
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`Financial Disclosure
`Johns Hopkins University, the employer
`
`of Dr Nguyen has received researchof Dr. Nguyen, has received research
`funding from the National Eye Institute,
`Genentech, and Regeneron., g
`
`
`
`Dr. Nguyen receives the Physician
`Scientist Award from the Research to
`Prevent Blindness Foundation.
`
`This presentation will discuss the off-
`
`l b llabel use of ranibizumab and VEGF Trap f ibi b d VEGF T
`
`
`
`
`Eye for diabetic macular edema.
`
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`READ 2 Study:
`Ranibizumab for Edema of the
`
`mAcula in DiabetesmAcula in Diabetes
`
`Preliminary One Year Updates
`
`
`
`
`
`QQuan Dong Nguyen, MD, MSc, Jeffrey S. Heier, MD, Syed D N MD MS J ff S H i MD S d
`Mahmood Shah, MB BS, Diana V. Do, MD, Jennifer Lim, MD,
`David Boyer, MD Prema Abraham, MD, Pravin Dugel, MD, and
`Peter Campochiaro, MD
`for
`the READ-2 Research Group
`
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`The READ-2 Study is sponsored by the
`Juvenile Diabetes Research Foundation
`
`The study drug, ranibizumab, is
`
`provided by Genentech, Inc.p y ,
`
`
`
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`New England New England
`
`
`Retina Retina
`
`ConsultantsConsultants
`
`
`
`Ophthalmic Ophthalmic Ophthalmic Ophthalmic
`
`Consultants Consultants
`
`of Bostonof Boston
`
`Rush Rush
`
`
`UniversityUniversity
`
`MidwestMidwest
`
`Eye InstituteEye Institute
`
`Eye Care Eye Care Eye Care Eye Care
`
`
`
`
`SpecialistsSpecialists
`
`Wilmer Wilmer
`
`Eye InstituteEye Institute
`
`
`
`East Bay Retina ConsultantsEast Bay Retina Consultants
`
`Black Hills Black Hills
`
`
`Regional Regional
`
`
`
`Eye InstituteEye InstituteEye InstituteEye Institute
`
`Retina Consultants Retina Consultants
`University of Southern University of Southern
`
`
`CaliforniaCalifornia
`
`of Nevadaof Nevada
`
`Retina Institute Retina Institute
`
`University of University of
`
`
`
`of Californiaof Californiaof Californiaof California
`
`
`
`New MexicoNew MexicoNew MexicoNew Mexico
`
`RetinaRetina--Vitreous Vitreous
`
`
`Retina Consultants Retina Consultants
`
`Associates Associates
`
`of Arizonaof Arizona
`
`Medical GroupMedical Group
`
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`The READ 2 Research Group
`
`READ-2 Executive Committee
`Peter Campochiaro, MD
`Jeffrey Heier, MD
`Jennifer Lim, MD
`Quan Dong Nguyen, MD, MSc
`
`READ-2 DSMCREAD 2 DSMC
`
`Brian P. Conway, MD
`David Wilson, MD
`
`READ 2 R diREAD-2 Reading CenterC t
`
`
`Syed Mahmood Shah, MBBS and the
`Retinal Imaging Research and
`Reading Center at Wilmer
`
`READ-2 Coordinating Center
`Afsheen Khwaja, MD
`Mohamed Ibrahim, MD
`
`Kashif Janjua, MDKashif Janjua, MD
`Gulnar Hafiz, MD, MPH
`Velma Pack, BA
`
`READ-2 Principal
`
`Investigatorsg
`Prema Abraham, MD
`David Boyer, MD
`Thomas Chang, MD
`Thomas Ciulla, MD
`Arup Das, MD
`Diana V. Do, MD
`
`Pravin Dugel MDPravin Dugel, MD
`Dean Eliott, MD
`Bradford Foster, MD
`
`Jeffrey Heier, MDy ,
`
`Eric Kruger, MD
`Eugene Lit, MD
`Jonathan Pollack, MD
`Alan Thach, MD
`
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`READ-2READ-2
`
`Study Design and Objectives
`
`• Evaluate the effects of intravitreal
`ibiranibizumab (0.5 mg) compared to b (0 5 ) d t
`
`
`
`
`– Focal laser
`– Combination of ranibizumab + focal laser
`– Subjects with DME
`
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`Key Eligibility Criteria
`
`Age 18 ears• Age 18 years
`
`
`
`• BCVA (Snellen equivalent) 20/40 to 20/320BCVA (Snellen equivalent) 20/40 to 20/320
`
`
`
`• DME with retinal thickness ≥ 250 µm on OCTµ
`
`• Prior treatment allowed if:
`
`FFocal laser ≥ 3 monthsl l ≥ 3 th
`
`
`
`Intraocular steroids ≥ 3 months
`Panretinal photocoagulation ≥ 3 monthsg
`
`Vitrectomy surgery ≥ 3 months
`Anti-angiogenic agents ≥ 2 months
`
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`Study DesignStudy Design
`
`Patients with DMEPatients with DME
`
`N = 126
`
`Randomization 1:1:1
`
`Group 1
`Ranibizumab
`(0.5mg)
`
`Group 2
`
`Focal LaserFocal Laser
`
`Group 3
`Ranibizumab
`
`(0 5mg)(0.5mg)
`Focal Laser
`
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`READ 2 Treatment Design
`
`0
`
`1
`
`2
`
`3
`
`4
`
`5
`
`Month
`6
`7
`
`8
`
`9
`
`10 11 12
`
`23 24
`
`Group 1
`Ranibizumab
`
`Group 2
`
`LLaser
`
`Group 3
`
`R ibiRanibizumabb
`+
`Laser
`
`
`
`or
`
`at investigator’s
`
`discretiondiscretion
`
`= ranibizumab
`
`= laser
`
`Primary Outcome
`
`Retreat if OCT ≥ 250µm
`
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`Baseline CharacteristicsBaseline Characteristics
`
`Group 1Group 1
`
`Ranibizumab
`(n=42)
`
`Group 2Group 2
`
`Laser
`(n=42)
`
`30.9%
`76.2%
`
`62 562.5
`24.3
`
`
`
`20/8020/80
`
`204.2
`
`7.39
`
`45.2%
`64.3%
`
`62 162.1
`27.7
`
`
`
`20/80+220/80
`
`224.1
`
`7.58
`
`Group 3
`Ranibizumab
`+ Laser
`(n=42)
`47.6%
`69.1%
`
`62 162.1
`25.1
`
`
`
`20/8020/80
`
`256.6
`
`7.76
`
`Gender (% women)
`Race (% white)
`
`Age (mean years)Age (mean years)
`Mean VA (letters read)
`Mean VA (~Snellen
`equivalent)
`Mean Excess Foveal
`Thickness (µm)
`Hemoglobin A1C
`
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`READ-2 Updates at Month 12READ 2 Updates at Month 12
`
`• Analyses were performed on 115 patients for• Analyses were performed on 115 patients for
`
`the 6-month results
`
`• 112 of 126 participants have remained in the
`
`Study at month 12Study at month 12
`• 10 patients have discontinued from the study
`• 4 patients missed month 12 visits
`• Analysis being done, including LOCF, for 116 subjects
`
`P li• Preliminary data analyses of the 12-month i d t l f th 12 th
`
`
`
`
`results are being presented
`
`
`
`
`
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`Visual Acuity and
`OCT Results
`
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`Month 6
`
`Change in Visual Acuity from BaselineChange in Visual Acuity from Baseline
`Ranibizumab
`group gained
`7.62 letters
`
`Combination
`group gained
`3.8 letters
`
`Laser group
`lost 1.07
`
`lettersletters
`
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`Month 6
`
`IImprovement in Visual Acuity (≥ 3 Lines)t i Vi l A it (≥ 3 Li )
`
`24%
`
`RanibizumabRanibizumab
`group
`
`
`
`
`
`12%%
`Combination
`group
`
`0%
`Laser group
`
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`Month 6
`
`Mean Change in Excess Retinal ThicknessMean Change in Excess Retinal Thickness
`
`Laser groupLaser group
`
`had reduction
`of 11%
`
`Ranibizumab groupRanibizumab group
`
`had reduction of
`57%
`
`Combination
`group had
`reduction of
`42%
`
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`Month 12
`Visual Acuity and
`OCT Results
`
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`Month 12 Results:
`
`Di t ib tiDistribution of Treatment Subtype f T t t S bt
`
`
`
`among Three Groups
`
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`Month 12: Mean Change in Visual
`
`A itAcuity from Baseline f B li
`
`
`
`
`Ranibizumab
`
`+6.46
`
`+4.48
`
`
`
`2 08+2.08
`
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`Month-12: Excess Central Foveal
`
`ThicknessThickness
`
`Ranibizumab
`
`Ranibizumab
`
`0=212µm
`
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`
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`Safety ResultsSafety Results
`
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`SafetySafety
`
`St d• Study conduct monitored by the DSMCd t it d b th DSMC
`
`
`
`
`• No drug/laser-related serious ocular
`adverse events
`• No drug/laser-related serious systemic g y
`
`adverse events
`
`
`
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`Summary
`• Treatment of DME for 6 months with ranibizumab produces
`greater gain in visual acuity and a greater reduction of
`
`excess retinal thickening compared toexcess retinal thickening compared to
`– Laser photocoagulation
`– Combination of ranibizumab plus laser
`
`• During months 6-12, patients in the laser and combination
`groups were switched to ranibizumab
`
`• Patients who were randomized to ranibizumab during the
`first 6 months showed no additional improvement between
`months 6 and 12 in visual acuity or excess retinal thickness
`– More frequent treatments with ranibizumab may be necessary to
`enhance benefits
`
`L• Long term follow-up is necessary to determine if benefits t f ll i t d t i if b fit
`
`
`
`
`from ranibizumab are sustained
`
`
`
`
`
`
`
`
`
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`VEGF Trap-Eye
`for DME
`
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`VEGF Trap-Eye
`
`Specifically Designed to Block VEGFSpecifically Designed to Block VEGF
`Fusion protein of key domains
`from human VEGF receptors 1 and
`
`2 with human IgG Fc2 with human IgG Fc
`
`VEGFR1 VEGFR2
`
`Fc portion of IgG
`
`VEGF Trap-Eye
`
`Blocks all VEGF-A isoforms and
`placental growth factor (PlGF)
`
`High affinity - binds VEGF-A and
`PlGF more tightly than native
`receptors p
`
`
`Contains all human amino acid
`sequences
`
`Penetrates all layers of the retina
`(MW ~110,000)
`
`VEGF Trap-Eye is speciallyVEGF Trap Eye is specially
`
`purified and formulated for
`intravitreal injection
`IgG=immunoglobulin G; MW=molecular weight
`
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`VEGF Trap-Eye DME Phase 1:
`Study Design
`
`O• Open label, 5 patientsl b l 5 ti t
`
`
`
`• Single intravitreal injection of 4 mg VEGF Trap-Eye
`
`• Patients followed for 6 weeks for safety BCVA• Patients followed for 6 weeks for safety, BCVA,
`centerpoint retinal thickness on OCT
`
`• Key eligibility criteriay g y
`
`
`– BCVA score of 73 to 24 letters (20/40 to 20/320)
`– DME with retinal thickness at the center point ≥250 microns
`
`– Prior treatment allowed:– Prior treatment allowed:
`• Focal/grid macular photocoagulation, peribulbar corticosteroids,
`or any other non-intraocular treatment of DME > 4 months
`• Intraocular steroid or anti-VEGF treatment > 6 monthsIntraocular steroid or anti VEGF treatment > 6 months
`
`• Panretinal scatter photocoagulation (PRP) > 4 months
`
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`VEGF Trap-Eye DME Phase 1:
`Study Schedule
`
`Day 1
`
`Day 3 Wk 1
`
`Wk 2 Wk 3 Wk 4
`
`Wk 5 Wk 6
`
`Visits
`
`4 mg
`
`VEGFVEGF
`Trap-Eye
`
`Intravitreal
`Injection
`
`Primary and
`Secondary Endpoints
`
`Patient assessment at each visit:
`• Safety
`• BCVA
`• Centerpoint retinal thickness
`• Macular volume by OCT
`
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`VEGF Trap-Eye DME Phase 1:
`
`BBaseline Characteristicsli Ch t i ti
`
`
`
`
`
`Age (years)
`Gender (M:F)
`
`Duration of Diabetes (years)Duration of Diabetes (years)
`IDDM/NIDDM
`
`Patients with Prior TreatmentsPatients with Prior Treatments
`Disease Status
`OCT Excess Retinal Thickness
`Macular Volume
`Median BCVA (Snellen equivalent)
`
`Median
`65.7
`2:3
`
`25 825.8
`4:1
`
`4*4
`
`108
`8.0
`20/50 +1
`
`Range
`56-75
`
`
`
`20 4120-41
`
`88-424
`2.6-11.6
`
`*Focal Laser (3); IVK (1); PRP, IVK (1)
`IDDM/NIDDM=insulin-dependent diabetes mellitus/non–insulin dependent diabetes mellitus;
`IVK=intravitreal Kenalog [triamcinolone acetate]
`Do DV et al. In press , BJO 2008
`
`Samsung Bioepis Exhibit 1023 - Page 34
`Biocon Exhibit 1023 - Page 34
`
`
`
`Results of Phase 1
`VEGF Trap-Eye for DME
`
`Samsung Bioepis Exhibit 1023 - Page 35
`Biocon Exhibit 1023 - Page 35
`
`
`
`VEGF Trap-Eye DME Phase 1VEGF Trap Eye DME Phase 1
`
`Safety Results
`
`• All ocular adverse events were mild and
`related to the injection procedure
`
`• No serious ocular or systemic adverse
`
`events were reportedevents were reported
`
`Do DV et al. In press , BJO 2008
`
`Samsung Bioepis Exhibit 1023 - Page 36
`Biocon Exhibit 1023 - Page 36
`
`
`
`VEGF Trap-Eye for DME
`
`Samsung Bioepis Exhibit 1023 - Page 37
`Biocon Exhibit 1023 - Page 37
`
`
`
`Intravitreal
`VEGF Trap
`4mgg
`
`Back-Up
`
`Samsung Bioepis Exhibit 1023 - Page 38
`Biocon Exhibit 1023 - Page 38
`
`
`
`VEGF Trap-Eye for DME
`
`Samsung Bioepis Exhibit 1023 - Page 39
`Biocon Exhibit 1023 - Page 39
`
`
`
`VEGF Trap-Eye
`DME Phase 1 Summary
`
`O• Open-label, short term, safety study of intravitreal l b l h f d f i i l
`
`
`
`
`VEGF Trap-Eye in eyes with DME
`
`
`
`
`
`
`
`• Single injection of 4 mg of VEGF Trap-Eye was well
`tolerated
`
`• VEGF Trap-Eye demonstrated bioactivity in DME:
`– Decreases retinal thickness
`
`– Improvement in visual acuityImprovement in visual acuity
`
`• Phase 2 clinical study underway
`
`Samsung Bioepis Exhibit 1023 - Page 40
`Biocon Exhibit 1023 - Page 40
`
`
`
`VEGF Trap-Eye
`
`DME Phase 2 St d DesignDME Phase 2 Study Design
`
`Randomized, multicenter,
`double-masked trial
`N=200
`
`Subjects randomized
`1:1:1:1:1
`
`0.5 mg q4 wks
`
`2.0 mg q4 wks
`
`2.0 mg q8 wks*
`
`2.0 mg PRN*
`
`Focal Laser
`
`Primary endpoint: Primary endpoint:
`
`
`Mean change in BCVAMean change in BCVA
`
`Treatment to Week 24 (primary
`endpoint)
`
`Secondary endpoint: Secondary endpoint:
`
`
`Change in foveal thickness Change in foveal thickness
`
`(OCT)(OCT)
`
`Continued treatment to 1 year
`
`*Following 3 monthly loading doses
`
`Samsung Bioepis Exhibit 1023 - Page 41
`Biocon Exhibit 1023 - Page 41
`
`
`
`Conclusion
`
`Potential Treatments for DME withPotential Treatments for DME with
`Anti-Angiogenic Approach
`• Ranibizumab has demonstrated bioactivity and safety
`through one year of follow up in the READ 2 study
`• Phase 3 studies of ranibizumab underwayy
`
`• VEGF Trap-Eye has demonstrated short-term bioactivity
`and safety in phase 1 studies
`
`Phase 2 studies underway• Phase 2 studies underway
`
`• Other therapeutic agents with anti-angiogenic activities in
`clinical trials
`– Sirolimus
`– PF-04522655 (siRNA)
`
`• Combination therapiesCombination therapies
`
`Samsung Bioepis Exhibit 1023 - Page 42
`Biocon Exhibit 1023 - Page 42
`
`
`
`Update on Laser for Diabetic Macular Edema
`Diana V. Do, MD
`Assistant Professor of Ophthalmology
`The Wilmer Eye Institute, The Johns Hopkins University
`
`ETDRS Laser:
`
` Reduced risk of at least moderate visual acuity loss (most cases enrolled had
`mild or moderate non-proliferative DR)
`
`• CSME immediate focal: 15% by 3 years
`
`• CSME deferred focal: 30% by 3 years
`
`• ME, not CS, immediate focal: 8% by 3 years
`
`• ME, not CS, deferred focal: 14% by 3 years
`
` Increased chance of moderate visual acuity gain (if 20/40 or worse and fovea
`involved) from 5% (deferred) to 17% (immediate rx)
`
`Laser Technique:
`
`Part 1 (focal): Direct treatment to microaneurysms (MAs):
`50 – 100 micron spot
`•
`Intensity: change color of MA or retina around MA
`•
`• Duration: 0.05 – 0.10 second
`Location: areas of edema
`•
`
`Part 2 (Grid): Scatter (“grid”) to areas of edema not associated with MAs:
`50 – 100 micron spot
`•
`1 to 2 burn widths apart
`•
`Intensity: change color of retina or MA
`•
`• Duration: 0.07 – 0.10 second
`
`Samsung Bioepis Exhibit 1023 - Page 43
`Biocon Exhibit 1023 - Page 43
`
`
`
`DRCR Study: Focal Laser vs. Intravitreal Triamcinolone for DME
`
`Re-treatment (within 4 wks) unless any of the following:
`
`• Treatment successful
`
`• Substantial improvement in macular edema
`
`• Adverse events or maximal treatment
`
`• Further treatment appears futile
`
`Efficacy Outcomes:
` Primary outcome assessment at 2 years
` Primary measure: Visual acuity (VA)
`• Scientific objective: Mean change in VA
`• Regulatory objective for FDA: Proportion with decrease in VA letter score
`> 15
` Secondary measure: Retinal thickening on OCT
`
`Major Eligibility Requirements:
` At least 18 years old
` Type 1 or type 2 diabetes
` Center-involved DME confirmed on OCT
`
`Samsung Bioepis Exhibit 1023 - Page 44
`Biocon Exhibit 1023 - Page 44
`
`
`
`(central subfield thickness >250 microns)
`•
` Best-corrected VA letter score 73 to 24
`(Snellen equivalent 20/40 to 20/320)
`•
`
`Baseline characteristics
` Mean age: 63 years
` Diabetes type: 5% type 1, 95% type 2
` Visual acuity (Snellen equivalent)
`20/40 to 20/63: 58%
`•
`• Worse than 20/63 to better than 20/200: 38%
`20/200 to 20/320: 5%
`•
` OCT central subfield thickness
`• Mean: 424 microns
`Range: 133 to 1164 microns
`
`Primary Outcome: Mean Change in BCVA at 2 years
`
`Samsung Bioepis Exhibit 1023 - Page 45
`Biocon Exhibit 1023 - Page 45
`
`
`
`Change in OCT central subfield Thickness
`
`ADVERSE EVENTS:
`
`IOP elevation
`
`Laser group
`
`1mg IVT
`
`4mg IVT
`
`≥10mmHg rise
`
`>30mmHg rise
`
`4%
`
`1%
`
`16%
`
`9%
`
`33%
`
`21%
`
`Samsung Bioepis Exhibit 1023 - Page 46
`Biocon Exhibit 1023 - Page 46
`
`
`
`Cataract Surgery
`
`Laser group
`
`1mg IVT
`
`13%
`
`23%
`
`4mg IVT
`
`51%
`
`CONCLUSIONS:
`
` VA benefit in 4 mg IVT group at 4 months consistent with published case series
`
` However, no difference in VA between 4 mg IVT and laser group by 1 year
`
` Greater VA benefit and fewer side effects (IOP and cataract) in laser group at 2
`years, and sustained effect thru 3 years
`
` OCT results mirrored VA results
`
` Results re-affirm importance of laser in management of DME
`
` Focal/grid should be used for DME regardless of:
`
` Baseline visual acuity
`
` Baseline CSF thickness
`
` Prior macular photocoagulation for DME
`
` Phakic or pseudophakic
`
` Focal/grid currently benchmark for clinical trials for DME
`
`
`
`Samsung Bioepis Exhibit 1023 - Page 47
`Biocon Exhibit 1023 - Page 47
`
`
`
`Diagnosis of Diabetic Macular Edema
`
`Sophie J. Bakri, MD
`Associate Professor of Ophthalmology
`Vitreoretinal Diseases and Surgery
`Mayo Clinic
`Rochester, MN
`
`Diabetic macular edema (DME) is the commonest cause of visual loss in diabetic
`retinopathy. It is important to accurately diagnose it, quantify its extent and differentiate
`it from other entities.
`
`The gold standard for diagnosing DME has been to perform slit lamp biomicroscopy of
`the posterior pole using a contact lens. It is important to characterize:
`-presence of cystoid macular edema
`-location of retinal thickening relative to the fovea
`-presence and location of lipid exudates.
`
`A combination of these 3 criteria make up the definition of Clinically Significant
`Macular Edema, defined by the ETDRS study. The ETDRS used CSME as the criterion
`for treatment with focal laser photocoagulation.
`
`Definition of Clinically Significant Macular Edema
`
`1. Retinal edema located at or within 500 microns of the fovea
`2. Hard exudates at or within 500 microns of the fovea, if associated with thickening
`of adjacent retina
`3. An area of retinal thickening greater than 1 disc area, if located within 1 disc area
`of the center of the macula.
`
`Use of fluorescein angiography in Diabetic Macular Edema
`
`Fluorescein angiography is used as an adjunct to clinical examination in the diagnosis of
`macular edema. It identifies the source and severity of DME. It aids in classifying DME
`into focal and diffuse types. Depending on the type of DME, the response to laser and
`pharmacologic treatments can be different; therefore classification is important to ensure
`optimal treatment. Microaneurysms can be more accurately targeted with laser treatment.
`FA also identifies capillary nonperfusion and the extent of the foveal avascular zone,
`thereby describing the extent of retinal ischemia.
`
`Samsung Bioepis Exhibit 1023 - Page 48
`Biocon Exhibit 1023 - Page 48
`
`
`
`Use of OCT in Diabetic Macular Edema
`
`OCT is used to classify DME into various subtypes, including:
`-cystoid macular edema
`-diffuse macular edema
`-macular edema with subretinal fluid
`-macular edema with epiretinal membrane
`-macular edema with posterior hyaloidal traction
`
`In addition, SD-OCT can show underlying RPE atrophy which may limit the prognosis
`for treatment.
`
`It is important to look at the vitreoretinal interface in DME, as this may alter treatment
`strategies. With the different treatment strategies available including focal/grid laser,
`intravitreal anti-VEGF agents, intravitreal and periocular steroids, pars plana vitrectomy,
`and combination treatment, it is important to correctly classify DME in order to decide on
`the optimal treatment algorithm for the patient.
`
`Samsung Bioepis Exhibit 1023 - Page 49
`Biocon Exhibit 1023 - Page 49
`
`
`
`Proliferative Diabetic Retinopathy
`Application of Recent Clinical
`
`• Laser photocoagulation highly
`
`
`
`Trials Results to Management of
`effective in causing regression of PDR
`
`
`Proliferative Diabetic Retinopathy
`• Cuts risk of severe visual loss 50 °/4
`
`Jennifer I. Lim, M.D.
`
`Professor of Ophthalmology
`Charles I Young Chair of Ocular Research
`University of Illinois Department of Ophthalmology
`Director of the Retina Service
`AAO Annual Meeting 2009
`
`1I.im.MI>
`
`
`
`DRS Study. Ophthalmology 1978;85:82-1
`
`
`
`Proliferative Diabetic Retinopathy
`
`Proliferative Diabetic Retinopathy
`
`PRP side effects
`• 5- l O % chance of decreased reading vision
`
`New information in management of PDR:
`
`
`
`• Single versus multiple session PRP
`
`• Decreased visual field
`• Decreased night vision
`
`• ? Increase in DME
`
`• Adjunctive use ofanti-VEGF, steroids
`
`• Concurrent DME and PDR management
`
`
`Jl.im.�11>
`
`
`
`DRS Study. Ophthalmology 1978;85:82-106.
`
`Jl.im. MD
`
`Background:
`The Diabetic Retinopathy Clinical
`
`
`
`
`Panretinal Photocoagulation (PRP) for PDR
`
`Research Network
`
`An Observational Study of the Development of Diabetic
`Macular Edema Following Panretinal (Scatter)
`Photocoagulation (PRP) Given in I or 4 Sittings
`
`• PRP is the standard treatment of PDR
`
`• Usually performed over I or more sittings
`(ETDRS 2 or more sittings)
`
`Sponsored by the National Eye lnstilutc,
`
`
`
`
`
`
`National Institutes of Hcallh. U.S. Department of Hcahh and Human Scr\·iccs.
`
`• 2004 survey of DRCR.net investigators: one-quarter
`routinely use one sitting for PRP
`
`II
`
`i®i��:::::::;I
`
`!
`j llllGHI l�\IUQlll" �11lH
`
`Samsung Bioepis Exhibit 1023 - Page 50
`Biocon Exhibit 1023 - Page 50
`
`
`
`Edema
`PRP and Macular
`
`What are Some Pros and Cons of Delivering
`PRP in 1 Sitting?
`
`• PRP associated complications include macular
`edema
`• ETDRS - 18% developed macular edema 4 months
`after full PRP ( 1200 - 1600 spots)
`
`• Theories:
`• Oncotic fluid accumulation related to tissue destruction
`• PRP induced inflammation leading to cytokine release
`and increased penneability of the retinal capillaries
`
`• Pros
`• Convenience
`• Completion before complications occur (VH)
`
`• Cons (theoretical):
`• May cause macular edema with VA loss
`• Greater patient discomfort
`• Need for retrobulbar or peribulbar anesthetic
`• Higher risk of acute pressure rise, angle closure, or
`choroidal effusion
`
`Primary Study Objective
`
`Assessment
`Outcome
`
`• Determine the incidence of new macular edema on OCT,
`following PRP in diabetic eyes without center edema at
`34 weeks
`
`• To compare the incidence ofmacular edema with a I
`sitting versus 4-sitting regimen
`
`at 3 mete1s "1th
`n1t•.1su1ed
`.1<.:uItv
`• \ 1stial
`\cu,t\
`rsu,rl
`I IJRS \
`the I lect10111c-l
`I I•\ \) de, Ill'
`
`l!smg Zt.·1ss
`• < e11t1al Suhheld I
`luddless
`Str ,rtu,
`O< I
`
`Study Enrollment
`
`Thickness
`Subfield
`Central
`
`r a;;;;;;;;■
`■ ;u;;,g;u;;;;;w;;;;;;;;
`
`4sittings
`71 subjects
`il
`
`4sittings
`82%
`
`-
`
`l-s1t1111u 4-srttrn!! /' ,.il11e
`
`/lc11, /111,
`
`20- I
`
`I 98 I
`
`111hro11,
`-111et!1a11
`('ltan�e /10111 INne!i11e
`JJ
`0.0 I
`~S
`-+ <J
`0.003
`+S
`➔ I J
`4ll l,s
`0.08
`+IS
`➔ 14
`)7\\kS
`+14
`,22 0.06
`
`J4llks
`
`Samsung Bioepis Exhibit 1023 - Page 51
`Biocon Exhibit 1023 - Page 51
`
`
`
`Central Subfield Retinal Thickness:
`34 Weeks vs. Baseline
`
`CSF 2':250 Microns and Change from Baseline
`2': 25 Microns
`
`100
`
`100
`
`160
`
`200
`
`260
`
`300
`
`Baseline OCT Central &ilfield (Mcrans)
`
`Macular Edema on Fundus Photos at 34
`weeks
`
`Treatment of DME
`
`• One eye in each group was treated for DME prior to
`34 weeks
`• No difference in final outcome
`
`Laser-Ranibizumab-Triamcinolone
`for DME Plus PRP Study
`J
`DRCR.net Protocol
`
`Sponsored by the National Eye Institute, National Institutes of Health, U.S. Department
`of Health and Human Services
`
`Study Objective
`
`• To determine whether intravitreal anti
`
`
`
`
`
`VEGF drug or intravitreal corticosteroid can
`
`
`reduce the risk of VA loss fol lowing PRP in
`eyes with DME.
`
`Samsung Bioepis Exhibit 1023 - Page 52
`Biocon Exhibit 1023 - Page 52
`
`
`
`Major
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